Tilo Kircher’s research while affiliated with University of Giessen and other places

Large language models provide high-dimensional representations (embeddings) of word meaning, which allow quantifying changes in the geometry of the semantic space in mental disorders. A pattern of a more condensed (‘shrinking’) semantic space marked by an increase in mean semantic similarity between words has been recently documented in psychosis across several languages. We aimed to explore this pattern further in picture descriptions provided by a transdiagnostic German sample of patients with schizophrenia spectrum disorders (SSD) ( n = 42), major depression (MDD, n = 43), and healthy controls ( n = 44). Compared to controls, both clinical groups showed more restricted dynamic navigational patterns as captured by the time series of semantic distances crossed, while also showing differential patterns in the total distances and trajectories navigated. These findings demonstrate alterations centred on the dynamics of the flow of meaning across the semantic space in SSD and MDD, preserving previous indications towards a shrinking semantic space in both cases.

Reduced hippocampal volumes are a feature of many mental disorders. Childhood maltreatment is a known risk factor for the development of psychopathology and has consistently been linked to hippocampal volume reductions in adults, but not in children and adolescents. We propose that maltreatment‐related difficulties in coping with developmental tasks in adolescence and young adulthood might underlie the delayed emergence of hippocampal volume reductions in maltreated individuals. In a study with 196 healthy young adults (mean age [years]: 24.0 ± 3.2, 50% female, 20.6% living with a partner (missings: n = 2)), we investigated the interaction between childhood maltreatment (Childhood Trauma Screener) and the breakup of a steady romantic relationship (List of Threatening Experiences Questionnaire) on hippocampal magnetic resonance imaging grey matter volumes. The experience of a romantic relationship breakup moderated the association between childhood maltreatment and bilateral hippocampal volumes, revealing more negative associations with hippocampal volumes in participants with at least one breakup compared to those with no breakup experience (right hippocampus: β = − 0.05 ± 0.02, p = 0.031, p (FDR) = 0.031; left hippocampus: β = −0.06 ± 0.02, p = 0.005, p (FDR) = 0.009). Moreover, our findings provide some evidence that childhood maltreatment is related to smaller bilateral hippocampal volumes only in those adults who suffered from a relationship breakup (right hippocampus: β = −0.23 ± 0.10, p = 0.018, p (FDR) = 0.018; left hippocampus: β = −0.24 ± 0.10, p = 0.016, p (FDR) = 0.018;). Our study highlights the interaction of adult social bonds with early adversity on vulnerability to psychopathology.

Previous studies have suggested that alterations in white matter (WM) microstructure are implicated in suicidal thoughts and behaviours (STBs). However, findings of diffusion tensor imaging (DTI) studies have been inconsistent. In this large-scale mega-analysis conducted by the ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium, we examined WM alterations associated with STBs. Data processing was standardised across sites, and resulting WM microstructure measures (fractional anisotropy, axial diffusivity, mean diffusivity and radial diffusivity) for 25 WM tracts were pooled across 40 cohorts. We compared these measures among individuals with a psychiatric diagnosis and lifetime history of suicide attempt (n=652; mean age=35.4, sd=14.7; female=71.8%), individuals with a psychiatric diagnosis but no STB (i.e., clinical controls; n=1871; mean age=34, sd=14.8; female=59.8%), and individuals with no mental disorder diagnosis and no STB (i.e., healthy controls; n=642; mean age=29.6, sd=13.1; female=62.9%). We also compared these measures among individuals with recent suicidal ideation (n=714; mean age=36.3, sd=15.3; female=66.1%), clinical controls (n=1184; mean age=36.8, sd=15.6; female=63.1%), and healthy controls (n=1240; mean age= 31.6, sd=15.5; female=61.0%). We found subtle but statistically significant effects, such as lower fractional anisotropy associated with a history of suicide attempt, over and above the effect of psychiatric diagnoses. These effects were strongest in the corona radiata, thalamic radiation, fornix/stria terminalis, corpus callosum and superior longitudinal fasciculus. Effect sizes were small (Cohens d < 0.25). Recent suicidal ideation was not associated with alterations in WM microstructure. This large-scale coordinated mega-analysis revealed subtle regional and global alterations in WM microstructure in individuals with a history of suicide attempt. Longitudinal studies are needed to confirm whether these alterations are a risk factor for suicidal behaviour.

Deviations in syntax production have been well documented in schizophrenia spectrum disorders (SSD). Recently, we have shown evidence for transdiagnostic subtypes of syntactic complexity and diversity. However, there is a lack of studies exploring brain structural correlates of syntax across diagnoses. We assessed syntactic complexity and diversity of oral language production using four Thematic Apperception Test pictures in a sample of N = 87 subjects (n = 24 major depressive disorder (MDD), n = 30 SSD patients both diagnosed according to DSM-IV-TR, and n = 33 healthy controls (HC)). General linear models were used to investigate the association of syntax with gray matter volume (GMV), fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivity (MD). Age, sex, total intracranial volume, group, interaction of group and syntax were covariates of no interest. Syntactic diversity was positively correlated with the GMV of the right medial pre-and postcentral gyri and with the FA of the left superior-longitudinal fasciculus (temporal part). Conversely, the AD of the left cingulum bundle and the forceps minor were negatively correlated with syntactic diversity. The AD of the right inferior-longitudinal fasciculus was positively correlated with syntactic complexity. Negative associations were observed between syntactic complexity and the FA of the left cingulum bundle, the right superior-longitudinal fasciculus, and the AD of the forceps minor and the left uncinate fasciculus. Our study showed brain structural correlates of syntactic complexity and diversity across diagnoses and HC. This contributes to a comprehensive understanding of the interplay between linguistic and neural substrates in syntax production in psychiatric disorders and HC.

Background: Schizophrenia (SCZ) is characterized by a disconnect from reality that manifests as various clinical and cognitive symptoms, and persistent neurobiological abnormalities. Sex-related differences in clinical presentation imply separate brain substrates. The present study characterized deep brain morphology using shape features to understand the independent effects of diagnosis and sex on the brain, and to determine whether the neurobiology of schizophrenia varies as a function of sex. Methods: This study analyzed multi-site archival data from 1,871 male (M) and 955 female (F) participants with SCZ, and 2,158 male and 1,877 female healthy controls (CON) from twenty-three cross-sectional samples from the ENIGMA Schizophrenia Workgroup. Harmonized shape analysis protocols were applied to each site's data for seven deep brain regions obtained from T1-weighted structural MRI scans. Effect sizes were calculated for the following main contrasts: 1) Sex effects; 2) Diagnosis-by-Sex interaction; 3) within sex tests of diagnosis; 4) within diagnosis tests of sex differences. Meta-regression models between brain structure and clinical variables were also computed separately in men and women with schizophrenia. Results: Mass univariate meta-analyses revealed more concave-than-convex shape differences in all regions for women relative to men, across diagnostic groups (d = -0.35 to 0.20, SE = 0.02 to 0.07); there were no significant diagnosis-by-sex interaction effects. Within men and women separately, we identified more-concave-than-convex shape differences for the hippocampus, amygdala, accumbens, and thalamus, with more-convex-than-concave differences in the putamen and pallidum in SCZ (d = -0.30 to 0.30, SE = 0.03 to 0.10). Within CON and SZ separately, we found more-concave-than-convex shape differences in the thalamus, pallidum, putamen, and amygdala among females compared to males, with mixed findings in the hippocampus and caudate (d = -0.30 to 0.20, SE = 0.03 to 0.09). Meta-regression models revealed similarly small, but significant relationships, with medication and positive symptoms in both SCZ-M and SCZ-F. Conclusions: Sex-specific variation is an overriding feature of deep brain shape regardless of disease status, underscoring persistent patterns of sex differences observed both within and across diagnostic categories, and highlighting the importance of including it as a critical variable in studies of neurobiology. Future work should continue to explore these dimensions independently to determine whether these patterns of brain morphology extend to other aspects of neurobiology in schizophrenia, potentially uncovering broader implications for diagnosis and treatment.

Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current < 65) and good outcome (GAF current ≥ 65). Pooled non-linear support vector machine (SVM) classifiers trained on the separate cohorts identified patients with a poor outcome with cross-validated balanced accuracies (BAC) of 65-66%, but BAC dropped substantially when the models were applied to patients from a different FES cohort (BAC = 50-56%). A leave-site-out analysis on the merged sample yielded better performance (BAC = 72%), highlighting the effect of combining data from different study designs to overcome calibration issues and improve model transportability. In conclusion, our results indicate that validation of prediction models in an independent sample is essential in assessing the true value of the model. Future external validation studies, as well as attempts to harmonize data collection across studies, are recommended.

Background Emotional disorders such as depression and anxiety disorders share substantial similarities in their etiology and treatment. In recent decades, these commonalities have been increasingly recognized in classification systems and treatment programs crossing diagnostic boundaries. Methods To examine the prospective effects of different transdiagnostic markers on relevant treatment outcomes, we plan to track a minimum of N = 200 patients with emotional disorders during their routine course of cognitive behavioral therapy at two German outpatient clinics. We will collect a wide range of transdiagnostic markers, ranging from basic perceptual processes and self-report measures to complex behavioral and neurobiological indicators, before entering therapy. Symptoms and psychopathological processes will be recorded before entering therapy, between the 20th and 24th therapy session, and at the end of therapy. Discussion Our results could help to identify transdiagnostic markers with high predictive power, but also provide deeper insights into which patient groups with which symptom clusters are less likely to benefit from therapy, and for what reasons. Trial Registration The trial was preregistered at the German Clinical Trial Register (DRKS-ID: DRKS00031206; 2023–05-09).

Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. It remains uncertain how much these signatures overlap across different phenotypes due to a lack of well-powered cross-disorder comparisons. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in functional connectivity (FC) in a cross-disorder sample of AD patients and healthy controls (HC). Before treatment, 439 patients from two German multicenter clinical trials at eight different sites fulfilling a primary diagnosis of panic disorder and/or agoraphobia (PD/AG, N = 154), social anxiety disorder (SAD, N = 95), or specific phobia (SP, N = 190) and 105 HC underwent an 8 min rsfMRI assessment. We performed categorical and dimensional regions of interest (ROI)-to-ROI analyses focusing on connectivity between regions of the defensive system and prefrontal regulation areas. AD patients showed increased connectivity between the insula and the thalamus compared to controls. This was mainly driven by PD/AG patients who showed increased (insula/hippocampus/amygdala—thalamus) and decreased (dorsomedial prefrontal cortex/periaqueductal gray—anterior cingulate cortex) positive connectivity between subcortical and cortical areas. In contrast, SAD patients showed decreased negative connectivity exclusively in cortical areas (insula—orbitofrontal cortex), whereas no differences were found in SP patients. State anxiety associated with the scanner environment did not explain the FC between these regions. Only PD/AG patients showed pronounced connectivity changes along a widespread subcortical-cortical network, including the midbrain. Dimensional analyses yielded no significant results. The results highlighting categorical differences between ADs at a systems neuroscience level are discussed within the context of personalized neuroscience-informed treatments. PROTECT-AD’s registration at NIMH Protocol Registration System: 01EE1402A and German Register of Clinical Studies: DRKS00008743. SpiderVR’s registration at ClinicalTrials.gov: NCT03208400.