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Abstract Diagnosis of a clinical high-risk (CHR) state enables timely treatment of individuals at risk for a psychotic disorder, thereby contributing to improving illness outcomes. However, only a minority of patients diagnosed with CHR will make the transition to overt psychosis. To identify patients most likely to benefit from early intervention, several studies have investigated characteristics that distinguish CHR patients who will later develop a psychotic disorder from those who will not. We aimed to summarize evidence from systematic reviews and meta-analyses on predictors of transition to psychosis in CHR patients, among characteristics and biomarkers assessed at baseline. A systematic search was conducted in Pubmed, Scopus, PsychInfo and Cochrane databases to identify reviews and meta-analyses of studies that investigated specific baseline predictors or biomarkers for transition to psychosis in CHR patients using a cross-sectional or longitudinal design. Non-peer-reviewed publications, gray literature, narrative reviews and publications not written in English were excluded from analyses. We provide a narrative synthesis of results from all included reviews and meta-analyses. For each included publication, we indicate the number of studies cited in each domain and its quality rating. A total of 40 publications (21 systematic reviews and 19 meta-analyses) that reviewed a total of 272 original studies qualified for inclusion. Baseline predictors most consistently associated with later transition included clinical characteristics such as attenuated psychotic and negative symptoms and functioning, verbal memory deficits and the electrophysiological marker of mismatch negativity. Few predictors reached a level of evidence sufficient to inform clinical practice, reflecting generalizability issues in a field characterized by studies with small, heterogeneous samples and relatively few transition events. Sample pooling and harmonization of methods across sites and projects are necessary to overcome these limitations.

Abstract The increasing use of machine learning approaches on neuroimaging data comes with the important concern of confounding variables which might lead to biased predictions and in turn spurious conclusions about the relationship between the features and the target. A prominent example is the brain size difference between women and men. This difference in total intracranial volume (TIV) can cause bias when employing machine learning approaches for the investigation of sex differences in brain morphology. A TIV-biased model will not capture qualitative sex differences in brain organization but rather learn to classify an individual’s sex based on brain size differences, thus leading to spurious and misleading conclusions, for example when comparing brain morphology between cisgender- and transgender individuals. In this study, TIV bias in sex classification models applied to cis- and transgender individuals was systematically investigated by controlling for TIV either through featurewise confound removal or by matching the training samples for TIV. Our results provide strong evidence that models not biased by TIV can classify the sex of both cis- and transgender individuals with high accuracy, highlighting the importance of appropriate modeling to avoid bias in automated decision making.

Abstract Functional connectivity (FC) refers to the statistical dependencies between activity of distinct brain areas. To study temporal fluctuations in FC within the duration of a functional magnetic resonance imaging (fMRI) scanning session, researchers have proposed the computation of an edge time series (ETS) and their derivatives. Evidence suggests that FC is driven by a few time points of high-amplitude co-fluctuation (HACF) in the ETS, which may also contribute disproportionately to interindividual differences. However, it remains unclear to what degree different time points actually contribute to brain-behaviour associations. Here, we systematically evaluate this question by assessing the predictive utility of FC estimates at different levels of co-fluctuation using machine learning (ML) approaches. We demonstrate that time points of lower and intermediate co-fluctuation levels provide overall highest subject specificity as well as highest predictive capacity of individual-level phenotypes.

Abstract Background The development of machine learning models for aiding in the diagnosis of mental disorder is recognized as a significant breakthrough in the field of psychiatry. However, clinical practice of such models remains a challenge, with poor generalizability being a major limitation. Methods Here, we conducted a pre-registered meta-research assessment on neuroimaging-based models in the psychiatric literature, quantitatively examining global and regional sampling issues over recent decades, from a view that has been relatively underexplored. A total of 476 studies (n = 118,137) were included in the current assessment. Based on these findings, we built a comprehensive 5-star rating system to quantitatively evaluate the quality of existing machine learning models for psychiatric diagnoses. Results A global sampling inequality in these models was revealed quantitatively (sampling Gini coefficient (G) = 0.81, p 15). In light of this, we proposed a purpose-built quantitative assessment checklist, which demonstrated that the overall ratings of these models increased by publication year but were negatively associated with model performance. Conclusions Together, improving sampling economic equality and hence the quality of machine learning models may be a crucial facet to plausibly translating neuroimaging-based diagnostic classifiers into clinical practice.

The link between metabolic syndrome (MetS) and neurodegenerative as well as cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, brain morphology, and cognitive function in 40,087 individuals. Multivariate, data-driven statistics identified a latent dimension linking more severe MetS to widespread brain morphological abnormalities, accounting for up to 71% of shared variance in the data. This dimension was replicable across sub-samples. In a mediation analysis, we could demonstrate that MetS-related brain morphological abnormalities mediated the link between MetS severity and cognitive performance in multiple domains. Employing imaging transcriptomics and connectomics, our results also suggest that MetS-related morphological abnormalities are linked to the regional cellular composition and macroscopic brain network organization. By leveraging extensive, multi-domain data combined with a dimensional stratification approach, our analysis provides profound insights into the association of MetS and brain health. These findings can inform effective therapeutic and risk mitigation strategies aimed at maintaining brain integrity.

Summary: Cerebellar involvement in both motor and non-motor functions manifests in specific regions of the human cerebellum, revealing the functional heterogeneity within it. One compelling theory places the heterogeneity within the cerebellar functional hierarchy along the sensorimotor-association (SA) axis. Despite extensive neuroimaging studies, evidence for the cerebellar SA axis from different modalities and scales was lacking. Thus, we establish a significant link between the cerebellar SA axis and spatio-molecular profiles. Utilizing the gene set variation analysis, we find the intermediate biological principles the significant genes leveraged to scaffold the cerebellar SA axis. Interestingly, we find these spatio-molecular profiles notably associated with neuropsychiatric dysfunction and recent evolution. Furthermore, cerebello-cerebral interactions at genetic and functional connectivity levels mirror the cerebral cortex and cerebellum’s SA axis. These findings can provide a deeper understanding of how the human cerebellar SA axis is shaped and its role in transitioning from sensorimotor to association functions.

BackgroundPatients with rare and complex diseases often experience delayed diagnoses and misdiagnoses because comprehensive knowledge about these diseases is limited to only a few medical experts. In this context, large language models (LLMs) have emerged as powerful knowledge aggregation tools with applications in clinical decision support and education domains. ObjectiveThis study aims to explore the potential of 3 popular LLMs, namely Bard (Google LLC), ChatGPT-3.5 (OpenAI), and GPT-4 (OpenAI), in medical education to enhance the diagnosis of rare and complex diseases while investigating the impact of prompt engineering on their performance. MethodsWe conducted experiments on publicly available complex and rare cases to achieve these objectives. We implemented various prompt strategies to evaluate the performance of these models using both open-ended and multiple-choice prompts. In addition, we used a majority voting strategy to leverage diverse reasoning paths within language models, aiming to enhance their reliability. Furthermore, we compared their performance with the performance of human respondents and MedAlpaca, a generative LLM specifically designed for medical tasks. ResultsNotably, all LLMs outperformed the average human consensus and MedAlpaca, with a minimum margin of 5% and 13%, respectively, across all 30 cases from the diagnostic case challenge collection. On the frequently misdiagnosed cases category, Bard tied with MedAlpaca but surpassed the human average consensus by 14%, whereas GPT-4 and ChatGPT-3.5 outperformed MedAlpaca and the human respondents on the moderately often misdiagnosed cases category with minimum accuracy scores of 28% and 11%, respectively. The majority voting strategy, particularly with GPT-4, demonstrated the highest overall score across all cases from the diagnostic complex case collection, surpassing that of other LLMs. On the Medical Information Mart for Intensive Care-III data sets, Bard and GPT-4 achieved the highest diagnostic accuracy scores, with multiple-choice prompts scoring 93%, whereas ChatGPT-3.5 and MedAlpaca scored 73% and 47%, respectively. Furthermore, our results demonstrate that there is no one-size-fits-all prompting approach for improving the performance of LLMs and that a single strategy does not universally apply to all LLMs. ConclusionsOur findings shed light on the diagnostic capabilities of LLMs and the challenges associated with identifying an optimal prompting strategy that aligns with each language model’s characteristics and specific task requirements. The significance of prompt engineering is highlighted, providing valuable insights for researchers and practitioners who use these language models for medical training. Furthermore, this study represents a crucial step toward understanding how LLMs can enhance diagnostic reasoning in rare and complex medical cases, paving the way for developing effective educational tools and accurate diagnostic aids to improve patient care and outcomes.

Characterizing a reliable, pain-related neural signature is critical for translational applications. Many prior fMRI studies have examined acute nociceptive pain-related brain activation in healthy participants. However, synthesizing these data to identify convergent patterns of activation can be challenging due to the heterogeneity of experimental designs and samples. To address this challenge, we conducted a comprehensive meta-analysis of fMRI studies of stimulus-induced pain in healthy participants. Following pre-registration, two independent reviewers evaluated 4,927 abstracts returned from a search of 8 databases, with 222 fMRI experiments meeting inclusion criteria. We analyzed these experiments using Activation Likelihood Estimation with rigorous type I error control (voxel height p < 0.001, cluster p < 0.05 FWE-corrected) and found a convergent, largely bilateral pattern of pain-related activation in the secondary somatosensory cortex, insula, midcingulate cortex, and thalamus. Notably, these regions were consistently recruited regardless of stimulation technique, location of induction, and participant sex. These findings suggest a highly-conserved core set of pain-related brain areas, encouraging applications as a biomarker for novel therapeutics targeting acute nociceptive pain.

The growth of α-Ga2O3 and α-(InxGa1−x)2O3 on m-plane α-Al2O3(101̄0) by molecular beam epitaxy (MBE) and metal-oxide-catalyzed epitaxy (MOCATAXY) is investigated. By systematically exploring the parameter space accessed by MBE and MOCATAXY, phase-pure α-Ga2O3(101̄0) and α-(InxGa1−x)2O3(101̄0) thin films are realized. The presence of In on the α-Ga2O3 growth surface remarkably expands its growth window far into the metal-rich flux regime and to higher growth temperatures. With increasing O-to-Ga flux ratio (RO), In incorporates into α-(InxGa1−x)2O3 up to x ≤ 0.08. Upon a critical thickness, β-(InxGa1−x)2O3 nucleates and, subsequently, heteroepitaxially grows on top of α-(InxGa1−x)2O3 facets. Metal-rich MOCATAXY growth conditions, where α-Ga2O3 would not conventionally stabilize, lead to single-crystalline α-Ga2O3 with negligible In incorporation and improved surface morphology. Higher TTC further results in single-crystalline α-Ga2O3 with well-defined terraces and step edges at their surfaces. For RO ≤ 0.53, In acts as a surfactant on the α-Ga2O3 growth surface by favoring step edges, while for RO ≥ 0.8, In incorporates and leads to a-plane α-(InxGa1−x)2O3 faceting and the subsequent (2̄01) β-(InxGa1−x)2O3 growth on top. Thin film analysis by scanning transmission electron microscopy reveals highly crystalline α-Ga2O3 layers and interfaces. We provide a phase diagram to guide the MBE and MOCATAXY growth of single-crystalline α-Ga2O3 on α-Al2O3(101̄0).

Background: Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels. Methods: Maps of fractional amplitude of low-frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 females) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 females). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of co-localization is associated with the observed clinical symptoms. Results: Patients displayed significantly reduced fALFF in frontotemporal and frontoparietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b and 5-HT2a) and γ-aminobutyric acid type A (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with NET was associated with cognitive symptoms and disease severity of bvFTD. Conclusions: Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD. Funding: This study has been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (BMBF; grant no. FKZ01GI1007A).