Psychiatry Research: Neuroimaging

Background Brain abnormalities related to childhood adversity (CA) have been reported across clinical presentations in psychotic disorder (PD) and bipolar disorder (BD). This systematic review and meta-analysis examined gray matter volume (GMV) alterations linked to CA in PD and BD. Methods A PRISMA-compliant systematic review was conducted (PROSPERO ID: CRD42022351133). The EMBASE, MEDLINE, and PsycINFO databases were searched from inception to June 2024 for studies investigating CA and structural brain imaging in PD and BD. Study quality was assessed with the Newcastle Ottawa Scale (NOS). Data were extracted and synthesized accounting for sex differences and CA subtypes with brain findings categorized by the presence and direction of associations. Meta-analyses were performed for hippocampal and amygdala volumes. Results In the systematic review (k = 29), 3,056 participants with PD and BD (mean age = 36.6; SD =16.1; 47% female), published between 2011 and 2023, were included. Study quality was fair, with high heterogeneity. Most studies reported significant negative associations between CA and GMV, especially in prefrontal regions, while findings for the hippocampus and amygdala were largely null or inconsistent. Meta-analyses of a study subset identified no significant association between CA and hemisphere-specific and combined volumes of the hippocampus (k = 5; p [≥] 8805; 0.66) or amygdala (k = 4; p [≥] 8805; 0.87). Conclusion CA was not consistently associated with hippocampal or amygdala volume alterations in PD and BD. More consistent evidence emerged for reduced GMV in prefrontal regions, suggesting that neurobiological impact of CA may be more robustly captured at the cortical level.

Cognitive flexibility is an executive function that allows individuals to adjust behaviour in response to changing environmental demands. We assessed volitional switching under uncertainty, without rule-based learning, in the Change Your Mind task. Nineteen patients with obsessive-compulsive disorder (OCD), 19 patients with attention-deficit hyperactivity disorder (ADHD) and matched control participants (20 per group) completed the task whilst undergoing a functional MRI scan. The task was a two-alternative forced choice paradigm where each stimulus was presented twice successively, with spurious feedback following the first presentation. This allowed participants the opportunity to repeat or change their response. Participants with ADHD changed their response more frequently than controls following a previously correct response, associated with reduced accuracy on the second trial. This was accompanied with smaller differences between change and repeat trials in the superior frontal gyrus, paracingulate gyrus and frontal pole compared to controls. Participants with OCD did not differ from healthy controls in their performance but exhibited greater activity on both change and repeat trials in the pre- and postcentral gyri than controls. These results point to distinct neurobehavioural differences in patients with ADHD and OCD underlying what is often termed more broadly inflexible behaviour.

Background: Childhood adversity (CA) has been identified as one of the most robust risk factors for psychotic disorders; several treatable mediating mechanisms have been proposed. Aims: To conduct a systematic review and meta-analysis examining mediating pathways linking CA and psychosis. Method: This PRISMA-compliant systematic review (PROSPERO: CRD42024542972). consisted of a search conducted in January 2026 on Ovid (PsycINFO, Medline, and Embase) using search terms related to psychosis, CA, and mediation analyses. Evidence was appraised by calculating the percentage of the total effect mediated in each study, grouping mediators into meaningful groups. When possible, meta-analyses using two-stage meta-analytic structural equation modelling (METASEM) were conducted. Results: 117 studies were included (54 in clinical samples, 59 in non-clinical samples, and four studies in both clinical and non-clinical samples). 107 studies examined psychological mediators and 12 examined biological. The median percentages of total effect mediated across all analyses per mediator family were: 49% for dissociation (k = 24), 45% for psychosocial stressors (k = 6), 37.9% for negative schemas (k = 23), 35.2% for post-traumatic symptoms (k = 10), 31.5% for depressive symptoms (k = 14), 27.8% for anxiety (k = 11), 27.1% for attachment styles (k = 12), and 8.7% for mentalization domains (k = 5). Meta-analyses confirmed a robust mediating effect of dissociation (k = 7; N = 2143; indirect effect (I.E) =0.42 [0.17, 0.66] on psychosis; 50.49%), on delusions (k =7; N = 1053; I.E = 0.36, [0.27, 0.46]; 46.44%]) and on hallucinations (k =10; N = 5705; I.E = 0.28 [0.20, 0.36]; 57.59%). Robust mediation via depression (k =5; N= 5028; indirect effect= 0.33 [0.31, 0.35]; 31.05%) and negative schemas of the association between trauma and psychosis broadly defined (k = 7; N=10791; I.E= 0.26 [0.17, 0.35]; 26.36%) was also observed. High heterogeneity was observed across all meta-analyses. Fewer studies examined biological mediators, preventing quantitative synthesis. Conclusions: Childhood adversity impacts psychosis through psychosocial mediators, particularly dissociation. Further work is required to on the potential role of biological mechanisms and its interplay with psychological mechanisms.

Introduction Parkinson's disease (PD) is a multifactorial disorder, affecting multiple neurotransmitter systems, including the cholinergic system. Cholinergic denervation is heterogeneous across patients and difficult to predict based on clinical presentation. In this study, we assessed the sensitivity of structural MRI (sMRI) and functional MRI (fMRI) to cholinergic degeneration related to PD and to cognitive functioning in PD. We compared our results to results from previously reported [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) PET imaging, which is considered the gold standard for cholinergic imaging. Methods 34 PD patients and 10 healthy controls underwent structural T1-weighted MRI. A subset of 14 patients and 9 controls also underwent resting-state fMRI. We extracted the bilateral volumes of the nucleus basalis of Meynert (NBM) from the sMRI images. Functional connectivity (FC) from the NBM to the cortex (NBM-FC) was determined using fMRI data. Principal component analysis (PCA) was applied to reduce the dimensionality of the NBM-FC images. We assessed performances for NBM-FC in distinguishing patients from controls using stepwise logistic regression. Similarly, NBM volume was used using logistic regression. Furthermore, the relation between these measures and cognitive function in several domains was investigated with (stepwise) linear regression. Leave-one-out cross validation (LOOCV) and bootstrapping was performed to assess robustness of the results. Results NBM-FC was well able to discriminate patients from controls with an AUC of 0.84 (95% CI: 0.62-1). NBM volume showed lower performance, but was still better than chance: AUC: 0.75 (95% CI: 0.57-0.93). Significant correlations were found between 1) cognition in the attentional domain and NBM-FC (r=0.63; p=.015) and 2) global cognition and NBM volume (r=0.55, p=.001). These results were inferior to those previously reported using [18F]FEOBV tracer uptake (see Chapter 6). Bootstrapping revealed that NBM volume of only the left hemisphere was stably related to PD diagnosis and global cognition in PD patients. We found that a lower NBM-FC in specific brain areas, including the fusiform gyrus, supramarginal gyrus and dorsolateral prefrontal cortex, was related to PD diagnosis. Bootstrapping revealed no stable NBM-FC pattern related to attention. Conclusion Although MRI results were slightly inferior to [18F]FEOBV PET data, MRI may provide a cheaper and more widely available alternative for cholinergic imaging. We recommend testing the utility of MRI as predictor and monitor of cholinergic treatment effect in a longitudinal study.

Executive function (EF) deficits are central features of schizophrenia and strongly influence long-term functional outcomes. Conventional cognitive assessments often lack ecological validity and cultural relevance. This study introduces the Luk Chup Augmented Reality (LCAR) tool a video guided, clay modeling task delivered through wearable AR that integrates culturally familiar activity with realtime neurophysiological monitoring. Thirty individuals diagnosed with schizophrenia (mean age = 38.9, SD. = 7.15 years) completed a series of modeling and memory tasks using LCAR while undergoing quantitative EEG (QEEG). Task duration and theta/beta power were analyzed across procedural and color shape memory phases. Memory phases took significantly longer to complete and were associated with decreased lateral prefrontal theta and increased frontal midline theta activity (Fz, Cz), indicating higher EF demand. A repeated-measures ANOVA revealed significant condition, site, and interaction effects on theta power. The LCAR tool shows promise as a culturally grounded, dual-mode assessment of EF in schizophrenia. It offers a novel integration of performance-based and neurophysiological metrics that may inform future interventions in psychiatric rehabilitation.

IntroductionBipolar disorder (BD) is characterized by recurring episodes of mania and depression. Despite extensive research, the pathophysiology underlying these mood swings remains elusive. Emerging evidence indicates a potential role for neuroinflammation and microglial activation in the pathophysiology of BD. MethodsWe employed a reverse-translational approach to generate directly induced microglia-like (iMG) cells from peripheral blood monocytes of a single patient with BD, repeatedly sampled across depressive, manic, and subsequent depressive phases. RNA sequencing was performed on iMG cells at each time point to identify differentially expressed genes related to mood state transitions. ResultsA thorough analysis of longitudinal gene expression data has led to the identification of three functional gene categories: "state-dependent genes", "depression-to-mania transition genes (named: firing genes)", and "mania-to-depression transition genes (named: extinguishing genes)". A total of 168 firing, 59 extinguishing, and 77 state-dependent genes were identified. Notably, functional annotation revealed that, compared to the extinction gene set, the firing gene set was enriched in immune and inflammatory response pathways, particularly early-response cytokines such as IL1B and TNF. ConclusionsBased on these findings, we propose that inflammatory immunomodulation by microglia contributes to mood switching in BD, especially in the process of depression-to-mania transition. The classification of genes by their relationship to state transitions offers a novel framework for understanding the molecular mechanisms underlying this complex disorder and may identify potential therapeutic targets to stabilize mood. Further validation with larger cohorts is warranted.

Background: Emotion dysregulation is a core feature of bipolar disorder (BD), yet its behavioral expression during depressive episodes, and potential differences between its types, BD-I and BD-II, remain unclear. This study used automated facial-expression analysis during naturalistic affective film viewing to examine subtype-specific and context-dependent emotional responding in bipolar depression. Methods: The sample included 135 participants: 69 healthy controls and 66 patients with BD (BD-I, 23; BD-II, 43). Participants viewed nine emotionally evocative film clips spanning negative, positive, neutral, and socially threatening contexts, while their facial expressions were continuously recorded and quantified using computer vision-based facial-expression analysis. Results: Patients with BD-I showed a distinct, context-dependent facial-expression profile, characterized by greater negative responses across multiple contexts than other groups. Specifically, they showed increased sadness during sad, reward, and amusing clips, and elevated anger during sad and neutral clips. In socially threatening contexts, BD-I participants showed a multivalent pattern of elevated anger, fear, and joy, suggesting poorly coordinated or context-incongruent affective expression. In contrast, BD-II participants did not differ significantly from healthy controls on any emotion, despite depressive symptom severity comparable to BD-I participants. Conclusions: These findings suggest that facial-expression patterns in bipolar depression differ across subtypes. BD-I may be characterized by heightened negative reactivity and altered context-appropriate modulation of emotional expression, whereas BD-II may not show comparable alterations in overt facial output. Automated facial-expression analysis during naturalistic stimulation may provide a useful behavioral marker for characterizing subtype-specific affective disturbance in bipolar depression and related psychopathology.

Objective Psychosis spectrum symptoms (PSS) are common among children and youth. These symptoms may be clinically significant as studies indicate a heightened risk of mental health disorders, in general, as well as psychotic disorders, specifically, in youth that endorse PSS. This systematic review and meta-analysis investigates the longitudinal association between PSS in children and youth and subsequent mental health diagnosis. Methods A comprehensive search of Ovid Medline, PsycINFO, and EMBASE databases was conducted to identify longitudinal studies that: (i) assess PSS at a baseline timepoint, (ii) in individuals under 25 years, and (iii) assess mental health disorder diagnosis using a structured assessment at a later time point in the same sample. We conducted a meta-analysis and calculated pooled odds ratios (ORs) for mental health and psychotic disorders using random-effects models. Post-hoc meta-regressions were performed to examine the influence of a number of moderators on the relationship between earlier recorded PSS and subsequent mental health disorders or psychotic disorders. Results The search yielded 41 eligible studies of which 25 were included in the meta-analysis. Most included studies assessed PSS using brief self-report measures and recruited their samples from clinical or community settings. Among children and youth without an identified mental health diagnosis at baseline assessment, baseline PSS were associated with a 2-fold (OR = 2.07, CI = 1.61 - 2.66, I2 = 86.92%, p < 0.0001) increased risk of meeting diagnostic criteria for subsequent mental health disorder diagnosis and a 3-fold increased risk (OR = 3.11, CI = 2.11 - 4.58, (I2 = 60.93%, p < 0.0090) of meeting diagnostic criteria for a subsequent psychotic disorder diagnosis with a minimum 1 year follow-up time from baseline assessment. Meta-regression analysis indicated that study quality and sample size explained a substantial proportion of between-study heterogeneity for psychotic disorder outcomes. Conclusions Our results suggest that administration of simple self-report measures of PSS in both clinical and community settings may be helpful to identify children and youth at higher risk of subsequently meeting criteria for a mental disorder generally, and for a severe mental illness (i.e., psychotic disorder), specifically. Future longitudinal studies should focus on improving study design characteristics to increase confidence in identified longitudinal associations. The results of our work suggests that integration of self-report measures of PSS may be useful in a variety of settings to identify youth at increased risk of subsequent mental illness.

Background: Post-traumatic stress disorder (PTSD) remains highly prevalent affecting ~23% of World Trade Center (WTC) responders more than two decades after 9/11. While MRI studies have identified neural differences associated with PTSD, these findings have not translated into improved treatment. We introduce a novel multimodal MRI approach, DAta-driven Network Connectivity Estimate (DANCE), integrating structural and functional magnetic resonance imaging (MRI) to better capture PTSD mechanisms and inform biomarkers. Methods: In 96 WTC responders , including 45 with current WTC-related PTSD and 51 without PTSD. We applied graph theory to resting-state functional MRI to identify functional hubs via eigenvector centrality and identified divergence between groups using partial least squares discriminant analysis (PLS-DA). From diffusion MRI, we reconstructed five anatomical tracts (i.e., streamlines) in the temporal lobes. Using DANCE, we quantified the differential distribution of streamlines of the reconstructed tracts connecting the functional hubs. We then tested whether WTC exposure duration moderated associations between PTSD and DANCE indices. Results: Responders with PTSD showed altered centrality in nine functional hubs (AUC=0.75 (0.651-0.847)) including bilateral anterior inferior temporal gyrus, right superior parietal lobule, right anterior parahippocampal gyrus, right anterior/posterior superior temporal gyrus (STG), right caudate nucleus, left amygdala and brainstem. Connectivity differences emerged in four tracts: hippocampus, parahippocampus, inferior and superior temporal gyri (STG). DANCE differed in the inferior fronto-occipital fasciculus (IFOF), medial (IFLmed) and lateral (IFLlat) components of the inferior longitudinal fasciculus and in the middle longitudinal fascicle (MdLF). WTC exposure duration significantly moderated the association between PTSD and DANCE values in the IFLmed, right posterior STG (p= 0.035). Conclusion: Our novel DANCE approach revealed converging functional and anatomical connectivity alterations uniquely associated with PTSD in WTC responders and offers compelling evidence for distinct neurobiological signatures of the disorder. These findings significantly advance our understanding of PTSD pathophysiology and highlight potential biomarkers for diagnosis and targeted intervention.

Psilocybin shows therapeutic promise for several psychiatric disorders, but the acute perceptual and cognitive alterations produced by conventional doses (10-25 mg) require in-clinic supervision, which limits scalability. Whether the therapeutically relevant pharmacology of psilocybin can be separated from its hallucinogenic activity remains unresolved. To address this gap, we conducted a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study to characterize the safety, pharmacokinetics and pharmacodynamics of low doses of psilocybin. Fifty-six healthy adults received a single oral dose of psilocybin (0.5, 1.0, 1.5, 2.5, 3.5 or 4.0 mg) or matching placebo across seven sequential cohorts, with each dose escalation reviewed by a Drug Safety Review Committee. All participants completed the study with no serious adverse events or discontinuations. Treatment-emergent adverse events were comparable to placebo and most prominently arose as somnolence. Plasma psilocin appeared rapidly with a median time to maximum concentration < 1 h with dose-proportional exposure and a short terminal half-life. Subjective drug effects were dose-related and became distinguishable from placebo at doses at or below 2.5 mg. Peak subjective ratings increased with dose, while any signs of hallucinations or altered-states scores remained low and not different than placebo. Psychophysiological engagement was confirmed by a clear dose-dependent pupillary dilation while cognitive performance (attention, vigilance, working memory, impulse control) showed no dose-dependent decrement and state anxiety did not increase at any dose. These findings indicate that the perceptible pharmacology of psilocybin can be dissociated from significant perceptual alterations and cognitive impairment at low doses. They further support controlled investigations in outpatient Phase 2 studies evaluating the safety and feasibility of repeated, self-administered low-dose psilocybin. ClinicalTrials.gov #NCT07710027

Autistic psychiatrists occupy a paradoxical position: trained to recognise and assess autism in others, yet navigating a professional culture in which their own autistic identity remains largely concealed. Despite growing visibility of autistic clinicians, the barriers autistic psychiatrists face to formal diagnosis and professional disclosure remain unexplored. This study used interpretive phenomenological analysis to examine the experiences of seven autistic psychiatrists in relation to diagnosis and disclosure. Data were generated through in-depth interviews and Retzinger's framework for identifying shame in discourse was applied as an analytical tool within the interpretive process. Shame emerged as the overarching theme across the dataset, operating through four group experiential themes. Its origins lay in childhood experiences of difference and perceived defectiveness, transmitted through family, peers, and the broader social environment. In professional life, shame was sustained and amplified by colleagues' misconceptions about autism, anticipated loss of credibility, and the deficit-based diagnostic criteria - which rendered self-recognition difficult and made formal diagnosis a perceived professional liability. Critically, shame did not only create barriers: it functioned as an override mechanism, rendering the known benefits of disclosure - to participants themselves, to colleagues, and to patients - insufficient to translate into action. This override function was not explained by fear of discrimination or rational career protection alone; it reflected shame's operation as an internal prohibition, dissociated from its original social source and persisting even where stigma had been intellectually processed and rejected. These findings reposition shame not as one barrier among many but as the organising force through which all barriers operate. Interventions aimed at increasing disclosure by raising awareness of its benefits misread the operative mechanism. Creating conditions in which autistic psychiatrists can make decisions about their identities freely requires naming and addressing shame - in research, in clinical training, and in the culture of psychiatry.

Objective: Working memory (WM) deficits are a co-occurring feature to numerous neuropsychiatric disorders, particularly attention-deficit/hyperactivity disorder (ADHD), and there remain no treatments that directly target WM. The coupling between the phase of theta band activity and amplitude of gamma band activity (i.e., TGC) is an established neural correlate of WM. However, no studies have examined WM-related TGC in ADHD or whether neuromodulation can modulate these oscillatory dynamics in youth. This set of studies examined the effects of intermittent theta burst stimulation (iTBS) to the left dorsolateral prefrontal cortex (DLPFC) and left posterior parietal cortex (PPC) on TGC in youth with ADHD. Methods: In two randomized, double-blind, sham-controlled crossover trials, adolescents with ADHD and clinically significant parent-reported WM symptoms first completed a single-session study comparing DLPFC versus PPC iTBS targeting (n = 47) and then a multi-session clinical trial comparing 10 sessions of active versus sham left DLPFC iTBS (n = 29). Participants completed a computerized visuospatial Sternberg WM task with concurrent electroencephalography (EEG) before and after the single sessions, as well as at baseline, midway through treatment, and approximately 24 hours after the final session within the multi-session trial. Phase-amplitude coupling between theta phase and gamma amplitude was quantified using the Kullback Leibler modulation index at frontoparietal electrodes. Linear mixed-effects models examined treatment effects and associations between change in TGC and WM status (including accuracy, reaction time, and clinical symptoms). Results: Across participants, lower TGC was associated with lower symptoms and better WM performance, including higher accuracy, faster and more consistent RT. Active iTBS increased frontoparietal TGC relative to sham stimulation, with effects observed both acutely after a single session and ~24 hours after multiple sessions. DLPFC-targeted iTBS increased TGC, whereas PPC-iTBS had no measurable effect. Change in TGC was associated with change in WM, such that a decrease in TGC was associated with faster RT and decreased RT variability. Higher baseline TGC was associated with greater improvement in WM. Active iTBS decoupled the TGC-WM association observed during sham iTBS, and greater electric field intensity of iTBS was associated with greater improvement in WM accuracy and greater decrease in TGC. Conclusions: Active iTBS to the left DLPFC modulated WM-related TGC in youth with ADHD. These findings provide preliminary evidence that neuromodulation may improve WW by modifying oscillatory dynamics within frontoparietal networks. Larger clinical trials with higher stimulation doses are needed to determine whether targeting oscillatory coupling represents a potential therapeutic strategy for WM deficits.

Mapping hierarchical brain networks within traditional Euclidean space causes significant structural distortion, undermining neuroimaging diagnostic frameworks. While hyperbolic models like the Poincare ball preserve these nested topologies, they demand heavy computational overhead due to intricate Mobius operations and curved geodesics. This paper introduces a highly efficient non-Euclidean framework for analyzing neurocognitive decline utilizing the Beltrami-Klein ball model. By projecting hyperbolic geodesics as Euclidean straight lines, this approach converts complex distance calculations into simple dot products, radically reducing processing demands. We validated our methodology against state-of-the-art Poincare and Lorentz baselines using datasets for Schizophrenia, Parkinsons Disease, and Alzheimers Disease. The Klein-based framework demonstrates superior performance, delivering both higher diagnostic precision and accelerated processing velocities across all three neurocognitive disorders.

Purpose: To develop an accelerated motion-compensated diffusion-weighted pseudo-continuous arterial spin labeling (MCDW-pCASL) method using a spatial subspace low-rank reconstruction method for efficient quantification of blood-brain barrier (BBB) water exchange (kw) and permeability (PSw). Methods: An accelerated multidelay MCDW-pCASL sequence was developed to simultaneously encode intravascular and extravascular diffusion-weighted ASL signals across multiple post-labeling delays (PLDs). A spatial subspace low-rank reconstruction framework was optimized to enable joint estimation of cerebral blood flow (CBF) and BBB water exchange rate and permeability. Fourteen young healthy adults underwent test-retest scans (separated by ~1 week) at 3T with both the accelerated MCDW-pCASL and a conventional diffusion-prepared (DP) pCASL sequence. Whole-brain, gray-matter, and white-matter CBF and kw values were quantified to assess test-retest repeatability and cross-method agreement. An additional cohort of 30 older adults underwent single-session MCDW and DP scans to evaluate age-related perfusion and BBB kw/PSw differences. Intraclass correlation coefficients (ICCs) were used to assess reliability and agreement. Results: Accelerated MCDW-pCASL demonstrated excellent agreement with DP-pCASL for CBF (ICC = 0.89) and fair agreement for kw (ICC = 0.56). Test-retest repeatability of MCDW-pCASL was good for CBF, BBB kw and PSw (ICC {approx} 0.6). Across both sequences, younger subjects exhibited significantly higher CBF and kw compared with older adults. Conclusion: Incorporating a spatial low-rank subspace reconstruction enables accelerated MCDW-pCASL acquisition with reliable simultaneous quantification of CBF, BBB kw and PSw. Clinical applications of this method for assessing perfusion and BBB function are warranted.

Multimodal imaging approaches that combine structural and functional neuroimaging provide a robust framework for examining neuroplastic adaptations that may not be captured by any single modality. The present study investigated the effects of a four-week expiratory muscle strength training (EMST) program on structural and resting-state functional connectivity in healthy young adults. Five healthy young adult males (aged 19-35 years) completed a standard four-week EMST protocol and underwent pre- and post-training imaging assessments. Structural neuroimaging included T1-weighted and diffusion-weighted MRI, which were analyzed using voxel-based morphometry, surface-based morphometry, and white-matter structural connectivity. Functional neuroimaging consisted of resting-state fMRI to assess training-related changes in functional architecture, network connectivity, and global network measures. Structural MRI analyses revealed no significant changes in gray or white matter volume, cortical morphology, or white-matter structural connectivity following EMST (all FWE- or FDR-corrected p > .05). In contrast, resting-state fMRI demonstrated a significant increase in whole-brain functional connectivity (FDR-corrected p = .036), accompanied by greater network integration, reflected in increased local efficiency and transitivity and reduced modularity. Network-level analyses showed enhanced within- and between-network connectivity in sensorimotor and cognitive circuits. Our findings demonstrate robust functional reorganization following EMST, despite the absence of detectable macrostructural or large-scale white-matter connectivity changes, at least within the timescale and sample characteristics of the current study. These results reflect early-stage neuroplasticity, both globally and within the networks underlying speech and swallowing control and suggest that functional reorganization occurs early in training and likely precedes longer-term structural modifications in these networks.

Importance: Patients who achieve remission from major depressive disorder (MDD) often face a preference-sensitive decision between continued antidepressant maintenance and discontinuation with active monitoring. Quantifying the tradeoff between depression burden and long-term medication exposure may support more individualized shared decision-making. Objective: To quantify tradeoffs between continuous antidepressant maintenance and active monitoring after MDD remission, and to identify preference thresholds favoring each strategy across relapse-risk strata. Design: Individual-level decision-analytic health-state transition model calibrated to randomized maintenance-discontinuation trials and a longitudinal first depressive episode cohort, with a 5-year time horizon. Setting: Outpatient clinical decision after completion of an 8-month continuation phase following remission from MDD. Participants: Adults in remission from MDD, represented across 4 clinically anchored relapse-risk strata ranging from very low risk after a first mild episode to high risk after highly recurrent depression. Exposures: Continuous antidepressant maintenance vs discontinuation with active monitoring and antidepressant restart after detected relapse. Main Outcomes and Measures: Severity-weighted depression-months, antidepressant medication-years, medication-years per depression-month averted, and net benefit across preference thresholds defined as the maximum additional medication-years a patient would be willing to accept to avert 1 depression-month. Results: Continuous maintenance reduced depression burden but required substantially more medication exposure, with efficiency strongly dependent on relapse risk. Medication-years per depression-month averted ranged from 11.8 (95% uncertainty interval [UI], 7.8-19.6) in the very low-risk group to 1.5 (95% UI, 0.8-3.0) in the high-risk group. At a preference threshold of 3 medication-years per depression-month averted, maintenance was preferred for moderate- and high-risk patients; at a threshold of 2, only for high-risk patients; and at a threshold of 1, for no risk group. Conclusions and Relevance: In this decision-analytic model, the value of continuous antidepressant maintenance depended strongly on baseline relapse risk and patient preferences regarding long-term medication exposure. These findings provide a quantitative framework for shared decision-making about antidepressant maintenance after remission from MDD.

Alzheimers disease (AD) causes progressive memory loss and disorientation. It is preceded by a prolonged preclinical phase marked by pathological changes in medial temporal lobe regions involved in spatial navigation. Spatial navigation tasks have been proposed for early AD detection, and altered navigation performance was reported in older carriers of the apolipoprotein E (APOE) {varepsilon}4 allele, the major genetic risk factor for sporadic AD. However, whether spatial navigation or other cognitive abilities are affected in younger {varepsilon}4 carriers remains unclear. Here, we genotyped 1000 healthy young adults (18-35 years) who completed the app-based navigation game "Sea Hero Quest" and several tasks assessing working memory, processing speed, executive functioning, and face recognition. {varepsilon}4 carriers ({varepsilon}3{varepsilon}4, N = 88) showed no significant differences from non-carriers ({varepsilon}3{varepsilon}3, N = 327) in spatial navigation or other cognitive abilities, supported by equivalence testing and Bayesian analyses. Exploratory findings suggested altered spatial navigation in {varepsilon}2 carriers ({varepsilon}2{varepsilon}2/{varepsilon}2{varepsilon}3/{varepsilon}2{varepsilon}4, Ns = 7/51/7) versus {varepsilon}3{varepsilon}3 controls, who stayed closer to environmental borders and showed better memory updating, face recognition, and processing speed. Therefore, APOE-related behavioural differences in young adults appear small at best, highlighting the need for paradigms sensitive to very subtle changes decades before potential dementia onset.

Background: Actigraphy-derived rest-activity rhythm (RAR) features are widely used to characterize clinical states in bipolar disorder (BD). Both mean levels and temporal variability of these features have been associated with mood episodes; however, variability measures are often statistically coupled with the mean, particularly in skewed distributions. This raises a question as to whether variability reflects a separate characteristic of the data or whether the observed association arises from statistical properties of the data. Objective: In this study, we aim to determine whether temporal variability of actigraphy-derived RAR features provides standalone information on mood episodes in BD beyond mean activity levels after accounting for mean-variance dependence. Methods: We analyzed actigraphy data from a subset of 72 participants with BD drawn from a larger longitudinal study, extracting 22 daily RAR features aggregated weekly as sample mean (MEAN) and within-week temporal variability computed as sample standard deviation (VAR). Variance-stabilizing transformations (Box-Cox or Yeo-Johnson) were applied to the entire study cohort to reduce mean-variance dependence. Associations with mood episodes and remission (mania: n=34; depression: n=58 annotated participants) were evaluated using generalized linear mixed-effects models with a logistic link function, including univariate (MEAN or VAR) and multivariate (MEAN+VAR) specifications, assessed by likelihood-based metrics and the area under the receiver operating characteristic curve (AUC). Results: Transformations reduced mean-absolute correlations from 0.43 to below 0.06. Temporal variability remained significantly associated with clinical state for 11/22 RAR features in mania and 16/22 features in depression, with all significant associations remaining after false discovery rate correction (p<0.05). Joint models showed modest incremental gains (AUC 3%-4% overall; up to 12% in mania, 7% in depression), with absolute performance remaining limited (AUC 0.50-0.66). In both mania and depression, nearly all significant variability-based regressors contributed incremental information beyond mean-based models. Only sleep duration and activity changes around wake time (+-1 hour), did not improve discrimination between mania and remission. Conclusions: Temporal variability in RAR features can be considered a standalone state marker of mood episodes not captured by mean activity. We found it to be more consistently associated with depression than mania. Its incremental discriminative contribution is modest, suggesting greater utility within multivariate or multimodal frameworks.

Objective: Polygenic risk scores (PRS) for posttraumatic stress disorder (PTSD) often account for a low amount of variance. Ancestry-related differences in PRS scale and variance limit cross-group comparisons. This methodological challenge further complicates gene-by-environment (GxE) analyses, given that socioenvironmental exposures are inequitably distributed across ethnoracial groups. We constructed an ancestry-calibrated polygenic risk score (AC-PRS) for PTSD in the largest longitudinal study of trauma survivors to date and investigated GxE interactions. Method: Recent trauma survivors (N=1,801) provided a blood specimen for genotyping. Six PTSD trajectories were previously identified from PTSD Checklist for DSM-5 (PCL-5) scores at 2-weeks, 8-weeks, 3-months, and 6-months post-trauma. Greenspace (normalized difference vegetation index [NDVI) and socioeconomic disadvantage (area deprivation index [ADI]) were derived from residential addresses. Logistic regressions examined interactions between newly developed AC-PRS and neighborhood factors on trajectories after adjusting for sociodemographic and trauma-related covariates. Secondary linear models considered GxE interactions on 6-month PCL-5 scores. Results: AC-PRS performed well across ethnoracial groups, explaining significant variability in PTSD trajectories (R2=.053). ADI moderated the association between AC-PRS and the likelihood of assignment in a high nonremitting trajectory of PTSD symptoms and severity of symptoms at 6-months (ps < .05). There were no NDVI x AC-PRS interactions in any models. Conclusions: AC-PRS captures genetic risk for PTSD in admixed trauma survivors, demonstrating good discrimination between nonremitting and resilient courses of PTSD. However, neighborhood disadvantage may modify utility of PRS for PTSD, warranting careful consideration when applying these scores across contexts.

Large Language Models are increasingly used in consumer-facing mental health tools, many of which claim that prompt engineering alone can ensure safe therapeutic behavior. This study evaluates that assumption by testing 20 proprietary and open-source LLMs on high-risk psychiatric scenarios, using prompts grounded in behavioral therapy principles. Prompt engineering reduced some predictable risks, such as explicit endorsement of self-harm, but consistently failed in ambiguous or clinically nuanced situations. Models frequently validated harmful statements, colluded with hallucinations, minimized symptoms, or used stigmatizing language, including in the newest and largest models. These failures reflect structural limitations such as lack of memory, insufficient contextual reasoning, and training-related biases. Prompt engineering alone is therefore insufficient for safe AI-mediated psychotherapy; clinician-guided fine-tuning, integrated safety mechanisms, and system-level oversight will be required. This work provides early evidence motivating deeper clinician-led evaluation and safety-oriented model development.