Brain Imaging and Behavior

Laboratory stress tasks are widely used to assess individual differences in acute stress reactivity, yet it remains unclear how these responses correspond to stress experienced in everyday life. Here, we combined the Montreal imaging stress task (MIST) with ecological momentary assessment (EMA) over three months to assess acute and everyday stress in 67 healthy women. Greater within-person variability in everyday stress, but not average stress levels, were associated with stronger overall stress-related brain responses (b = 0.73, p = .039), with a whole-brain association particularly evident in the bilateral caudate (rROI = .32, pcluster.FWE < .001). Greater everyday stress variability was also associated with stronger stress-related functional connectivity between the ventromedial prefrontal cortex (vmPFC) and parietal and posterior medial regions (pcluster.FWE < .001). We conclude that acute neural stress responses relate more closely to fluctuations in perceived stress than to how stressed an individual feels on average. This suggests that laboratory stress tasks capture acute stress responsivity that is distinct from average stress exposure, highlighting the importance of considering what these tasks measure when interpreting individual differences in acute stress responses.

Lesion Network Mapping (LNM) is a framework used for identifying symptom-related brain circuits by projecting lesion locations onto a normative connectome. Recent methodological investigations have raised concerns about the biological interpretation and specificity of the circuits derived using this method, with published LNM maps often showing high similarity across clinically unrelated conditions. Specificity testing has subsequently been put forward as the decisive step to ensure specificity to the symptom in question, accompanied by the argument that this step was not evaluated in the original methodological investigation. Yet, sensitivity testing, specificity testing, case-control LNM, permutation of group labels, and symptom-based LNM involve related operations on connectivity matrix C. We expand on specificity testing in LNM, clarify its relationship to other LNM steps and variants, and examine the persistent repetition among LNM specificity networks across studies. These considerations advance our understanding of the disease-specificity limitation of LNM and encourage the development of new methodological approaches for identifying brain circuits underlying psychiatric and neurological disorders.

Background Alcohol use disorder (AUD) is highly prevalent in schizophrenia, yet the neurobiological basis of this vulnerability remains poorly understood. Neurodevelopmental models suggest that pre-existing brain dysconnectivity may increase vulnerability to AUD. We therefore tested whether schizophrenia-like neurodevelopmental pathology alters how alcohol-related experience is incorporated into large-scale brain networks. Methods Resting-state functional connectivity was assessed in male Sprague-Dawley rats (n = 18-21/group) with neonatal ventral hippocampal lesions (NVHL), a neurodevelopmental model of schizophrenia, and sham-operated controls, with or without voluntary adolescent alcohol exposure. Functional connectivity was assessed using seed-to-voxel and seed-to-seed analyses within a cortico-striato-limbic network. We additionally examined whether individual alcohol intake during adolescence predicted adult functional connectivity according to neurodevelopmental status. Results NVHL and adolescent alcohol exposure independently produced predominantly hypoconnected cortico-striato-limbic networks. However, alcohol exposure did not exacerbate NVHL-associated dysconnectivity but instead induced a distinct network reorganization characterized by functional hyperconnectivity. Although alcohol intake was comparable between groups, dose-dependent relationships between adolescent alcohol consumption and adult functional connectivity were observed in sham animals but were absent or markedly attenuated in NVHL rats. These effects were primarily centered on prelimbic cortex connectivity with the amygdala, hippocampus, and dorsal striatum, highlighting this circuitry as a major locus of altered experience-dependent remodeling. Conclusions These findings suggest that vulnerability to AUD associated with schizophrenia-like neurodevelopment may arise less from additive network dysfunction than from an altered capacity of large-scale brain networks for experience-dependent functional remodeling. Schizophrenia-like neurodevelopmental pathology may therefore change how alcohol-related experience is translated into persistent brain network organization.

Background: Storage symptoms after stroke-isolated urgency, urgency with frequency, and isolated frequency are common but traditionally attributed to a single overactive bladder mechanism via suprapontine disinhibition. However, clinical heterogeneity in symptom presentation suggests distinct underlying mechanisms. We aimed to characterize the neural substrates of three storage symptom subtypes after stroke using comprehensive lesion-symptom mapping. Methods: We prospectively evaluated 1,498 consecutive subacute stroke patients admitted for inpatient rehabilitation (1,105 men, 73.8%; median age 61 years). Storage symptoms were classified into three subtypes: isolated urgency (n=109), urgency with frequency (n=32), and isolated frequency (n=19). Multivariable logistic regression models with Bonferroni correction identified independent predictors across demographic, clinical, white matter hyperintensity (WMH), brain atrophy, and lesion location variables. Results: The three subtypes demonstrated largely distinct sets of independent predictors. The left genu of the corpus callosum (aOR=20.06, 95% CI 7.78-51.74, P<0.001) and the inferior frontal gyrus (aOR=3.48, 95% CI 1.81-6.67, P<0.001) were independently associated with isolated urgency and survived Bonferroni correction, together with a right IFG-insula synergistic effect (OR=21.46, 95% CI 10.49-43.88, P<0.001). Urgency with frequency was associated with a broad fronto-cingulate network-the IFG (aOR=11.45, 95% CI 3.10-42.33, P<0.001, surviving Bonferroni correction) and the ACC (aOR=11.53, 95% CI 2.40-55.49, P=0.002) with diffuse right-hemisphere dominance, older age and brain atrophy. Isolated frequency was associated with anterior corona radiata involvement (aOR=5.46, 95% CI 1.92-15.54, P=0.002) and male sex (aOR=10.62, 95% CI 1.36-82.98, P=0.024), though none reached the strict Bonferroni threshold. Conclusions: These findings identify three mechanistically distinct post-stroke storage symptom subtypes with separable neural substrates, lateralization profiles, and clinical determinants. The triple dissociation across subtypes supports a discrete pathway model over the traditional unitary OAB framework, providing a neuroanatomically grounded basis for subtype-stratified treatment Keywords: storage symptoms; subacute stroke; hemispheric lateralization; structural synergy; lesion-syndrome mapping

Background: Hippocampal sclerosis (HS) is a common cause of drug-resistant focal epilepsy (DRFE) and amenable to neurosurgical treatment. Detection relies on MRI but can be challenging. 7 Tesla (T) ultra-high field MRI and automated MRI post-processing tools have independently been shown to improve radiological diagnosis of HS. However, combining these approaches remains underexplored. This study evaluated whether AID-HS, a tool for HS detection developed using 3T MRI, generalises to 7T MRI data. Methods: We collated a dataset of paired 3T and 7T T1-weighted MRI from four epilepsy centres, including 23 patients with HS, 39 healthy controls, and 23 individuals with focal cortical dysplasia as disease controls. Histopathology served as the gold standard for defining HS where available (n=7), otherwise radiological findings (n=16). AID-HS was applied to images acquired at both field strengths, and sensitivity and specificity for detection and lateralisation of HS were compared. Additionally, agreement of hippocampal features across 3T and 7T was evaluated. Results: We found no evidence of a difference in performance of AID-HS between 3T and 7T. Sensitivity for detection of unilateral HS was 63% (12/19) at 3T and 68% (13/19) at 7T (McNemar's exact test p=1.0). Specificity in controls was 97% (60/62) at 3T and 100% (62/62) at 7T (p=0.5). Bilateral HS was correctly flagged in 3 of 4 cases using feature-based criteria, with high specificity in controls. Quantitative hippocampal features showed moderate to good agreement across field strengths (ICC 0.70 to 0.98), with small differences observed for volume and thickness estimates. Conclusion: AID-HS provides robust detection and lateralisation of HS across multiple 7T MRI centres, highlighting its potential to enhance lesion detection. Future work is needed to investigate whether models trained on 7T data can leverage the improved image quality for further gains in HS detection performance.

Background: Bipolar disorder is associated with persistent social, cognitive, and functional impairment during euthymia, yet the neural mechanisms underlying these deficits remain unclear. Alterations to self-referential processing are a candidate mechanism, but existing electrophysiological studies rely on emotionally valenced paradigms that potentially confound self-processing with emotional biases. Methods: We analysed electroencephalography from 28 patients with bipolar disorder (type I or II) and 28 age- and sex-matched healthy controls during an emotionally neutral colour judgment task with self-related (preference) and non-self-related (similarity) conditions. Late positive potentials, temporal generalisation decoding, and frequency band decoding (theta, alpha, beta) were used to characterise the temporal dynamics and oscillatory correlates of self versus non-self processing. Results: Controls showed higher overall event-related potential amplitudes and greater self versus non-self differentiation than patients (condition by group interaction, 337 to 946 ms). Broadband temporal generalisation decoding revealed extensive cross-temporal generalisation of the self versus non-self representation in controls, spanning most of the trial, but no significant generalisation in patients. Frequency analyses showed that alpha and beta carried self versus non-self information in both groups, with broader extent in controls, and that anterior theta carried this information in patients but not controls. Exploratory correlations linked decoding measures to rumination and anxiety but not to manic symptoms. Conclusions: The neural representation distinguishing self-referential from externally guided processing was both smaller in amplitude and less temporally sustained in bipolar disorder. Reduced persistence is not detectable by conventional amplitude analyses, and may bear on the self-related and social cognitive difficulties reported in this population.

Background The prevalence and pattern of secondary causes of first-onset psychosis (FEP) in Asian populations are understudied. Our objectives are to investigate the prevalence and pattern of secondary causes of FEP presenting in an acute medical setting in a metropolitan, Chinese-predominant population, and to investigate the prevalence and pattern of undiagnosed conditions presenting as psychosis. Method This is a retrospective observational study. We reviewed medical records of patients referred to the consultation psychiatry team at a tertiary acute teaching hospital in Hong Kong from January 2015 to Apr 2025. The inclusion criteria of the study are 1) age 18-64 at the time of the assessment, and 2) FEP confirmed by the consultation liaison team. Patients diagnosed with delirium were excluded. Result Among the 384 patients included in the study (mean age = 40.0 {+/-}13.7 years, 69% female), secondary causes of psychosis were found in 9.6% (n=37) of the cohort. Substance use is the most common secondary cause found (n=11, 2.9% of all FEPs) overall. Among those with secondary psychoses, patients' underlying conditions were revealed only by the workup in relation to the FEP in 16 of them, of which definitive or probable autoimmune encephalitis (n=5) and early-onset dementia (n=4) were the most common conditions uncovered. Conclusion The prevalence of secondary psychoses in our FEP cohort is lower than published international figures. Clinicians need to be aware of the suspicious clinical features suggestive of autoimmune encephalitis and early-onset dementia in FEP patients with otherwise unremarkable past history and toxicology test.

Background: The primary neuroanatomical site of Huntington-s disease (HD) pathology resides in the striatum and its atrophy identifies important disease progression from HD-ISS Stage 0 to Stage 1. Immune-associated proteins may capture variation in HD that is incompletely represented by markers of neuroaxonal injury. Objectives: To determine whether cerebrospinal-fluid myeloperoxidase contributes information about striatal volume loss beyond genetic disease burden and neurofilament light. Methods: Cross-sectional data from 88 persons with HD were analyzed. Cerebrospinal-fluid myeloperoxidase and neurofilament light were measured with a nucleic acid-linked immunosandwich assay. Normalized putamen volume was derived from structural magnetic resonance imaging. Linear regression adjusted for genetic disease burden and sex. Results: Higher neurofilament light was associated with smaller normalized putamen volume (standardized {beta} = -0.322, (P=.0066)). Higher myeloperoxidase was associated with larger normalized putamen volume after adjustment for genetic disease burden, sex, and neurofilament light (standardized {beta} = 0.183, (P=.0386)). Adding myeloperoxidase increased explained variance in striatal loss. Conclusions: Cerebrospinal fluid myeloperoxidase contributed modest incremental information about striatal volume in this cross-sectional sample. Independent longitudinal studies are needed to determine its biological source, temporal behavior, and potential biomarker value. Findings advance efforts to characterize multicomponent biological markers of HD.

Abstract: Objective: Post-traumatic epilepsy (PTE) is a common sequela of traumatic brain injury (TBI). Research indicates that individuals with PTE tend to experience greater cognitive difficulties compared to those with TBI alone. However, it is plausible that a distinct cognitive profile exists that distinguishes between TBI cases with and without PTE. We aimed to identify longitudinal changes in cognitive measures among TBI patients to better assess the changes associated with developing PTE. Setting: Outpatient. Participants: Prospective subjects who had suffered TBI within 6 months post-injury (TBI-6M, n=32), retrospective subjects with pre-existing PTE diagnoses (PTE, n=20), and healthy control subjects (HC, n=41). Design: We examined cognitive performance for TBI patients within 6 months post-injury, then again within 12 months (TBI-12M, n=26), and within 18-months (TBI-18M, n=25), and compared this with cognitive performance among HC and PTE. Main Measures: Cognitive tests administered yielded 15 test components for analysis. We utilized linear mixed effects modeling to examine cohort-level differences cognitive function. Results: 11/15 tests showed a significant performance deficit in the PTE subjects compared to HC. TBI-6M was not significantly different from the PTE subjects; with time, 9/15 tests showed some degree of recovery in TBI subjects. Tests for information processing speed/working memory and executive function showed strong recovery (TBI-6M vs. TBI-18M, SDMT written: p<0.0001, SDMT oral and COWAT: p<0.001). Tests for visual attention/working memory also showed a smaller but significant recovery (TBI-18M vs. PTE, p<0.05). By contrast, tests for verbal memory [HVLT-R Delayed Recall] showed chronic impairment in TBI (TBI-18M vs HC, p<0.0001). TBI subjects generally trend towards recovery in cognitive performance post-TBI. Conclusions: Information processing speed/working memory are strong indicators for TBI recovery, while auditory learning/memory shows chronic impairment. The stagnation of recovery in cognitive domains typically characterized by robust recovery may correlate with an elevated risk of developing PTE.

During wakefulness, we are used to perceive the environment through our senses, act on it and take these inputs to update our experiences and build the perceptions. When the inputs are not longer accurate or structured, people would sometimes have hallucinatory experiences. Whether such experiences are associated with distinct patterns of thought, and how they relate to large scale brain dynamics, remains unclear. To address these questions, we combined experience sampling protocol with EEG recording during multimodal Ganzfeld, where participants were exposed to unstructured, uniform visual and auditory stimulation. Participants repeatedly reported the complexity of their visual experiences together with ongoing thoughts related to perceptual belief, prediction perception mismatch, active updating, and prior mentation. EEG microstates were extracted to characterize the temporal dynamics of large-scale brain networks. We found that visual complexity was related to all four dimensions, but partly distinct in simple and complex visual experiences. These phenomenological changes were accompanied by distinct, and often nonlinear, dynamics of large-scale brain networks involved in visual processing, salience detection, and internally directed cognition. It also indicates that this paradigm might be a valuable model for investigating the mechanisms underlying hallucinatory experiences in psychosis.

Objective: The Brief-cope questionnaire explore coping behavior. However, the underlying factor structure remains a subject of ongoing debate. Exploratory factor analyses (EFA) conducted across different populations have identified factor solutions ranging from two to fourteen factors. As of yet, the underlying factor structure of the Brief-cope has not been investigated in patients with seropositive rheumatoid arthritis (RA). Therefore, the aim of this study was to explore the underlying factor structure of the Brief-cope in a German population of seropositive RA. Methods: 216 outpatients with seropositive RA completed the Brief-cope. An EFA with principal axis factoring and Promax rotation was conducted. Results: EFA indicated a five-factor solution. The five-factor solution explained 51.95% of variance. The identified factors were: (1) problem-focused coping (Cronbach's = .851), (2) emotion-focused coping ( = .754), (3) maladaptive coping ( = .747), (4) religious coping ( = .851), and (5) substance-use coping ( = .869). Conclusion: A five-factor solution provided the most appropriate representation of the underlying factor structure of the Brief-cope in patients with seropositive RA. This factor structure may serve as a suitable basis for future analyses of Brief-cope data in comparable RA populations.

Aim: The Patient Safety Screener-3 (PSS-3) is a brief suicide-risk screening tool. Item 1 of this scale assesses depressive mood but is not included in the total score. We examined the association of item 1 with depressive symptom severity and characterized the suicide-related risk captured by PSS-3 total positivity. Methods: We conducted a nationwide cross-sectional survey among resident physicians in Japan. Associations between PSS-3 item 1 endorsement and Patient Health Questionnaire-9 (PHQ-9) scores were evaluated using the Wilcoxon rank-sum test. Diagnostic performance of item 1 was evaluated using PHQ-9 positivity ([&ge;]10) as reference standard. We also compared Short-form Scale for Suicide Ideation (SIS-6) scores according to PSS-3 total positivity and PHQ-9 item 9 positivity. Results: A total of 1,844 participants were included. PSS-3 item 1 was endorsed by 443 physicians (24.0%), and 47 (2.5%) met the criteria for PSS-3 total positivity. Item 1 showed 79.3% sensitivity and 79.5% specificity for PHQ-9 positivity. SIS-6 scores were higher in the PSS-3 total-positive group than in the total-negative group (median [IQR], 6 [5-9] vs 0 [0-1]; p<0.001). The SIS-6 showed a higher area under the receiver operating characteristic curve (AUC) and Youden index using PSS-3 total positivity (AUC, 0.961; optimal cutoff, 3) than PHQ-9 item 9 positivity (AUC, 0.907; optimal cutoff, 2). Discussion: PSS-3 may support brief, simultaneous screening for depressive symptoms and suicide-related risk. Compared with PHQ-9 item 9, PSS-3 may capture a more severe spectrum of suicide-related risk. PSS-3 may facilitate identification of individuals requiring further mental health assessment.

Objective: To examine how medial plantar nerve shear wave speed (Cs) and viscosity coefficient (Vi) are associated with the severity of diabetic peripheral neuropathy (DPN), and to assess their ability to differentiate adjacent severity categories. Materials and Methods: Based on TCSS, the 113 patients with type 2 diabetes mellitus were assigned to the non-DPN (n = 33), mild DPN (n = 46), and moderate DPN (n = 34) groups. Medial plantar nerve Cs and Vi were measured using shear wave elastography and viscosity imaging. Receiver operating characteristic analysis evaluated Cs, Vi, and their logistic regression-based combination; areas under the curves (AUCs) were compared using DeLong tests. Results: Cs and Vi increased progressively across the three groups (both P < 0.001). For non-DPN versus mild DPN, the AUCs of Cs, Vi, and the combined model were 0.688 (95% CI, 0.604-0.772), 0.741 (0.660-0.822), and 0.745 (0.665-0.826), respectively, without significant pairwise differences. For mild versus moderate DPN, the corresponding AUCs were 0.707 (0.625-0.789), 0.794 (0.724-0.865), and 0.799 (0.731-0.867). The combined model outperformed Cs (P = 0.045), whereas Cs versus Vi and Vi versus the combined model did not differ significantly (P = 0.162 and 1.000, respectively). Conclusion: Medial plantar nerve Cs and Vi increased with DPN severity. Their combination improved discrimination between mild and moderate DPN compared with Cs alone but not with Vi alone. Quantitative medial plantar nerve viscoelastic assessment may complement clinical severity grading.

Background: The Centiloid (CL) scale standardizes global amyloid PET quantification and is widely used to define amyloid positivity. As a global summary measure, however, CL may not fully reflect the regional distribution of amyloid deposition, which can carry additional prognostic information about the rate of cognitive decline. Objective: To develop and externally validate a fixed, regional amyloid PET composite score that complements CL for predicting cognitive decline in Alzheimer's disease. Methods: The Regional Amyloid PET Score (RAPS) was derived from 82 FreeSurfer regions using machine learning with bootstrap stability selection to predict the rate of change in CDR-Sum of Boxes (CDR-SB) in 433 amyloid-positive ADNI [18F]florbetapir participants. The fixed nine-region weights were applied without retraining in a cross-tracer ADNI [18F]florbetaben subset (N = 71; largely overlapping the discovery participants) and two external validation cohorts, NACC SCAN (N = 1531; four tracers) and OASIS-3 (N = 428). Results: RAPS comprised nine regions. In ADNI, RAPS correlated more strongly with CDR-SB slope than CL and showed higher discrimination of rapid decliners (AUC 0.813 vs 0.713). Performance was directionally consistent across validation cohorts; in NACC SCAN, RAPS and CL independently predicted clinical progression. Cross-cohort meta-analysis of the three independent cohorts supported incremental discrimination beyond CL (pooled {Delta}AUC +0.066; I2 = 0%). Conclusions: RAPS, a fixed regional amyloid PET-derived score, may complement CL for prognostic stratification in Alzheimer's disease research.

This document describes the Statistical Analysis Plan (SAP) for PETRA, a randomised controlled trial in people with generalised anxiety disorder comparing pregabalin plus an antidepressant and standard care, with placebo plus an antidepressant and standard care, with respect to the primary outcome of the GAD-7 score at week 12.

Cross-sectional studies suggest associations between physical exercise and white matter in older adults, but evidence from randomized controlled trials is scarce. Neurite orientation dispersion and density imaging indices are biophysically informed metrics of white matter microstructure. Here, we tested whether a remotely delivered, 8-week multicomponent physical exercise intervention impacts neurite density (NDI) and orientation dispersion (ODI) across major white matter tracts in older adults. This secondary analysis of a randomized controlled trial included participants with available diffusion MRI data (n = 66; age: 66.4 {+/-} 3.6 y; 43 females). Participants were randomized to a multicomponent exercise (PAG, n = 34) or an active control (CON, n = 32) intervention. Intervention effects on NDI/ODI were tested using linear mixed-effects and Bayesian multilevel models adjusted for age and sex. A significant Timepoint x Group interaction was observed for NDI (p = 0.003) but not for ODI (p = 0.785), further confirmed in Bayesian analyses for 22 white matter tracts, indicating a greater increase in NDI in the PAG. The standardized composite VO2max score increased from pre- to post-intervention within the PAG, although the Timepoint x Group interaction was not significant (p = 0.079). Across all participants, pre-to-post changes in mean NDI were positively correlated with changes in VO2max, but this association did not differ between groups. Our results indicate that white matter microstructure remains responsive to short-term, multicomponent physical exercise in older adults.

Background: Multiple sclerosis (MS) is a chronic neurodegenerative disorder in which inflammatory demyelinating lesions affect the brain, optic nerve and spinal cord. MS lesion formation is accompanied by profound changes to blood vessels, including the density of PDGFR{beta}+ mural cells, historically identified as pericytes. Intriguingly, in recent years, single-cell and lineage tracing studies have shown that the PDGFR{beta}+ cell population is heterogeneous, comprising both pericytes and perivascular fibroblasts. Yet, due to their overlapping expression profiles, the spatial distribution of these cell populations in MS lesions remains poorly understood. Methods: We employed multiplex immunohistochemistry for endothelial cells (CD31), basement membrane (laminin), fibroblasts (PDGFR{beta}, COL1A1, SMA), pericytes (PDGFR{beta}, SLC6A12) and immune cells (CD45, CD68) to characterize the spatial localization of fibroblasts and pericytes in MS lesions, and how this relates to perivascular space enlargement and immune cell presence. Results: We analysed 17633 individual vessels across 5 control white matter, 5 normal-appearing white matter, 4 active and 4 chronic active MS lesions. By carefully delineating endothelium and perivascular compartments, we find that perivascular space area but not number of vessels is increased in MS lesions. Through mining of publicly available sequencing datasets, we confirm COL1A1 and SLC6A12 as fibroblast and pericyte markers, respectively, in the human brain. COL1A1+ and SLCA12+ vessels were largely distinct of one another. Unsupervised clustering of the expression profile of PDGFR{beta}, COL1A1 and SLC6A12 in individual vessels distinguished three partially overlapping vessel clusters. Of these, the fibroblast-associated vessel type (COL1A1 high, SLC6A12 low) was increased in chronic active lesion rim and center. Importantly, fibroblast-associated vessels were related to increased perivascular space enlargement and more accumulation of immune cells. Conclusion: We identify distinct fibroblast- and pericyte-associated vascular phenotypes in human white matter. Notably, fibroblast-associated vessels are increased in chronic active lesions, where they are related to immune cell cuffs. These findings provide a spatial link between perivascular fibroblasts and chronic inflammation in MS.

Background: Major depressive disorder (MDD) is a severe mental illness associated with severe clinical consequences and substantial societal burden. It's characterized by immune-inflammatory dysregulation and immune sensitization. Objective: To determine whether in vitro ketamine attenuates phytohemagglutinin (PHA)/lipopolysaccharide (LPS)-induced immune sensitization in patients with MDD and healthy controls (HCs). Methods: Whole blood from 18 patients with MDD and 18 HCs was stimulated with PHA/LPS and exposed to ketamine (0.3 M, 0.6 M, and 6 M) for 72 hours. Cytokines, chemokines, growth factors, and composite immune profiles, including M1/M2 macrophages, T helper (Th)1/2/17, the immune-inflammatory response system (IRS), and compensatory immunoregulatory system (CIRS), were synthesized and determined. Results: Under PHA and LPS stimulation in vitro, the MDD group exhibited markedly elevated immune profiles, including M1, M2, Th1, Th2, Th17, IRS, CIRS, chemokines, and growth factors, consistent with immune sensitization. Significant group-by-treatment interactions were observed for Th1-Th2, M2, growth factors, IL-12(p70), M1, and chemokines. Ketamine produced minimal changes in HCs but broader suppression in MDD, particularly at the highest concentration, without normalizing the sensitized immune phenotype. Among the immune markers with no notable group-by-treatment interactions, ketamine exerted diagnosis-independent effects, decreasing MIP-1{beta}, IL-1&{beta}, Th1, TNF-{beta} IRS, IFN-{gamma}, and IL-2 compared to the control condition. Conclusions: Ketamine exhibited two distinct immunoregulatory patterns: selective, disease-dependent attenuation of sensitized immune pathways and broader, diagnosis-independent suppression of the stimulated immune response, predominantly at higher concentrations. However, these effects were insufficient to normalize the immune-sensitized phenotype of MDD.

Background: Cognitive impairment is the leading cause of disability in schizophrenia with limited treatments. A major barrier to treatment development is the absence of reproducible, mechanistically grounded neural targets. Cross-sectional studies have identified dorsomedial prefrontal cortex (DMPFC)-somatomotor connectivity as a neural marker of cognitive performance on the Auditory Continuous performance task (ACPT), a measure of attention. To test the stability of this marker, we tested the relationship between DMPFC-somatomotor connectivity and ACPT performance in a longitudinal psychosis sample. Methods: Individuals with early psychosis (n=251) and matched controls (n=90) were enrolled and underwent resting-state neuroimaging and neurocognitive assessment. A subset completed longitudinal assessments over 2-4 years. We calculated DMPFC-somatomotor resting-state functional connectivity using a previously identified DMPFC region and a seed in the somatomotor cortex. We performed linear mixed effects models to predict ACPT performance based on connectivity, time, psychosis type, and their interaction. Results: In the psychosis sample, time (p=.0037) and affective psychosis diagnosis (p<.0001) predicted better ACPT performance. In a model predicting ACPT performance, we observed a significant interaction effect of DMPFC-somatomotor connectivity*psychosis subtype (p=.0079) such that DMPFC-somatomotor connectivity predicted ACPT performance only in individuals with non-affective psychosis (p=.0051). We then tested the specificity of this connectivity-cognitive performance relationship. In a model predicting DMPFC-somatomotor connectivity, only ACPT performance (p=.017), but not fluid cognition, was a significant predictor. Conclusions: DMPFC-somatomotor connectivity is longitudinally associated with cognitive performance in early psychosis. This relationship is strongest in nonaffective psychosis, suggesting a novel, reliable target for intervention for cognitive deficits in early psychosis.

Background: Unruptured intracranial aneurysms (UIAs) are increasingly identified incidentally, and management balances rupture risk against treatment risk. UIA diagnosis has been linked to psychological distress, but psychotropic medication initiation after UIA discovery has not been compared across the full UIA management spectrum. Methods: We conducted a retrospective cohort study using IBM MarketScan claims (CCAE, MDCD, and MDCR; 2009-2023) among adults with a UIA diagnosis, continuous enrollment for 365 days before and after the index date, and no SAH/rupture on or before the index date. We compared the prevalence of 6 mental-health diagnoses before versus after UIA discovery and used adjusted logistic regression to examine psychotropic medication initiation within 365 days by management strategy (untreated observation as the reference). Results: Among 54,945 patients (untreated, 78.5%; endovascular, 11.3%; clipping, 3.0%; other/uncertain, 7.2%), prevalence of every mental-health diagnosis was higher after UIA discovery, most for depression (+4.6 percentage points) and anxiety (+4.5 points). Medication initiation was most common for benzodiazepines (8.7%). Endovascular treatment was associated with higher adjusted odds of benzodiazepine (aOR, 1.21), SSRI (aOR, 1.20), and sedative-hypnotic (aOR, 1.25) initiation.Surgical clipping demonstrated the broadest association, with higher odds across 5 of 6 classes, including benzodiazepines (aOR, 1.71) and sedative-hypnotics (aOR, 1.86). Benzodiazepines had the lowest 1-year persistence (10.5%) despite being the most commonly initiated class. Findings were consistent across sensitivity analyses, with the exception of the increase in panic disorder, which was no longer observed after applying a 30-day post-index lag. Conclusions: Mental-health diagnoses and psychotropic medication initiation increased after UIA discovery, and medication initiation was most pronounced among patients treated with surgical clipping. These findings support psychological assessment as part of aneurysm management regardless of strategy.