Psychiatry Research: Neuroimaging

Key Points Question: Is striatal hemodynamic latency, a novel indirect correlate of dopamine physiology, altered in individuals with early psychosis? Findings: In this cross-sectional study of 105 individuals with early psychosis and 55 healthy comparison participants, early psychosis was associated with significantly lower striatal hemodynamic latency. Differences were observed in the dorsal striatum (caudate and putamen), whereas ventral striatal (nucleus accumbens) latency did not significantly differ between groups. Meaning: These findings support further evaluation of striatal hemodynamic latency as a noninvasive, indirect marker of dopamine-linked physiology in early psychosis. Abstract Importance: Psychosis is strongly associated with striatal dopamine dysfunction, but noninvasive measures that capture variation in dopamine remain limited. Hemodynamic latency, which quantifies the timing of low-frequency blood oxygen level-dependent (BOLD) fluctuations, may provide a way to indirectly probe dopamine dysfunction in psychosis. Objective: To determine whether striatal hemodynamic latency differs between individuals with early psychosis (EP) and healthy control (HC) participants and whether latency is associated with positive or negative symptom severity. Design: Cross-sectional analysis of resting-state functional magnetic resonance imaging (fMRI) data from the Human Connectome Project (HCP)-EP dataset. Setting: Multisite study at 4 sites using 3T Siemens Prisma MRI scanners. Participants: 105 individuals with EP and 55 HC participants with usable resting-state fMRI and hemodynamic latency data. Exposure: EP status. Main Outcomes and Measures: Voxel-wise hemodynamic latency was estimated using RapidTide and summarized within 6 striatal regions: nucleus accumbens core and shell, anterior and posterior caudate and putamen. Group differences were evaluated using linear mixed-effects models accounting for region and subject-level random effects and controlling for age, sex, and mean framewise displacement. Positive symptoms were measured using the Positive and Negative Syndrome Scale positive subscale; negative symptoms using the Clinical Assessment Interview for Negative Symptoms. Associations with symptoms were assessed using nested linear regressions within the EP group. Results: Latency was significantly lower in the dorsal than ventral striatum in HC and EP, with a greater difference in EP (b=-119.46 ms, SE=52.16, p=.022). Follow-up six-subregion models found significant main effects of group F(1,156.55)=7.79, p=.006, and region F(5,2760)=187.99; p< .001, but no group-by-region interaction F(5,2760)=1.74; p=.121. Region-specific contrasts showed lower latency in EP in the anterior caudate (p=.014), posterior caudate (p<.001), anterior putamen (p=.007), and posterior putamen (p=.029), but not NAc core or shell. Striatal latency was not significantly associated with positive or negative symptom severity among participants with EP. Conclusions and Relevance: EP was associated with broadly reduced striatal hemodynamic latency, with the strongest differences in the caudate and putamen. Altered striatal latency in psychosis warrants further evaluation as a noninvasive indirect marker of striatal pathophysiology linked to dopamine.

Background: Schizophrenia has been conceptualised as a disorder of brain disconnectivity, with white matter abnormalities contributing to altered neural communication. However, fibre-specific white matter alterations in early illness and their potential sex-related differences remain insufficiently characterised. We applied fixel-based analysis to investigate sex-stratified white matter microstructural alterations in first-episode schizophrenia (FES). Methods: Diffusion MRI data from individuals with FES and healthy controls were stratified by biological sex. The male cohort included 79 patients and 29 controls, and the female cohort included 48 patients and 46 controls. Fixel-based analysis was performed separately in males and females to assess fibre density, fibre-bundle cross-section, and their combined measure. Head motion was included as a covariate in the fixel-based analyses. A descriptive follow-up voxel-scale analysis extracted mean fibre density from a binary mask derived from significant male fixels and applied the same region to the female cohort. Results: Males with first-episode schizophrenia showed significantly reduced fibre density compared with male controls, primarily in bilateral frontal white matter and a thin segment of the anterior corpus callosum. The voxel-scale follow-up confirmed lower mean fibre density in males within the significant fixel-derived mask. In contrast, females showed no significant group differences in any fixel-based metric or within the male-derived region. Conclusions: Early white matter microstructural alterations were detected in males with FES but not in females. These findings highlight a differential pattern emerging from sex-stratified analyses and support further investigation of sex-related differences in white matter alterations during the early stages of schizophrenia.

Socio-cognitive alterations are widely observed across different psychiatric conditions, yet it remains unclear whether these deficits map onto distinct diagnostic categories or represent a shared transdiagnostic phenotype, driven by dimensional psychopathological symptom severity.This study evaluates Theory of Mind (ToM) network activation during a naturalistic functional magnetic resonance imaging (fMRI) movie paradigm in 313 participants, including 91 healthy controls and 222 psychiatric inpatients across five distinct diagnostic clusters (substance use, schizophrenia spectrum, affective, anxiety, and personality disorders). Frequentist analyses revealed decreased ToM-selective activity in psychiatric patients, compared to controls across all ToM regions of interest (ROIs). No significant difference emerged between diagnostic groups, but ROI activation correlated negatively with Adult Self-Report (ASR) scales (Total Problems, Internalising, Externalising). Subsequent Bayesian analysis of covariance (ANCOVAs) consistently favoured models that excluded traditional categorical diagnoses, suggesting that dimensional measures, especially Total Problems and Internalising, provided substantially greater predictive utility for ToM-related regional brain activation. Our findings challenge traditional categorical classifications in neurobiological research as they suggest that atypical mentalising might reflect a shared transdiagnostic vulnerability.

Background and Hypothesis Negative symptoms in schizophrenia spectrum disorder (SSD) are associated with poor functional outcomes and reduced quality of life; however, effective treatments remain limited. A better understanding of the underlying brain mechanisms is needed to develop better treatments. Neuroimaging studies implicate multiple brain networks in negative symptoms, though findings remain heterogeneous, potentially reflecting the multidimensionality of both symptoms and brain networks. Larger, more systematic dissections are required to identify the key hub(s) underlying negative symptoms. Study Design Structural MRI data from 394 participants (210 SSD, 184 healthy controls [HC]) were analyzed to identify cortical thickness and subcortical volume demonstrating both SSD-HC differences and associations with negative symptoms measured by the Brief Negative Symptom Scale (BNSS). Regions meeting both criteria were selected as seeds for resting-state functional connectivity analyses in 143 SSD patients to examine association with negative symptoms and their subdomains. Study Results The thalamus was the only region demonstrating significant structural abnormalities both in SSD and an association with BNSS total score (p-FDR<0.05). Functional-network-defined thalamic subregions were subsequently examined. Several thalamic hypoconnectivities were significantly corresponded with negative symptoms, involving thalamic subregions associated with the cortical default mode, somatosensory, medial temporal, and dorsal attention networks (p=0.001, corrected<0.05). Blunted affect showed the most extensive thalamic connectivity alterations, involving the striatum, cerebellum, and temporoparietal junction/superior temporal sulcus (TPJ-STS). Thalamic hypoconnectivity with TPJ-STS was also associated with overall negative symptoms and anhedonia. Conclusions This study identifies the thalamus as a central hub of negative symptom-related dysfunction in SSD and highlights specific thalamic subnetworks as potential targets for circuit-based interventions.

Background: Children of parents with schizophrenia (SZ) or bipolar disorder (BP) are at familial high risk (FHR) of developing severe mental illnesses. Based on findings in FHR populations and adults with SZ and BP, we hypothesized that children at FHR for schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) would show sex-specific differences in subcortical grey matter volume, particularly in the thalamus, amygdala, and hippocampus, compared with population-based controls (PBC). Methods: We examined eight major subcortical grey matter structures in 108 FHR-SZ, 69 FHR-BP, and 120 PBC children aged 11-12 years from the Danish High Risk and Resilience Study. Structural magnetic resonance imaging (MRI) was used to estimate subcortical volumes and R1, a measure of myelin, iron, water, and macromolecular content. Sex-specific group differences were tested across regions. Results: The thalamus and amygdala, but not hippocampus, showed sex-specific group differences in volume. FHR-SZ males showed smaller thalamic volumes than FHR-BP and PBC males, whereas FHR-BP females showed larger thalamic volumes compared with PBC females. FHR-BP males showed larger relative amygdala volumes (corrected for total brain volume) compared to PBC males. No significant differences were observed for subcortical R1. Conclusions: Children at FHR-SZ and FHR-BP exhibited sex-specific differences in subcortical brain volumes before the typical onset of SZ and BP. These differences may reflect early sex-specific neurodevelopmental correlates of familial risk and highlight the importance of modelling sex-specific effects in developmental neuropsychiatric research. Longitudinal studies are needed to determine how these volumetric differences evolve and whether they are associated with later clinical outcomes.

BackgroundSocial dysfunction is a major source of disability in schizophrenia, yet the neural mechanisms that contribute to impaired social understanding remain poorly understood. Converging evidence points to the role of the default mode network (DMN) in integrating social information over time to construct interpretations of social behaviors. Here, we tested the hypothesis that individuals with schizophrenia show reduced stimulus-driven coordination between brain regions within the DMN during free viewing of naturalistic social stimuli. MethodsA sample of 124 adults (schizophrenia: n=63; healthy controls: n=61) viewed naturalistic video clips during fMRI. Inter-subject functional connectivity (ISFC) was computed within the two groups. Group differences were identified via permutation testing. We also explored group differences in other brain networks to examine whether effects were specific to the DMN. ResultsIndividuals with schizophrenia showed weaker stimulus-driven coupling within the DMN compared to healthy controls, specifically between areas such as the parahippocampal gyrus, precuneus, and medial prefrontal cortex. Group differences in ISFC were specific to the DMN. Furthermore, no between-group differences emerged for within-participant functional connectivity in the DMN, suggesting that the observed effects reflect reduced stimulus-driven coordination among DMN regions when processing social stimuli rather than a more general decline in DMN connectivity. ConclusionsSchizophrenia is characterized by impaired coordination within the DMN as it dynamically integrates social information over time, which could contribute to difficulties in constructing coherent interpretations of real-world social situations. These findings suggest that disrupted stimulus-driven network coordination might underlie social cognitive impairments in schizophrenia, highlighting the value of naturalistic paradigms for revealing network-level dysfunction under conditions that closely approximate real-world experience.

Background: Schizophrenia Spectrum Disorders (SSD) is associated with spatially heterogeneous structural abnormalities across distributed brain systems, but the longitudinal evolution and neurochemical context of subcortical subregional changes remain poorly understood. We investigated longitudinal volume changes across thalamic, hippocampal, amygdalar, and brainstem subregions and their relationships with clinical characteristics and normative neurotransmitter distribution. Methods: A total of 357 SSD individuals with first-episode and 196 healthy controls were included. Clinical assessments were performed at baseline and at 1, 3, 5, 10, 15, and 20 years of follow-up. Using T1-weighted structural MRI, subregional volumes were quantified across the thalamus, hippocampus, amygdala, and brainstem. We examined baseline group differences, longitudinal volume changes, and associations with clinical variables, including symptom severity. Spatial patterns of regional associations were compared with normative maps of neurotransmitter receptor and transporter distributions. Results: Patients showed heterogeneous structural alterations across the examined subcortical subregions. The hippocampus showed prominent early volume deficits in specific subfields and demonstrated a strong association with antipsychotic medication doses. Amygdalar volumetric reductions were more widespread and were strongly associated with positive symptom severity. Localised structural abnormalities were also observed in the thalamus and brainstem, although these showed weak associations with clinical symptomatology. The spatial co-location of normative neurotransmitter maps with the structural and clinical associations revealed distinct overlapping with dopaminergic, GABAergic, glutamatergic, serotonergic and cholinergic systems. Conclusions: Longitudinal structural alterations in SSD showed marked anatomical heterogeneity across thalamic, limbic, and brainstem systems. Their spatial correspondence with normative neurochemical architecture suggests that regional and subregional structural vulnerability and clinical heterogeneity may be organized along distinct, partially overlapping neurotransmitter profiles.

Background and Hypothesis: Although psychotic disorders are characterized by widespread cortical thinning, translating these findings into individualized biomarkers remains challenging. Regional Vulnerability Index (RVI) and Neuroscore are candidate individual-level biomarkers that quantify the similarity between an individual's structural brain pattern and generic psychosis-associated alterations. This study investigated cortical thickness (CT)-based RVI and Neuroscore, along with mean CT deviation from healthy individuals, across the psychosis spectrum. Study Design: Using structural 3T MRI data from 289 participants (clinical high risk for psychosis [CHR], n=39; first episode psychosis [FEP], n=44, chronic psychosis [CP], n=86; healthy controls [HC], n=120), RVI, Neuroscore, and mean CT deviation (z) scores were computed from region-wise CT measures quantified using FreeSurfer v7.2. Group differences and associations with symptoms were evaluated. Study Results: RVI and Neuroscore were significantly higher, and mean CT z-scores lower, in FEP and CP compared with CHR and HC, with moderate-to-large effect sizes (|Cohen's d| = 0.55-1.15). No differences were observed between FEP and CP or CHR and HC. Indices were not associated with psychosis-spectrum symptom severity in the CHR, FEP, or CP groups. RVI (r = -0.561, p < .001) and Neuroscore (r = -0.997, p < .001) were strongly negatively correlated with the mean CT z-score. Conclusions: CT-based RVI and Neuroscore appear to index established disease status but not risk status, while showing substantial overlap with mean CT deviation. These findings highlight the need to further refine these biomarkers through data-driven and multimodal approaches to improve their utility for risk and prognostic prediction.

Schizophrenia may involve a fundamental disruption in the ability to construct a shared understanding of social reality, yet conventional neuroimaging studies have largely examined social cognition using simplified and highly structured paradigms that may not capture how individuals interpret complex and ambiguous interpersonal events in everyday life. Using an ecologically valid naturalistic fMRI paradigm, we examined shared and paranoia-related neural representations during ambiguous social narrative processing in 38 patients with schizophrenia and 46 healthy controls. Intersubject correlation was used to quantify neural convergence across individuals, whereas intersubject representational similarity analysis was used to examine how individual differences in paranoid ideation were reflected in neural representations. Compared with healthy controls, patients with schizophrenia showed reduced neural convergence within distributed systems supporting social inference, contextual integration, and salience attribution, including temporoparietal, temporal, insular, and inferior frontal regions. Furthermore, paranoid ideation was associated with altered neural representational structure. In healthy controls, higher paranoia was linked to reduced neural similarity across social-cognitive and affective regions, suggesting reduced convergence toward shared interpretations of ambiguous social information. In schizophrenia, paranoia-related representations showed sparse within-group associations but elevated patient-control differences across a distributed social-affective circuit, indicating a reorganization rather than a simple amplification of paranoia-related processing. Together, these findings demonstrate that schizophrenia involves both impaired alignment of neural responses during shared social meaning construction and organization of paranoia-related representations, providing an ecologically grounded framework for understanding abnormal social inference in psychosis.

Monoamine oxidase B (MAO-B) is a high-density protein located mainly in astrocytes that influences mitochondrial function and transition to astrogliosis. MAO-B produces hydrogen peroxide while metabolizing non-serotonergic monoamines. Elevated MAO-B level is implicated in the pathophysiology of several common neuropsychiatric diseases. The aims are to examine the effect of treatment resistant major depressive episodes, sex, and antidepressant treatment on MAO-B total distribution volume ([11C]SL25.1188 VT), index of MAO-B level. [11C]SL25.1188 PET was applied in 95 adults (29 with MDE and no history of treatment-resistance (NTR-MDE), 26 with MDE and history of treatment-resistance (TRD), and 40 healthy control (HC)). A subset of NTR-MDE and TRD (n=13) were scanned before and after treatment with phenelzine, rasagiline, or duloxetine. [11C]SL25.1188 VT was higher in grey matter regions in females (10%, p<.001). [11C]SL25.1188 VT was also higher in prefrontal cortex in TRD compared to HC (23%, p<.001) and TRD compared to NTR-MDE (6%, p=.033). Duloxetine had minimal effect on [11C]SL25.1188 VT, but occupancy of rasagiline and phenelzine was ~94%. This study discovered sex differences in MAO-B level, which may explain sex differences in prevalence or trajectory of illnesses with greater MAO-B level like Alzheimer's disease, traumatic brain injury and major depressive disorder. Given our findings of greater MAO-B level in prefrontal cortex of TRD and its insensitivity to serotonin reuptake inhibition, combined with potential harm of highly elevated MAO-B level, development of MAO-B inhibitors could be considered for a subset of TRD. Rasagiline and phenelzine demonstrate similarly potent occupancy in vivo at clinical dosage.

Gambling disorder (GD) is a behavioural addiction that may help identify addiction-related neural features without the direct neurobiological effects of a primary substance of dependence. We examined regional grey matter volume (GMV) and resting-state functional connectivity (rsFC) in the same well-characterised sample. Eighteen men with GD and 21 matched healthy controls underwent high-resolution structural and resting-state functional MRI. GMV was quantified across 214 cortical and subcortical regions, and seed-based rsFC analyses focused on striatal subdivisions and mesocorticolimbic regions. Group differences were evaluated using permutation testing and cluster-corrected mixed-effects modelling. GD was associated with lower GMV in the ventromedial prefrontal cortex, orbitofrontal regions and other cortical and subcortical areas, alongside higher GMV in a subset of limbic and default-mode regions. Participants with GD also showed lower connectivity between the limbic striatum and the hippocampus, thalamus and putamen. In exploratory analyses, somatomotor connectivity was positively associated with gambling severity (Problem Gambling Severity Index: Spearman's rho = 0.71, p = 0.003, false-discovery-rate-adjusted q = 0.016). Structural and functional findings overlapped spatially in regions associated with valuation, memory, reward and habit formation, but regional GMV did not mediate group differences in rsFC. These findings are broadly consistent with corticostriatal models of GD and identify candidate circuit-level differences for independent replication. Larger, more diverse and longitudinal samples are required to establish their reproducibility, temporal direction and clinical relevance.

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.

**Importance** Average gray matter volume (GMV) loss in early psychosis may conceal clinically relevant differences in brain change. **Objective** To identify longitudinal GMV-change patterns, their cross-site correspondence, and clinical associations. **Design, Setting, and Participants** Prospective cohort with T1-weighted MRI acquired during 2011-2026 at 2 Czech sites; median follow-up, approximately 13 months. Participants were 222 patients with first-episode schizophrenia-spectrum psychosis and 178 healthy controls frequency-matched by site and baseline age. **Exposure** First-episode psychosis vs healthy control status. **Main Outcomes and Measures** Diagnosis-blind clustering by site of image-quality-corrected, subsequently annualized GMV change across 333 cortical parcels; longitudinal voxel-based morphometry (VBM); Global Assessment of Functioning and consensus 5-factor Positive and Negative Syndrome Scale negative-symptom scores. **Results** Among 400 participants (mean [SD] age, 28.2 [7.5] years), 208 (52.0%) were male. Each site independently yielded 3 clusters: C1 (near-stable GMV), C2 (pronounced decrease), and C3 (increase). Cross-site centroid correlations across 333 parcels were strong for C2 and C3 (Spearman rho = 0.865 and 0.861); C1 correlation was weak (rho = 0.138), as expected for near-zero profiles with little regional variation. C2/C3 correspondence supported pooling matched site-specific clusters for post hoc analyses. Pooled clusters contained 77 patients and 125 controls in C1, 66 patients and 16 controls in C2, and 79 patients and 37 controls in C3. Suffixes -P and -HC identify patient and control subgroups. To situate patient changes relative to controls, post hoc VBM revealed an unanticipated gradient of increasingly pronounced GMV reduction across C1-HC to C1-P to C2-P, prominently involving association cortex, and bilateral ventral temporal GMV increase in C3-P (familywise error-corrected P < .05). The opposite contrast along this ordering showed periventricular changes consistent with progressively greater ventricular enlargement. C2-P had the lowest mean follow-up functioning and highest mean negative-symptom severity (adjusted omnibus P = .005 and .02); clinical changes from baseline did not differ significantly among patient groups. **Conclusions and Relevance** Early GMV change in psychosis was not uniform but comprised two contrasting directions: a clinically relevant, control-anchored pattern of increasingly pronounced GMV loss involving default mode regions and a distinct, directionally opposing ventral temporal increase.

Importance: Anhedonia, social withdrawal and executive deficits represent transdiagnostic symptoms in depression, schizophrenia and addition, yet transdiagnostic brain volumetric alterations and their contribution to these symptom domains have not been systematically characterized. Objective: To determine common and disorder-specific gray matter deficits in patients with schizophrenia (SZ), major depression disorder (MDD) and alcohol use disorder (AUD) compared to heathy controls. Data Sources: A comprehensive literature search using three databases including PubMed, Web of Science and PsycInfo (between January 2000 to March 2024) as well as searches on review articles. Study Selection: Studies had to be published in English, reporting whole-brain results, comparing patients and healthy controls. Data Extraction and Synthesis: This meta-analysis adhered to the PRISMA guidelines and was pre-registered (https://osf.io/s57uq) prior to data analysis. Data was independently extracted and verified by 3 contributors, and statistical brain maps were generated using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) random-effects model. 147 VBM studies encompassing 90 Schizophrenia, 44 MDD and 13 AUD studies were finally included. Main Outcomes and Measures: Statistical maps of common and disorder-specific gray matter deficits in patients versus healthy controls are presented. Statistical inference utilized permutation tests, with threshold at p < .0025 and cluster extent of 10 voxels. Heterogeneity was evaluated using the I2 statistic and publication bias using Eggers regression test. Results: Capitalizing on a coordinate-based meta-analysis involving n=13,041 participants, we found shared GMV alterations in the ventromedial prefrontal cortex, ventral anterior cingulate cortex, insula, superior temporal gyrus. On the network level, we found robust functional interactions of the identified shared regions with the cortical midline structures as well as social and theory of mind-related behavioral functions. Subsequent characterization analyses highlighted the involvement of dopaminergic and serotonergic neurotransmitters as well as associated genetic annotations. Conclusions and Relevance: Overall, the present meta-analysis found common as well as separate GMV abnormalities in schizophrenia, major depressive disorder and alcohol use disorder suggesting a common neurostructural substrate and treatment target for social withdrawal and anhedonia across these disorders. Keywords: alcohol-use disorder, depression, meta-analysis, schizophrenia, voxel-based morphometry

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: Approximately 25% of individuals with 22q11.2 deletion syndrome (22q11DS) develop a psychotic disorder, and the syndrome shares key neurodevelopmental features with psychosis in the general population. The olfactory system develops early in utero, providing a window into gestational disruptions relevant to psychosis risk. We hypothesized that 22q11DS would show impairments in olfactory function and structural anomalies of the olfactory system relative to psychosis spectrum (PS) youth without a known genetic syndrome and typically developing controls (TD). Methods: Participants included individuals with 22q11DS (n=101), PS (n=56), and TD (n=52). Sinonasal symptoms, odor identification, and discrimination (Sniffin' Sticks) behaviorally. Structural 3T MRI measured olfactory bulb volume, sulcus depth, and sulcus length. Sample sizes vary per analysis. Results: Relative to TD, 22q11DS showed elevated sinonasal burden (p<.001), lower odor identification (p<.001), and lower odor discrimination (p<.001). PS showed elevated sinonasal burden (p<.001) and marginally lower odor identification (p=.06), but no discrimination deficit. Olfactory bulb volume was significantly smaller in 22q11DS versus TD (p=.007, r=.39); PS showed a non-significant trend (p=.07). Olfactory sulcus depth (p=.52) and length (p=.82) did not differ across groups. Conclusions: 22q11DS is associated with elevated sinonasal burden, robust olfactory identification and discrimination deficits exceeding those of PS and reduced olfactory bulb volume. The co-occurrence of functional deficits and reduced bulb volume without sulcal anomalies may distinguish the 22q11DS olfactory phenotype from that of PS. These hypothesis-generating findings are consistent with partially dissociable neurodevelopmental mechanisms and support the utility of 22q11DS as a genetic model for psychosis risk.

Treatment resistance in obsessive-compulsive disorder (OCD) is common, with 40-60% of patients failing to respond to pharmacotherapy. Identifying functional differences between responders and non-responders may guide alternative treatment strategies. We investigated resting-state brain differences between selective serotonin reuptake inhibitor (SSRI) responders and non-responders and compared them with healthy controls (HC). 3T MRI scans were acquired from 80 participants with OCD and 50 HCs. Structural and 5-minute resting-state data were processed using the CONN toolbox. Regions showing group differences in amplitude of low-frequency fluctuation (ALFF) were identified for seed-based connectivity analysis. ANCOVA revealed significant ALFF differences among groups in the anterior middle temporal gyrus (R-aMTG) and temporal pole (R-TP). SSRI responders showed reductions in seed-to-voxel connectivity than non-responders between these regions and the left superior and inferior occipital cortices, left superior parietal lobule, and left temporo-occipital middle temporal gyrus. Responders also showed reductions in connectivity with the left superior parietal lobule compared with HCs. Across the OCD group, Y-BOCS scores positively correlated with ALFF in the R-aMTG (p=0.008) and R-TP (p=0.044). Altered temporal cortical activity and connectivity with posterior regions were associated with SSRI treatment response, supporting a role for temporal-posterior cortical networks in OCD treatment response.

BackgroundIndividuals with early psychosis (EP) have elevated risk for suicide, the leading cause of death in the first five years following diagnosis. Non-suicidal self-injury (NSSI) significantly predicts suicidal behavior, yet studies of self-injury often exclude participants with psychosis. We investigated effective connectivity in emotion regulation and reward network regions among participants with lifetime history of NSSI or suicide attempt (SA) with and without EP. MethodsResting-state fMRI data were acquired for 23 individuals with EP and 34 non-clinical controls (NCC). We estimated effective connectivity models for regions implicated in the self-injury literature: middle cingulate cortex (MCC), posterior cingulate cortex (PCC), caudate, putamen, posterior superior temporal gyrus (STG), orbitofrontal cortex (OFC), and insula. There were 3 models characterizing different groupings: diagnosis (NCC vs. EP); NSSI (present[+], n=21 vs. absent[-], n=36); and SA (present[+], n=21 vs. absent[-], n=36). ResultsEP was associated with increased STG to PCC and insula to putamen connectivity. NSSI+ (n=7 NCC, 14 EP) had increased PCC to insula lagged connectivity and increased contemporaneous bilateral putamen activity, relative to NSSI- (n=27 NCC, 9 EP). NSSI was positively correlated with lagged insula to putamen activity (p=0.016). SA and NSSI were associated with reduced PCC to caudate connectivity. ConclusionNSSI is associated with increased connectivity within emotion regulation regions and disrupted connectivity between emotion regulation and reward networks modulated by the STG and striatum. Findings are consistent with broader self-injury literature, supporting the utility of using similar interventions from other disorders to address self-injury within EP.

Altered white matter microstructure, commonly indexed by fractional anisotropy (FA), has been reported in individuals at clinical high-risk of psychosis (CHR-P) across multiple white matter tracts. However, the relationship between these alterations and later transition to psychosis remains unclear. To address this gap, we investigated whether baseline and longitudinally updated FA measurements were associated with risk of transition to psychosis in a large cohort of individuals at CHR-P. We analysed diffusion tensor imaging data from N = 205 participants at CHR-P, 23 of whom developed psychosis within 3 years of follow-up. Data were collected at baseline, 6 months, and 12 months. Associations between global and tract-specific FA and transition risk were examined using Cox proportional hazards models of baseline data and longitudinally updated data. Point estimates were directionally consistent, with hazard ratios <1 for FA across all white matter tracts in both baseline and longitudinal models. Associations reached nominal significance in the hippocampal cingulum, anterior thalamic radiation, and forceps minor, but none of these remained significant after correcting for multiple comparisons (pcorr > .05). The directionally consistent estimates are compatible with small, distributed effects across multiple white matter pathways being associated with transition to psychosis, although this requires replication. Longitudinally updated FA measurements did not yield stronger associations than were available from baseline imaging data alone. Studies at an even larger scale are needed to establish whether these associations are robust and clinically meaningful.

Dysfunctions in reward circuits, including projections from the orbitofrontal cortex (OFC) to the nucleus accumbens (NAcc), have been implicated in psychopathology. The OFC is functionally divided into the medial OFC (mOFC), which processes rewards, and the lateral OFC (lOFC), which responds to non-reward or punishment stimuli. We investigated the structural connectivity of the lOFC-NAcc and mOFC-NAcc pathways and their associations with psychopathological traits using tractography-defined ROI analysis. Diffusion-weighted imaging data from 165 participants (aged 22 - 35, 53% male) in the Human Connectome Project (HCP) were analysed using spherical deconvolution tractography. MegaTrack, a novel tool, enabled tract segmentation via a single manual dissection mapped back to native space. Virtual dissection identified four bilateral pathways connecting the lOFC and mOFC to the NAcc, from which fractional anisotropy (FA) was extracted, and an lOFC/mOFC ratio was computed. Psychopathological traits were measured using HCP Achenbach Adult Self-Report scores. The lOFC-NAcc pathway showed positive associations with psychopathology and the mOFC-NAcc pathway negative associations. The lOFC/mOFC ratio emerged as a stronger predictor than individual pathways, with significant associations for depression, somatic problems, anti-social personality traits, and inattention. Effects were lateralized to the left hemisphere. These findings show that the lOFC-NAcc and mOFC-NAcc pathways can be structurally separated with tractography and display opposing correlations with psychopathological traits in a healthy population. Their ratio may index reward-processing dysfunction, and future research should test whether it is sensitive to dysfunction in clinical populations.