Psychiatry Research: Neuroimaging

Recent developments in acquisition and reconstruction of 3-dimensional magnetic-resonance spectroscopic imaging (3D-MRSI) enable the high-resolution mapping of multiple neurometabolites in the whole-brain, in vivo. Leveraging this capability, we created a voxel-based pipeline that corrects and spatially normalizes whole-brain maps of total N-acetylaspartate (tNAA), myo-inositol (Ins), choline compounds, glutamate + glutamine, and creatine + phosphocreatine. We examined a clinical cohort of adolescents and young adults at risk for psychosis (n= 21) --meeting DSM-5 criteria for Attenuated Psychosis Syndrome (APS)or Schizotypal Personality Disorder (SCZT)-- and age-/sex-matched healthy controls (n =13), as well as an independent non-clinical sample of adolescents (n = 61). We first aimed at assessing the reproducibility of MRSI measures across datasets and scanning sites, then validate the feasibility of a whole-brain voxel-based analyses on 3D-MRSI data and eventually test the sensitivity of this approach. Metabolite distributions showed reproducible regional variation in standard space between the two independent samples and scanning sites (r ranging from 0.82 to 0.99). Relative to controls, at-risk participants exhibited higher tNAA in frontal grey matter; the SCZT subgroup additionally displayed widespread cortical and subcortical Ins elevations compared with both APS and controls. Voxel-based analyses of structural (i.e., gray and white matter volumes or densities) and dijusion (i.e., generalized fractional anisotropy) parameters yielded no significant dijerences between risk participants and controls. These findings suggest the sensitivity of high-resolution 3D-MRSI for detecting subtle neurometabolic alterations at the group level in the early stages of psychotic disorders. Detailed brain metabolic mapping has the potential to help with early identification of young people at risk for psychosis or other mental disorders.

BackgroundSchizotypy (ST) reflects subclinical traits linked to schizophrenia spectrum disorders and associated cognitive and social impairments. Theory of Mind (ToM) and discourse production deficits are well-documented in schizophrenia (SZ), yet the neural basis of discourse-related ToM processes in ST remains unclear. This study investigated brain activation during narrative planning and production in individuals with schizotypal traits. MethodsThirty young adults (mean age = 18.8 years) completed standardized assessments, including the Schizotypal Personality Questionnaire-Brief Revised (SPQ-BR), adverse childhood experiences (ACEs), depression (PHQ-9), and dissociation (DES-B). Participants performed a discourse task in an fMRI scanner, describing nine-panel cartoons requiring inference of character intentions. Behavioral discourse metrics included total and inferred events. fMRI analyses examined activation during planning and production phases, with SPQ-BR positive, negative, and disorganized traits entered as regressors. ResultsSchizotypal traits correlated with multiple psychosocial risk factors, including elevated depression, ACEs, and dissociation (r = .48-.82, p < .01). During planning, canonical ToM/self-referential regions (vmPFC, precuneus, insula) were recruited. Positive traits correlated with increased activation in the right temporo-parietal junction, precuneus, and lingual gyrus, whereas disorganized traits were associated with reduced activation in the precuneus and lingual gyri. During production, networks spanning vmPFC, hippocampus, right TPJ, and basal ganglia were engaged. Negative traits correlated with increased motor/premotor activation, while disorganized traits correlated with reduced activation in lingual gyrus, SMA, and cerebellum. ConclusionsFindings demonstrate distinct neural correlates of schizotypal traits during discourse planning and production, supporting models of schizophrenia-spectrum risk emphasizing disrupted inference and integration processes.

ObjectiveThe pathophysiology of psychosis remains unclear. Preclinical, postmortem, and imaging evidence implicates iron and neuromelanin, but the consistency and magnitude of effects are uncertain. We aimed to characterise brain iron and neuromelanin alterations in psychosis through a systematic review and meta-analysis of iron-sensitive MRI and neuromelanin-sensitive MRI (NM-MRI) studies. MethodsWe searched EMBASE, PubMed, and PsycINFO from inception to October 31, 2025, for case-control studies using iron-sensitive MRI or NM-MRI in patients with psychosis. We used random-effects models to calculate effect sizes (Hedges g) and meta-regressions to examine clinical confounders. The primary outcomes included effect sizes for NM-MRI and iron-sensitive MRI measures--transverse relaxation rate (R2), effective relaxation rate (R2*), and quantitative susceptibility mapping (QSM). ResultsTwenty-seven reports, including 879 individuals with psychosis and 813 controls, were analysed. Meta-analyses were conducted across the caudate nucleus, putamen, globus pallidus, thalamus, and substantia nigra. In psychosis, R2* was significantly lower across all examined regions (g= -0.27 to -0.40), QSM values were lower in the substantia nigra (g= - 0.61; 95% CI, -0.84 to -0.38), and R2 was lower in the caudate nucleus (g= -0.30; 95% CI, - 0.56 to -0.04). NM-MRI values in the substantia nigra were significantly higher (g= 0.39; 95% CI, 0.23 to 0.55), though this effect strongly correlated with chlorpromazine daily equivalent dose ({beta}= 0.001; 95% CI, 0.0003 to 0.0018), suggesting medication-related effects. ConclusionsPsychosis is associated with lower subcortical iron-sensitive MRI values. This was most marked in the substantia nigra, where NM-MRI values--which index neuromelanin-bound iron in dopamine neurones--were significantly higher. This suggests that while subcortical iron is overall lower in psychosis, neuromelanin-bound iron is increased within dopamine neurones. Investigating the mechanisms underlying iron alterations may provide new treatment targets.

IntroductionBipolar Disorder (BD) is characterized by marked disruptions in emotional regulation and cognitive control, often accompanied by structural abnormalities in the brains white matter. Diffusion tensor imaging (DTI) offers a window into white matter microstructure through metrics such as fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD). This study aimed to examine white matter tract alterations in individuals with BD compared to healthy controls (HCs) and to explore potential associations between DTI metrics and clinical symptom severity. MethodsWe conducted a voxel-wise whole-brain DTI analysis in a sample of BD patients and age-matched HCs, focusing on FA, MD, RD, and AD values. Group comparisons were performed to identify significant differences in white matter integrity. In addition, we assessed correlations between DTI metrics and psychological assessment scores to investigate links between structural alterations and clinical features. ResultsCompared to HCs, BD patients exhibited significantly lower FA in several major white matter tracts, including the cingulum (olfactory tract), forceps minor of the corpus callosum, fornix, inferior fronto-occipital fasciculus, and superior longitudinal fasciculus. These reductions suggest disrupted microstructural coherence. In parallel, elevated MD, RD, and AD in overlapping regions point to possible myelin degeneration or axonal injury. However, associations between DTI metrics and psychological symptom scores were weak and did not reach statistical significance. Discussion/ConclusionThese findings reinforce the presence of widespread white matter abnormalities in BD, particularly in tracts relevant to emotional and cognitive processing. While structural disruptions were evident, their weak correlations with symptom severity highlight the complex relationship between brain microstructure and clinical expression in BD. Future studies are warranted to clarify the diagnostic and prognostic relevance of DTI-based biomarkers in mood disorders.

Schizophrenia is associated with altered Amplitude of Low Frequency Fluctuations (ALFF), a functional Magnetic Resonance Imaging (fMRI) measure of spontaneous brain activity at rest. ALFF in healthy controls has been linked with presynaptic density levels measured by [11C]UCB-J positron emission tomography (PET). Given the growing body of evidence for low presynaptic density levels in schizophrenia, we set out to test if altered [11C]UCB-J binding may be associated with changes in ALFF in schizophrenia, and secondly to test whether the relationships between ALFF and [11C]UCB-J binding differ at the group level. Subjects with schizophrenia had higher ALFF in the medial prefrontal cortex and other regions, in line with published meta-analyses. In control subjects, there was a significant positive relationship between [11C]UCB-J distribution volume ratio (DVRcs) and ALFF in the medial prefrontal cortex (r=0.54, p=0.0365, n=16), but not in subjects with schizophrenia (r=-0.14, p=0.5564, n=22); r-coefficients significantly differed between groups (Zobserved=2.07, p=0.019). At the whole brain level, there were significant positive correlations between [11C]UCB-J DVRcs and ALFF in control subjects in the putamen, insular cortex, precentral gyrus and occipital regions, while in the schizophrenia group, there were significant positive correlations in the bilateral dorsolateral prefrontal cortex and negative correlations in the cuneus, parietal lobule and supramarginal gurus. Correlation coefficients were significantly different between groups across all cortical and subcortical regions with both higher and lower correlation coefficients in the control group. Our results suggest a link between spontaneous brain activity and presynaptic density in control subjects and that this relationship may be disrupted in schizophrenia patients, despite higher ALFF in this group, indicating altered neurobiological mechanisms. Widespread significant differences in ALFF-[11C]UCB-J DVRcs correlation coefficients between controls and schizophrenia subjects highlight the complexity of synaptic dysfunction in schizophrenia and underscore the need for further research to explore the underlying biological mechanisms.

BackgroundTreatment-resistant depression (TRD) poses a significant clinical challenge, demanding a deeper understanding of its neurobiological underpinnings to improve therapeutics. We examined white matter microstructure and structural connectivity in TRD, focusing on the subjective valuation network (SVN), which captures motivated behavior, reward processing, and emotional regulation circuits commonly altered in depression. This allowed us to identify potential neuroimaging biomarkers associated with treatment resistance. MethodsDiffusion tensor imaging (DTI) data were acquired from a sample of age-and-gender balanced individuals with TRD (n=44; female = 24, male=11, non-binary/unchecked =7) and non-depressed controls (n=42; female=27, male =12, non-binary/unchecked=5). Tract-Based Spatial Statistics were used to compare whole-brain white matter integrity differences between groups. Probabilistic tractography was then used to assess fractional anisotropy (FA) and white matter structural connectivity within the SVN across groups. SVN was defined a priori based on converging functional connectivity studies and included key regions such as the ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), ventral striatum, and insula and their connecting white matter tracts. Additionally, correlations between clinical measures of depression severity and cognition and structural features of the networks white matter fibers (i.e. FA and structural connectivity) were explored. ResultsCompared to non-depressed controls, individuals with TRD exhibited reduced FA within the left uncinate fasciculus, left inferior fronto-occipital fasciculus, and anterior cingulum, supporting widespread white matter integrity degradations in TRD. No correlations were found between FA and depression severity, suggesting a more specific association with anhedonic features. Whole-network measures of FA and structural connectivity of the SVN did not differ between groups. However, specific subcircuits structural connectivity within the SVN differed between groups; namely, the white matter tracts connecting the insula-vmPFC, striatum-insula, and striatum-vmPFC. Hyperconnectivity emerged for patients with TRD for tracts connecting the insula-vmPFC and striatum-vmPFC region-pairs, with exhibited hypoconnectivity between the striatum-insula. Exploratory analyses for the TRD group indicated the subcircuits with altered structural connectivity within the SVN correlated with depressive severity. This indicates subcircuit network alterations may associate with greater difficulty experiencing pleasure - a core symptom of depression and a potential marker of treatment resistance. ConclusionsThis study provides evidence for wide-spread disruption of white matter microstructure and altered structural connectivity within specific subcircuits of the SVN in TRD. These findings point to an intricate pattern of structural hyper-and-hypo-connectivity within the subcircuits of the SVN which may underlie the core symptoms of TRD. The altered structural connectivity within the SVN may contribute to the pathophysiology of TRD, especially concerning the motivational and emotional deficits associated with anhedonia. Future research employing multimodal neuroimaging techniques and longitudinal designs is warranted to further elucidate the functional consequences of these structural abnormalities and their potential as predictive biomarkers for personalized treatment interventions in TRD. Specifically, investigating how these white matter alterations change with successful treatment or targeted interventions aimed at improving anhedonia could inform more effective therapies for this challenging condition.

Treatment response in schizophrenia is heterogeneous and has been posited to divide into three distinct subcategories: treatment-responsive (first-line responders; FLR), treatment-resistant (TRS, responding to clozapine), and ultra-treatment-resistant schizophrenia (UTRS, requiring augmented antipsychotic therapy). Previous work suggests that white matter abnormalities drive antipsychotic resistance but little work has been carried out to identify differences between those with TRS and those with UTRS. The current study aimed to establish whether differences in white matter structure are present across both treatment-resistant subtypes of schizophrenia or if UTRS is distinct from TRS. Diffusion-weighted images were acquired for 18 individuals with TRS, 14 with UTRS, 18 FLR and 20 healthy controls. Measures of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and parallel diffusivity (PD) were obtained using tract-based spatial statistics. Analysis of variance (ANOVA) and post-hoc between-groups t-tests interrogating differences were conducted for each white matter measure. Those with TRS had lower FA than healthy controls across widespread regions of the brain, including the superior longitudinal fasciculus, corpus callosum, thalamic radiation, corticospinal tract, internal capsule, corona radiata and fronto-occipital fasciculus (p<.05 FWE-corrected). Lower FA was also observed in those with TRS compared with UTRS in the superior longitudinal fasciculus (p<.05 FWE-corrected). However, post-hoc tests failed to survive corrections for multiple comparisons across the 12 post-hoc contrasts. No differences in MD, PD or RD were observed between groups. These data suggest that TRS is distinct from UTRS and that lower FA could act as a biomarker of treatment resistance in people with schizophrenia.

BackgroundAlthough enlargement of the lateral ventricles was previously observed in individuals with mood disorders, the link between ventricular size and asymmetry with other indices of brain structure remains underexplored. In this study, we examined the association of lateral ventricular size and asymmetry with cortical myelin content in individuals with bipolar (BD) and depressive (DD) disorders compared to healthy controls (HC). MethodsMagnetic resonance imaging (MRI) was used to obtain T1w and T2w images from 149 individuals (age=27.7 (SD=6.1) years, 78% female, BD=38, DD=57, HC=54). Cortical myelin content was calculated using the T1w/T2w ratio. Elastic net regularized regression identified brain regions whose myelin content was associated with ventricular size and asymmetry. A post-hoc linear regression examined how participants diagnosis, illness duration, and current level of depression moderated the relationship between the size and asymmetry of the lateral ventricles and levels of cortical myelin in the selected brain regions. ResultsIndividuals with mood disorders had larger lateral ventricles than HC. Larger ventricles and lower asymmetry were observed in individuals with BD who had longer lifetime illness duration and more severe current depressive symptoms. A greater left asymmetry was observed in participants with DD than in those with BD (p<0.01). Elastic net revealed that both ventricular enlargement and asymmetry were associated with altered myelin content in cingulate, frontal, and sensorimotor cortices. In BD, but not other groups, ventricular enlargement was related to altered myelin content in the right insular regions. ConclusionsLateral ventricular enlargement and asymmetry are linked to myelin content imbalance, thus, potentially leading to emotional and cognitive dysfunction in mood disorders.

Large-scale mega-analyses of worldwide combined Magnetic Resonance Imaging (MRI) studies have demonstrated brain differences between individuals with mental disorders and controls. However, the potential of large-scale observational studies using population-based clinical MRI data remains unexplored. We analyzed clinical MRI data from 23,545 patients in the Eastern half of Denmark (Capital Region of Denmark and Region Zealand). 2,774 patients with mental disorders and 2,062 non-psychiatric controls fulfilled our inclusion and exclusion criteria. Patients with mental disorders exhibited smaller thalamic (d=-0.298) and amygdala volumes (d=-0.250), with larger ventricles (d=0.272), and thinner insula (d=-0.177), all p<0.0001. Analysis across all ROIs revealed a widespread pattern of thinner cortex (d=-0.180), especially in the temporal pole (d=-0.234) and superior frontal (d=-0.212) regions, and increased extracerebral cerebrospinal fluid (d=0.264). For volumetric measurements, findings were consistent across different inclusion and exclusion criteria but varied for cortical thickness measurements. Utilizing this currently largest population-based MRI cohort for mental disorders, we demonstrate that clinical MRI scans can detect brain structural differences among patients with mental disorders in real-world clinical settings, aiding in the stratification of patients without mental disorders. Cross-disorder analyses reveal shared neuroanatomical changes, including globally smaller brain volumes and thinner cortex. Integrating large-scale clinical MRI data with electronic health records holds promise for improved patient stratification and tracking of disease progression for future longitudinal cross-disorder studies, bridging real-world MRI data with clinical trajectories for further biological subgrouping.

IntroductionThe primary psychoactive component in marijuana is tetrahydrocannabinol (THC), which acts on receptors, such as cannabinoid 1 (CB1), that are distributed broadly throughout the brain. THC interferes with synaptic plasticity and neurogenesis and impacts the brains macrostructure, specifically white matter where CB1 receptors are abundant. The current study aims to investigate whether callosal morphology differs depending on how much experience individuals have with marijuana. MethodsThis is a quantitative between-group corpus callosum morphology analysis using cohort study data. The data for this study (n = 144) came from the S1200 Release from the Washington University - University of Minnesota Human Connectome Project Consortium (WU-Minn HCP). Marijuana use was quantified using self-reports and grouped as (1) no use, (2) low use, and (3) high use. T1-weighted MRI brain images were obtained and then processed using SPM12 and MATLAB. Each corpus callosum was manually traced and automatically separated into seven callosal areas according to the Witelson parcellation scheme. The resulting area measures were compared between the three groups, while covarying for total brain volume. ResultsOur ANCOVA analysis was significant (F(2, 145) = 4.38, p = .014), and posthoc tests revealed a significantly smaller anterior midbody in the high marijuana use group compared to the no marijuana use group (p = .012). ConclusionSmaller callosal areas in the high use marijuana group suggest that heavy cannabis may be related to weaker interhemispheric connectivity. Future research is required to replicate the current findings using well-powered designs.

The arcuate fasciculus (AF) has been implicated in the pathology behind schizophrenia and auditory verbal hallucinations (AVHs). White matter tracts forming the arcuate fasciculus can be quantified and visualized using diffusion tensor imaging (DTI) tractography. Although there have been a number of studies on this topic, the results have been conflicting. Studying the underlying white matter structure of the AF could shed light on functional connectivity between temporal and frontal language areas in AVHs. The participants were 66 patients with a schizophrenia diagnosis, where AVHs were defined from the Positive and Negative Syndrome Scale (PANSS), and compared with a healthy control group. DTI was performed on a 3T MR scanner, and tensor estimation was done using deterministic streamline tractography. Statistical analysis of the data showed significantly longer tracts along the AF in patients with severe and frequent AVHs, as well as an overall significant asymmetry with longer fibers on the left side. In addition, there were significant positive correlations between PANSS scores and tract length, tract volume, and number of streamlines for the posterior AF segment on the left side. It is concluded that the present structural results complement previous functional findings of fronto-temporal connectivity in AVH patients.

Finding reliable imaging biomarkers of mental illness has been a major challenge, on a par with the quest for biomarkers of the male versus the female brain, as the two types of imaging inform one another. We explored the hypothesis that the degree of coherence (internal isomorphism) between brain volumes of the left versus the right hemisphere for patients with psychopathological conditions follows the brain coherence pattern of the healthy male or healthy female. We developed the distance index (DI) as a biomarker of brain coherence and compared it with three ad hoc coherence measures. We found that only DI could reliably distinguish males from females and patients from controls. Also, cortical regions with highest DI scores were swapped between males and females across groups following male/female models of psychopathology. Furthermore, although indices were similar in predicting cognitive performance, DI provided a more proportionate prediction pattern across diagnosis groups, and more robust interactions with males/females. These findings highlight the importance of brain coherence, particularly measured by DI, for phenotyping sex and mental illness.

BackgroundThere has been increasing interest in the study of brain gyrification in schizophrenia since it may provide additional useful information on the cytoarchitecture and connectivity of the brain. Various methods have been developed to estimate brain gyrification that, so far, have yielded mixed and inconclusive results in schizophrenia studies. To the best of our knowledge, an alternative method to compute brain gyrification, known as surface ratio (SR), has not yet been applied to a schizophrenia sample. Our aim in this study was to assess whether SR could provide new insights on the brain structure of schizophrenia patients and the severity of symptoms. We also computed a more established brain gyrification measure, namely absolute mean curvature (AMC), for comparison. MethodWe processed and analyzed a total of 63 magnetic resonance images, 25 from schizophrenia patients with treatment-resistant auditory verbal hallucinations (SCH-H), 18 from schizophrenia patients without hallucinations (SCH-NH), and 20 from healthy controls (HC). We estimated brain gyrification with SR and AMC employing CAT software. ResultsThe SR measure mainly revealed that SCH-H patients had a more folded orbitofrontal cortex than SCH-NH patients and HC. Gyrification in this region was also negatively associated with positive symptoms, specifically with the delusions and conceptual disorganization items, only in the SCH-H group. Conversely, SCH-NH and HC showed more SR than SCH-H in other frontal areas. As for the AMC measure, we identified two areas where HC showed more gyrification than SCH-H patients, but no relationships arose with symptoms. DiscussionWe hypothesize that the hypergyrification of the orbitofrontal cortex displayed by SCH-H patients, as captured by the SR measure, suggests aberrant and/or excessive wiring in these patients, which in turn could give rise to auditory verbal hallucinations. Alternatively, we comment on potential compensatory mechanisms that may better explain the negative association between orbitofrontal gyrification and positive symptomatology. Importantly, the estimation of brain gyrification with the SR measure seems to capture the most relevant differences and associations, making it a promising biomarker in schizophrenia research.

The massa intermedia (MI) is a midline structure connecting the left and right thalamus that typically develops during the 2nd trimester of pregnancy. Missing and smaller MI has been linked to neurodevelopmental disorders, including schizophrenia (SZ), and subtle deficits in cognition. However, findings are inconsistent and the association between MI and other anatomical variants linked to atypical brain development in SZ, including incomplete hippocampal inversion (IHI), is unclear. Presence/absence and morphology of the MI were ascertained on structural T1-weighted MRI images obtained at 3T in SZ (n = 223) and healthy individuals (n = 194) and compared between groups. Associations between MI morphology, cognitive function, and incomplete hippocampal inversion (IHI) were assessed. Prevalence of missing MI was 1.7% and did not differ between groups. MI was significantly smaller in SZ (p <.001). However, follow-up analyses revealed that smaller MI size in SZ was due to a significant Diagnosis x Age interaction characterized by a stronger negative age effect in SZ. IHI was significantly more common in individuals with missing MI. Neurocognition was not correlated with MI size when controlling for age and diagnosis. Stronger effects of age on MI size in SZ suggests that abnormal MI size measured in adulthood may not be a reliable static indicator of atypical neurodevelopment, but may reflect disease progression or accelerated aging. Missing MI was rare in our sample. Conversely, missing MI is associated with IHI suggesting a shared neurodevelopmental disruption in the 2nd trimester.

In-scanner head motion is a recognized source of bias in structural magnetic resonance imaging (sMRI), yet it remains under-addressed in psychiatric neuroimaging where structural difference in patient populations are considered foundational. We examined motion-related bias in grey matter volume estimates across eight independent cohorts comprising 9,664 individuals, including 8,979 neurotypical controls (NC), 497 patients with schizophrenia (SCZ), and 188 patients with bipolar disorder (BD). Motion estimates were derived from multiple fMRI scans acquired within the same scanning session and summarized using principal component analysis. In NC, motion accounted for 1-6% of regional grey matter variance, a magnitude comparable to reported psychiatric case-control effect sizes. Adjusting for motion attenuated SCZ-NC group differences, reducing effect sizes in 85% of brain regions and yielding 5% fewer significant ROIs (pFDR<0.05). In BD, motion correction reduced effect sizes in 97% of regions, with a 24% reduction in significant ROIs. Cross-diagnostic spatial patterns were significantly correlated (r=0.63, p=3x10-{superscript 1}3), explaining a sizable portion of SCZ-BD commonalities. Critically, a falsification analysis in UK Biobank (N=5,123) showed that stratifying NC by motion alone produced grey matter differences accounting for 45-62% of SCZ case-control effect magnitude, underscoring how difficult it is to interpret SCZ-like morphometric differences as tissue properties rather than as motion-driven patterns. These findings urge caution in interpretations of sMRIdifferences in patient-control comparisons and use of systematic fMRI based motion control as standard practice in sMRI analyses.

Background and HypothesisIndividuals with schizophrenia spectrum disorders (SSD) often show diminished reward pursuit, whereas loss avoidance is relatively preserved. The neural mechanisms of this dissociation and its relation to negative symptoms remain unclear. We hypothesized that in SSD, cognitive resources are preferentially directed toward avoiding losses rather than pursuing rewards, potentially limiting reward processing and contributing to negative symptoms. Study DesignUsing computational modeling of behavior during a two-stage decision task which distinguished between goal-directed (model-based) and habitual (model-free) strategies under reward and loss conditions, we studied 42 stable individuals with SSD and 48 healthy controls (HC) during functional magnetic resonance imaging. Study ResultsIn individuals with SSD, model-based control was shifted toward loss avoidance relative to HC, with corresponding changes in prefrontal circuitry. In anterior cingulate, orbitofrontal, and dorsolateral prefrontal regions, individuals with SSD showed increased activation during model-based control in the loss condition. Within this group, loss-biased activation in the right anterior cingulate region was associated with anhedonia. In 25 patients with available follow-up data, loss-biased activation in the right anterior cingulate region at baseline was prospectively related to worsening of motivation and social engagement over the subsequent year. ConclusionsOur findings suggest that, compared to HC, those with SSD allocate their limited cognitive resources more toward loss avoidance relative to reward pursuit. The association between loss-biased anterior cingulate engagement and anhedonia supports a neurocomputational account of diminished pleasure in psychotic disorders, with potential implications for developing motivation-targeted treatments and early prediction of negative-symptom worsening.

Catatonia is a severe psychomotor syndrome that occurs across psychiatric diagnoses and is increasingly conceptualized as reflecting neurodevelopmental vulnerability. The anterior cingulate cortex (ACC) plays a central role in motor initiation and cognitive-affective integration and displays substantial interindividual variability in its sulcal morphology, which is established prenatally and remains stable across life. In this MRI study, we examined whether ACC sulcal patterns represent a structural trait marker of catatonia. We analyzed high-resolution T1-weighted images from a hospital-based cohort comprising patients with catatonia (N = 109), psychiatric patients without catatonia (N = 323), and healthy controls (N = 91). The presence of the paracingulate sulcus (PCS) in each hemisphere was determined through blinded visual inspection, and regression analyses tested associations with diagnostic group, adjusting for age, sex, scanner type, intracranial volume, and benzodiazepine and antipsychotic exposure. Patients with catatonia exhibited a significantly reduced prevalence of the left PCS and diminished hemispheric asymmetry compared with both non-catatonic patients and healthy controls. These effects were independent of whether catatonia occurred within psychotic or mood disorders. PCS size did not differ across groups, and sulcal pattern did not correlate with catatonia severity among affected individuals. The findings demonstrate that ACC sulcal deviations are specifically associated with catatonia across diagnostic categories, supporting a neurodevelopmental etiology and reinforcing ACC involvement in its pathophysiology. Early-determined sulcal morphology may represent a trait-level marker contributing to vulnerability for catatonia, with implications for early identification, risk stratification, and targeted intervention strategies.

Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. This shift in energy utilization persists beyond acute intoxication in individuals with alcohol use disorder (AUD), and may contribute to alcohol craving. We recently found that ketone therapies decrease alcohol withdrawal and alcohol craving in AUD. Here, we studied the effects of a single-dose ketone ester (KE) supplement on brain energy metabolism and alcohol craving. Five AUD and five healthy control (HC) participants underwent two 18F-fluorodeoxyglucose positron emission tomography (PET) scans, after consumption of 395 mg/kg KE or without (baseline), in randomized order. In the AUD group, KE reduced alcohol craving scores compared to baseline. KE decreased blood glucose levels and elevated blood {beta}-hydroxybutyrate (BHB) levels compared to baseline in both groups. Whole-brain voxel-wise maps of the cerebral metabolic rate of glucose (CMRglc) decreased by 17% in both groups, with the largest KE-induced CMRglc reductions in the frontal, occipital, and cingulate cortices, hippocampus, amygdala, and insula. There were no group differences between AUD and HC in blood or FDG measures, and no correlations between reductions in craving with CMRglc. Cingulate BHB levels, as assessed with 1H-magnetic resonance spectroscopy in 5 participant with AUD, increased 3-fold with KE compared to baseleline. In sum, administration of a single dose of KE rapidly shifted brain energetics from glucose to ketone metabolism in HC and AUD. KE also reduced ratings of alcohol craving, demonstrating its potential clinical effectiveness for supporting brain health and alcohol craving in AUD.

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

Schizophrenia is a complex psychiatric condition in which cortical, subcortical and neuromodulatory alterations have been implicated in its symptom expression. Long standing views of schizophrenia symptoms have posed that alterations in catecholaminergic systems, which explain psychotic symptoms, may be also associated with the cognitive impairments commonly observed in this condition. However, evidence on the involvement of catecholaminergic regions on cognitive functions in schizophrenia remains scarce. Working memory is one cognitive domain where schizophrenia patients present more impairments at higher levels of cognitive load. Here we explored the activation of catecholaminergic regions during a working memory task in schizophrenia. We reanalyzed an openly available functional magnetic resonance imaging dataset where schizophrenia patients and healthy controls were scanned while performing the N-back task. We compared activation of two dopaminergic areas, ventral tegmental area and substantia nigra, and of a noradrenergic nucleus, locus coeruleus, to the presentation of targets, and compared three different levels of cognitive load (0-, 1- and 2-back). We found that across nuclei, higher load was related to lower activation. Furthermore, schizophrenia patients showed reduced activation at the highest load level when compared to healthy controls. These findings point to catecholaminergic systems as mediators of the deficits in effort processing in schizophrenia. Our study lends further support for the importance of including catecholaminergic systems in the mechanisms of cognitive deficits in schizophrenia.