Psychiatry Research: Neuroimaging

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

Background and Hypothesis: Schizophrenia (SZ) and bipolar disorder (BD) share overlapping yet distinct clinical profiles and system-wide brain alterations. Macroscale functional connectivity gradients capture principal axes of cortical organization, including the separation of unimodal and transmodal systems, offering a low-dimensional lens on individual differences in brain architecture. Whether these axes reflect shared or diagnosis-specific variation across the SZ-BD spectrum is unknown. Study Design: Using resting-state fMRI from 187 adults (110 HC, 37 SZ, 40 BD) from the UCLA Consortium for Neuropsychiatric Phenomics, we derived individual low-dimensional gradients and applied three analyses: case-control comparisons at both the cortical network and subcortical region-of-interest level, Partial Least Squares (PLS) regression linking gradients to clinical phenotypes, and individual-level similarity indices (SI-PLS) positioning participants within a gradient-behaviour space. Study Results: While the gradient structure (G1: visual-somatomotor and G2: unimodal-transmodal) was preserved across groups, patient groups showed greater deviations along both axes. Network analyses revealed transdiagnostic frontoparietal compression in G2, alongside disorder-specific effects: visual pole contraction and subcortical amygdala displacement in SZ, and somatomotor displacement in BD. PLS identified a BD-associated profile of preserved gradient architecture and lower symptom burden, contrasting with an SZ-associated profile of greater cognitive impairment and symptom severity. SI-PLS scores placed SZ and BD in distinct regions of a shared two-dimensional neural space, with HC between them. Conclusions: Differences across the SZ-BD spectrum organize along two principal axes, revealing transdiagnostic alterations in higher-order association systems alongside disorder-specific sensory signatures. These findings support a multi-axis dimensional framework for understanding clinical heterogeneity in psychosis.

Schizophrenia is associated with cognitive impairments, including deficits in implicit learning. Probabilistic serial reaction time tasks (SRTT) offer an objective approach to characterizing these deficits through both motor execution (ME) and motor imagery (MI), the mental simulation of movement without physical action. Whether implicit probabilistic sequence learning is impaired across both modalities in schizophrenia remains poorly understood. Thirty individuals with schizophrenia (ME: n=12; MI: n=13) and 40 healthy controls (ME: n=20; MI: n=20) completed an auditory probabilistic SRTT. Symptom severity was assessed with the PANSS and cognitive functioning with the MCCB. Healthy controls demonstrated a robust signature of implicit probabilistic sequence learning, whereas participants with schizophrenia exhibited weaker and less consistent learning signatures, particularly during motor imagery. Sensitivity to probabilistic structure differed significantly between groups during motor execution but not motor imagery. Participants with schizophrenia also showed significantly longer reaction times than controls across both modalities, consistent with generalized psychomotor slowing. Greater PANSS-General severity was associated with greater deviation from the probabilistic learning patterns observed in healthy controls during ME, whereas higher MCCB verbal learning scores were associated with greater similarity to these learning patterns during MI. These findings indicate that implicit probabilistic sequence learning is impaired in schizophrenia across both motor execution and motor imagery, and that these deficits are meaningfully associated with clinical symptom severity and cognitive functioning.

The current study assessed whether N-acetylcysteine (NAC), which inhibits the kynurenic acid (KYNA)-synthesizing enzyme kynurenine aminotransferase (KAT) II, affects tryptophan (TRYP)-induced peripheral formation of the kynurenine pathway metabolites kynurenine and KYNA and improves selected functional outcome measures in people with schizophrenia. Fifty-eight participants with DSM-5 schizophrenia or schizoaffective disorder entered a double-blind, placebo-controlled, randomized cross-over challenge study, in which they were pretreated with either NAC (up to a maximum of 15 g) or placebo, then received TRYP, 6 g. Prior to and after receiving the study medications, participants underwent laboratory (serum kynurenine and KYNA), symptom (BPRS, SANS, and CDS), cognitive (6 MCCB tests) and brain MRI (ASL, DTI, 1H-MRS) assessments. In contrast to placebo pre-treatment, NAC significantly reduced the TRYP-induced increase in peripheral serum levels of kynurenine (t=-2.02; p<0.05) and KYNA (t=-3.21; p=0.002). NAC pre-treatment was associated with significantly smaller increases in total white matter (WM) cerebral blood flow (CBF) (t=-2.15; p=0.04) and a trend for smaller increases in total gray matter (GM) CBF (t=-1.81; p=0.08). NAC pre-treatment significantly reduced the TRYP-induced decrease in MCCB composite score (t=2.07; p=0.04). There was no differential treatment effect on DTI or 1H-MRS or symptom measures. The observation that NAC attenuated the de novo formation of KYNA, reduced WM CBF elevations, tended to decrease GM CBF, and blocked the worsening of cognitive performance in participants following TRYP administration, supports the concept that KAT II inhibition is a promising novel strategy for the treatment of cognitive impairments in people with schizophrenia.

Background. Psychosis spectrum symptoms (PSS) are prevalent in youth and are associated with increased risk for psychotic disorder, suicidality, and functional impairment. Computationally, PSS may stem from altered predictive coding of basic sensory surprises and environmental volatility. Formalized as hierarchical precision-weighted prediction errors (pwPEs), this altered processing is a proposed mechanistic substrate of aberrant perceptual inference across disorders, including psychosis-risk populations. While the auditory mismatch negativity (MMN) provides an electrophysiological index of pwPEs, it remains unknown if distinct hierarchical pwPE components distinguish youth who endorse PSS. Methods. A sample of 131 participants (PSS-=66, PSS+=65; ages 11-24) from the ongoing Toronto Adolescent and Youth (TAY-CAMH) Cohort study were stratified by PSS status using the PRIME Screen-Revised and were assessed for their psychosocial functioning. 64-channel EEG was recorded during an auditory oddball paradigm with stable and volatile phases. A hierarchical Bayesian model applied to the stimulus stream generated trajectories of low-level sensory and high-level volatility-related pwPEs. Alongside standard phase-averaged event-related potentials (ERPs), Bayesian trajectories derived model-based ERPs. Results. Replicating prior findings in non-clinical controls, stable-phase MMN significantly exceeds volatile-phase MMN and lower psychosocial functioning was associated with reduced volatile-phase MMN amplitude. Age significantly modulated oddball MMN and unweighted prediction errors ({delta}1, {delta}2). Group differences between PSS+ and PSS- were statistically significant for volatility-level pwPE ({epsilon}3), peaking at ~180 ms Peri-Stimulus Time (pFWE-peak =.024). Conclusions. Independent of age-related developmental effects, volatility-level pwPE learning ({epsilon}3) constitutes a more sensitive EEG marker associated with PSS status in help-seeking youth than low-level sensory pwPE.

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

Major depressive disorder (MDD) is a leading cause of disability worldwide with risk of onset and recurrence linked to depressive ruminative thought patterns. Mindfulness-based cognitive therapy (MBCT) is an evidence-based treatment for depression that targets the ability to recognise, decenter, and disengage from ruminative thought patterns. Elucidating how MBCT impacts hierarchical brain organisation may be key to understanding the processes by which MBCT can modulate ruminative tendencies. In a randomised controlled functional magnetic resonance imaging (fMRI) trial on individuals with MDD (N=80) before and after MBCT in addition to treatment as usual (TAU), we investigated changes in hierarchical brain organisation during resting-state and rumination. We built whole-brain models to obtain generative connectivity (GEC) matrices per patient and quantified brain hierarchy by measuring the global directedness and regional trophic levels in each GEC, in which greater directedness reflects more directional information flow and less recurrence. Global directedness in MBCT+TAU compared to TAU increased during rumination, with no changes during resting-state. Furthermore, increased regional breadth of hierarchy during rumination was related to improvements in clinical and behavioural outcomes following MBCT+TAU. Increased brain hierarchy during rumination following mindfulness training may be consistent with a shift away from self-reinforcing negative mental loops towards more differentiated and less coupled cognitive and bodily cycles, supporting MBCT's ability to interrupt ruminative processes. Hierarchical brain dynamics may hold promise as a treatment-sensitive marker and a potential mechanism of therapeutic change in MBCT for depression.

Background and Hypothesis. Motor alterations represent an important component of psychotic disorders. Chronic cannabis use, a key risk factor for psychosis, is also associated with sensorimotor dysfunctions. Yet, the hypothesis of a common sensorimotor disturbance remains underinvestigated. Study Design. In this study, we examined submovements, elementary units of motor output, to search for common subclinical impairments in these populations. Patients with psychosis (n = 17), heavy cannabis users (n = 21), and healthy controls (n = 17) performed a continuous visuomotor synchronization task, consisting in tracking a dot moving on a screen with a finger. Study Results. Individuals with psychosis and cannabis users exhibited less frequent and more variable submovements compared with healthy controls. Furthermore, when interacting with a pre-recorded human kinematic profile, both groups exhibited attenuated responses to the observed submovements. This alteration was found to be more pronounced in patients with psychosis. Conclusions. These findings suggest that submovement analysis may reveal subtle, shared alterations in sensorimotor integration in psychosis and chronic cannabis use, providing an objective window onto motor dysfunction not readily captured by current clinical tools.

Schizophrenia is characterized by persistent executive dysfunction and atypical engagement of prefrontal circuits underlying attentional control. However, the neural dynamics of executive processing during ecologically relevant tasks remain underexplored. This study examined frontal theta/beta oscillatory patterns and trial level EEG responsiveness as indices of adaptive cognitive control in schizophrenia compared to healthy controls. Thirty adults with schizophrenia (M age = 39.9, SD = 9.10 years) and a matched healthy control group (N = 30; M age = 32.25, SD = 6.50 years) underwent quantitative EEG during an eyes-open resting state and while performing two executive tasks: an augmented reality visuomotor challenge (LCAR) and a mobile guided daily routine task (B2B). Frontal theta/beta ratios (TBR) at Fz and Cz indexed attentional engagement. Trial level responsiveness was assessed via discrete Stimulus Response Events (SREs). Results: Both LCAR and B2B elicited significant TBR increases relative to eyes open rest at midline frontal sites (p < .001), reflecting elevated executive demand. Compared to healthy controls, participants with schizophrenia exhibited higher baseline TBR and reduced modulation across task segments. In contrast, controls showed stronger SRE linked variability and greater memory gains, indicating more efficient task locked cognitive adaptation. Age related effects were also observed, with participants under 40 years showing higher resting TBR at Fp1 (p =.01). Conclusion: Findings advance understanding of prefrontal theta/beta modulation as a neurophysiological marker of adaptive executive control during complex, ecologically valid tasks. By integrating real-world paradigms with trial level EEG analyses, this study contributes to models of dynamic information processing and cognitive resource allocation in schizophrenia. Keywords: schizophrenia; healthy controls; theta/beta ratio; QEEG; executive function; augmented reality; neural biomarkers

Smooth pursuit eye movement abnormalities are well established in psychosis, but the specific components of pursuit performance that vary across clinical states and symptom profiles remain insufficiently characterized. Here, we used a rapid smooth pursuit paradigm combining standard linear tracking (repeated short trials moving in different directions) with structured target occlusion to examine oculomotor performance in individuals with acute psychosis, chronic psychosis, and healthy controls. The occlusion condition allowed assessment of tracking when the target was temporarily hidden and gaze had to be maintained along the expected trajectory. Basic oculomotor measures, including full pursuit gain and initial catch-up saccade properties, were largely preserved in patients. In contrast, more specific trajectory-based measures revealed distinct abnormalities. Saccade-free smooth tracking gain was selectively reduced in acute psychosis, whereas tracking deviation during non-occluded pursuit was altered in both patient groups, reflecting reduced forward tracking relative to controls. During structured occlusion, patients showed reduced forward gaze progression along the expected trajectory, with a graded pattern across groups: controls showed the strongest predictive lead, chronic patients an intermediate response, and acute patients the weakest predictive lead. Tracking deviation and occlusion-related deviation were both associated with positive symptom severity, whereas smooth tracking gain was not. These findings suggest that smooth pursuit abnormalities in psychosis are measure-specific rather than uniform, involving both broader psychosis-related alterations in gaze-target alignment and state-sensitive disruptions in occlusion-related tracking. Structured occlusion may therefore offer a useful extension of conventional smooth pursuit paradigms for probing prediction-related sensorimotor control in psychosis and distinguishing acute from chronic clinical states.

BackgroundCognitive restructuring, the process of identifying and challenging negative thoughts, is a key technique for treating depressive and anxiety disorders. Although neuroimaging studies have characterised the brain systems supporting cognitive restructuring in healthy individuals, it remains unclear how these systems are altered in depression and anxiety, or whether each disorder is associated with distinct neural dysfunction. MethodsSeventy-three clinical participants with depressive or anxiety disorders and 70 healthy controls completed a cognitive restructuring paradigm during 7 Tesla functional magnetic resonance imaging (fMRI). The task required participants to either repeat a series of negative statements or challenge them using Socratic questioning. Group-level fMRI analyses examined the effects of depressive and anxiety symptom severity on brain activation, while dynamic causal modelling characterized the directional neural influences between implicated regions. ResultsDuring challenging compared to repeating statements, greater depressive symptoms were associated with reduced dorsolateral prefrontal cortex (dlPFC) activation. Conversely, greater anxiety symptoms were associated with greater dlPFC activation. Effective connectivity results revealed that depressive symptoms were associated with greater inhibition from the ventrolateral prefrontal cortex (vlPFC) to the ventromedial prefrontal cortex, whereas anxiety symptoms were associated with greater excitation from the dlPFC to amygdala and greater inhibition from the vlPFC to amygdala. ConclusionsWhile clinical participants modified negative beliefs as effectively as healthy controls, depressive and anxiety symptoms were associated with dissociable neural signatures during restructuring. This suggests that cognitive behavioral therapy may engage partially distinct mechanisms depending on symptom profile, a possibility that warrants longitudinal investigation of treatment response.

Moderate-to-severe traumatic brain injury (msTBI) is recognized as a chronic and evolving neurological condition characterized by progressive structural brain changes and persistent cognitive impairment. While prior studies have demonstrated widespread atrophy following msTBI, less is known regarding the longitudinal trajectory of gray matter (GM) changes during recovery and post-rehabilitation. The current study used longitudinal voxel-based morphometry (VBM) to characterize GM volume changes over a period of 9 months, in individuals with msTBI relative to healthy controls (HC). Associations between regional GM volume and neuropsychological functioning were examined. Twenty-eight participants (14 msTBI, 14 HC) completed MRI and neuropsychological assessments across three timepoints spanning outpatient rehabilitation and follow-up. Longitudinal VBM analyses revealed significant group and time interactions within subcortical and limbic regions. Relative to HC, individuals with msTBI showed lower GM volume in these regions at baseline, with trajectories that converged toward HC values (right hippocampus) or increased relative to HC over the rehabilitation period (bilateral pulvinar), whereas the right amygdala and inferior cerebellar vermis remained persistently reduced. Significant longitudinal improvements in memory and psychomotor speed during the rehabilitation period were demonstrated in msTBI. Greater (preserved) GM volume within the right hippocampus, thalamus, and bilateral pulvinar was associated with better performance across measures of verbal memory, processing speed, executive functioning, and cognitive flexibility. These findings suggest that msTBI is associated with dynamic structural brain changes involving subcortical, limbic, and cerebellar networks, and that the rehabilitation period was accompanied by relative volumetric stabilization in these regions and by meaningful cognitive improvement.

Alcohol drinking motives vary among individuals and shape experiences and beliefs about alcohol, influencing the processing of alcohol-related cues. In real-life settings, these cues are contextually rich, amplifying the role of such individualized drinking motives on cue processing. However, previous literature has primarily relied on images of alcohol, which lack contexts and differ significantly from real-life. Here, aiming to investigate real-life craving, we examined the role of alcohol drinking motives in craving in response to naturalistic alcohol-drinking videos. We asked fifty-three problematic alcohol users to speak about their reasons for drinking alcohol to capture unique alcohol drinking motives of each individual. Participants also underwent functional MRI while watching fifteen alcohol-drinking videos, and reported their subjective level of craving and self-relatedness for each video. Behavioral data analysis revealed that individuals with greater alcohol use severity tended to report greater cue-induced craving, but only when they reported that a video was related to themselves. Inter-subject representational similarity analysis showed that participants with similar alcohol drinking motives, reflected in shared drinking reasons and similar self-relatedness to the videos, exhibited synchronized craving-related neural responses during video-watching. Notably, these shared neural processes mediated the link between similar drinking motives and similar self-reported craving levels across participants. Together, our findings highlight the crucial role of alcohol drinking motives in shaping cue-induced alcohol craving, and provide deeper insights into craving in real-world contexts.

Introduction Limitations of current classifications of schizophrenia, schizoaffective disorder, and bipolar disorder are evident from their overlapping symptoms, aetiologies, treatments, and outcomes, and present a barrier to novel treatment discovery. Alternative conceptualisations are needed to address nosological validity, align diagnosis to aetiology, and improve prognostication and treatment choice. We aimed to identify latent classes across the psychosis spectrum based on premorbid functioning and outcomes, and assess these in relation to genetic liability and symptom dimensions. Method Participants with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder type 1, were ascertained from four UK clinical cohorts (total n=5,043). Latent class analysis was conducted using phenotypes not included within the diagnostic criteria, including premorbid functioning, age at illness onset, and measures of severity and course. Polygenic scores (PGS) for psychiatric disorders and behavioural traits were tested for associations with latent classes. We tested if diagnosis explained associations between PGS and classes. Results A three-class model provided the best fit. Class one had poorer premorbid functioning, lower rates of recovery, and higher PGS for schizophrenia and ADHD. Class three had the highest functioning, higher rates of psychosocial stressors before onset, higher intelligence PGS and lower PGS for psychiatric disorders. Class two was intermediate between classes one and three on measures of functioning, but was characterised by high levels of involuntary hospital admissions and high bipolar disorder PGS. Diagnosis only partially explained associations between PGS and class membership. Conclusions We identified classes across the psychosis spectrum characterised by different premorbid functioning and outcomes, that cut across diagnostic categories and captured genetic liability not explained by diagnosis. Our findings suggest alternative conceptualisations of psychotic disorders may complement diagnoses in mapping to the aetiology of these conditions, and could be useful to advance precision psychiatry.

Predicting real-world functional outcomes in schizophrenia (SCZ) remains a clinical priority, but existing models are limited by methodological constraints and a lack of established clinical utility. Cognition is a commonly used predictor, and the Normative Latent Cognitive Structure (N-LCS) approach provides a structure-informed representation that may address limitations of conventional domain-level scores. Data from two merged COBRE cohorts (163 SCZ, 180 healthy controls) were used to develop ridge regression models for economic (EF), occupational (OF), and social (SF) functioning, using N-LCS deviation metrics alongside a priori selected demographic and clinical predictors. Score-based models using MCCB domain T-scores were developed for comparison. Performance was evaluated using bootstrap-corrected AUC, balanced accuracy, and calibration for binary outcomes, and weighted kappa and log-loss for SF. Decision curve analysis (DCA) was used to assess clinical utility for the binary outcomes. The EF model achieved a corrected AUC of 0.76 and balanced accuracy of 0.73. The OF model achieved 0.72 and 0.71, respectively. The SF model showed modest performance (weighted kappa = 0.33). DCA indicated net benefit across the full threshold range for EF and above 0.37 for OF. N-LCS models demonstrated comparable or modestly superior performance to score-based models while using fewer predictors and showing better calibration for EF. These findings support the predictive utility of N-LCS for functional outcomes in SCZ and underscore the need for external validation in independent cohorts as a next step toward clinical application.

Audiovisual cues ("bells and whistles") are ubiquitous in commercial gambling products. Pairing wins with sound and light cues in laboratory-based gambling paradigms increases risky choice, but the neurocognitive basis of this effect is unclear. Here we compared patterns of neural activation using functional MRI in healthy volunteers (n = 31) while they performed a two-choice lottery task. Reward-paired cues were either present or absent in a mixed-block, event-related design. As predicted, participants made riskier choices on cued trials. Choice latencies were also longer when cues were present, particularly on trials following a win. Activity within the nucleus accumbens and orbitofrontal cortex was greater during the decision phase when participants made risky choices. Nucleus accumbens signal was also greater when participants were anticipating risky outcomes, and in response to risky wins. Contrary to our pre-registered hypotheses, cue condition did not alter patterns of activity across any task phase, in either of these a priori regions of interest. As such, cue-induced risky choice does not appear to be driven by altered representation of risk or value within this canonically reward-sensitive circuitry. Instead, exploratory analyses revealed that the anterior insula was selectively activated by cued, risky wins. Such activation may signal the saliency of these events, or their emotional impact, and may reflect one mechanism through which cue-induced craving develops in vulnerable individuals.

Purpose: {beta}-hydroxybutyrate (BHB), a ketone body and alternative cerebral energy substrate, can be measured in vivo using J-difference edited proton magnetic resonance spectroscopy (1H-MRS). Oral ketone supplementation with substrates such as the ketone monoester (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate (KME) and 1,3-butanediol (BD) have gained attention as a mechanism to elevate circulating BHB and induce ketosis without dietary restrictions. Elevated brain ketone availability is of growing therapeutic interest as a strategy to support neuronal energetics in conditions such as epilepsy, neurodegenerative disease, and alcohol use disorder (AUD). However, both pathways introduce BD into the bloodstream, which crosses the blood-brain barrier. Critically, BD exhibits a spectral signature that closely resembles the prominent BHB peak in JDE-MR spectroscopic imaging (MRSI), identified in a pilot AUD study. Methods: Two separate JDE-MRSI acquisitions tailored for BHB and BD editing were implemented, exploiting frequency separation between the BHB (4.14ppm) and BD (3.95ppm) coupling partners of the observed 1.2ppm resonance to independently quantify each metabolite. Results: Brain BD concentrations (0.25-0.58mM) were comparable to or exceeded corresponding BHB concentrations (0.20-0.27mM) in all volunteers after consumption of a single dose of the KME, indicating that BD constitutes a major fraction of the signal conventionally attributed to BHB. Combined BHB+BD concentrations (~0.45-0.85mM) were consistent with brain BHB values reported in prior studies employing similar doses of the KME, indicating that those measurements likely reflect a combined BHB+BD signal. Conclusions: Separate quantification of the two metabolites is important for interpreting brain ketone studies and for understanding the full pharmacology of KME supplementation.

Background: Psychotic illnesses are among the most debilitating classes of psychiatric disorders, requiring targeted and effective treatment strategies. Although antipsychotics are the primary pharmacological therapy for psychosis, their full range of effects remain unclear, including effects within the frontal cortex, a brain region linked structurally and functionally to psychotic disorders. Methods: To examine the effects of antipsychotic treatment on the frontal cortex, we conducted a meta-analysis of publicly available rodent (rat, mice) transcriptional profiling datasets (microarray, RNA-Seq). Five datasets (GSE45229, GSE93918, GSE2547, GSE4031.1, GSE66275) were identified within the Gemma database using pre-specified search terms and inclusion/exclusion criteria (date: 7/7/2024), yielding differential expression results for eight drug vs. control comparisons (collective n=68). A random-effects meta-analysis model was fit to the log2 fold changes for each gene, and p-values adjusted for false discovery rate (FDR), with follow-up analyses exploring robustness, heterogeneity, and publication bias. To increase the power and generalizability of our findings, an exploratory meta-analysis was also run incorporating antipsychotic effects from both rodents and nonhuman primates (collective n=101), and compared to findings from individuals with schizophrenia. Results: Our meta-analysis yielded stable estimates for 12,190 genes, identifying 63 genes that were differentially expressed following antipsychotic treatment ("DEGs", FDR<0.05). Differential expression included genes important for serotonergic and cholinergic signalling, and was enriched within pathways linked to oligodendrocyte development and myelination, physiological and cellular stress responses, and cardiovascular function. An exploratory meta-analysis combining rodent and nonhuman primate results confirmed these observations and yielded additional findings (117 DEGs total). Comparisons with human post-mortem findings suggested that some schizophrenia-related gene expression may instead reflect antipsychotic treatment. Conclusion: Further validation is necessary, but our findings suggest that antipsychotics may assist in the regulation of specific structural and functional changes within the frontal cortex linked to psychotic disorders.

INTRODUCTION Psychosis affects 40% of individuals with Alzheimer's disease (AD) and is associated with accelerated cognitive decline. Blood-based biomarkers, particularly plasma phosphorylated tau (ptau), have demonstrated utility in predicting cognitive decline in AD, with ptau217 showing superior performance in many studies. However, whether these biomarkers predict differential cognitive trajectories in AD with psychosis (ADP) remains unknown. METHODS Two independent cohorts were analyzed: Alzheimer's Disease Neuroimaging Initiative (ADNI; n=659: 172 cognitively unimpaired [CU], 406 AD, 81 ADP) and Litwin-Zucker Research Center (LZ; n=142: 68 CU, 57 AD, 17 ADP) with 6-year follow-up. Psychosis was defined by non-zero Neuropsychiatric Inventory delusions or hallucinations scores. In ADNI, plasma ptau181, ptau217, ptau231, amyloid-{beta}42/40, GFAP, and NfL were quantified using NULISA. In LZ, ptau181, ptau205, ptau212, ptau217, amyloid-{beta}42/40, GFAP, and NfL were quantified using Simoa. Linear mixed-effects models assessed prediction of cognitive decline across memory, language, visuospatial, and executive function domains. RESULTS In ADNI, baseline ptau181 predicted differential ADP decline in language (p<0.05), visuospatial (p<0.05), and executive function (p<0.05); ptau217 predicted language (p<0.05) and visuospatial (p<0.05) decline; GFAP predicted language (p<0.05) and visuospatial (p<0.05) decline; and NfL visuospatial decline (p=0.01). In LZ, ptau181 predicted decline in memory (p<0.05), language (p<0.0001), visuospatial (p<0.05), and executive function (p<0.05); ptau217 predicted memory (p<0.05) and visuospatial (p<0.05) decline; and GFAP predicted language decline (p<0.05). Johnson-Neyman analyses revealed ADP-AD divergence at low ptau181 thresholds in ADNI, while LZ showed crossover patterns with steeper ADP decline at low biomarker levels that attenuated at high levels where AD decline was steeper. DISCUSSION ADP exhibited accelerated cognitive decline across domains driven by a distinct biomarker landscape compared to non-psychotic AD. Plasma ptau181 demonstrated broader domain-specific associations with decline in ADP than other blood-based biomarkers and associated exclusively with executive function impairment, indicating its unique utility for predicting cognitive trajectories in this pathophysiological subtype.

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