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Background and Hypothesis: The glymphatic system (GS), a brain waste clearance pathway, is disrupted in various neurodegenerative and vascular diseases. As schizophrenia shares clinical characteristics with these conditions, we hypothesized GS disruptions in patients with schizophrenia spectrum disorder (SCZ-SD), reflected in increased brain macromolecule (MM) and decreased diffusion-tensor-image-analysis along the perivascular space (DTI-ALPS) index., Study Design: Forty-seven healthy controls (HCs) and 103 patients with SCZ-SD were studied. Data included 135 proton magnetic resonance spectroscopy (1H-MRS) sets, 96 DTI sets, with 79 participants contributing both. MM levels were quantified in the dorsal-anterior cingulate cortex (dACC), dorsolateral prefrontal cortex, and dorsal caudate (point resolved spectroscopy, echo-time = 35ms). Diffusivities in the projection and association fibers near the lateral ventricle were measured to calculate DTI-ALPS indices. General linear models were performed, adjusting for age, sex, and smoking. Correlation analyses examined relationships with age, illness duration, and symptoms severity., Study Results: MM levels were not different between patients and HCs. However, left, right, and bilateral DTI-ALPS indices were lower in patients compared with HCs (P < .001). In HCs, age was positively correlated with dACC MM and negatively correlated with left, right, and bilateral DTI-ALPS indices (P < .001). In patients, illness duration was positively correlated with dACC MM and negatively correlated with the right DTI-ALPS index (P < .05). In the entire population, dACC MM and DTI-ALPS indices showed an inverse correlation (P < .01)., Conclusions: Our results suggest potential disruptions in the GS of patients with SCZ-SD. Improving brain's waste clearance may offer a potential therapeutic approach for patients with SCZ-SD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Hypothesis: Identifying biomarkers that predict treatment response in early psychosis (EP) is a priority for psychiatry research. Previous work suggests that resting-state connectivity biomarkers may have promise as predictive measures, although prior results vary considerably in direction and magnitude. Here, we evaluated the relationship between intrinsic functional connectivity of the attention, default mode, and salience resting-state networks and 12-month clinical improvement in EP., Study Design: Fifty-eight individuals with EP (less than 2 years from illness onset, 35 males, average age 20 years) had baseline and follow-up clinical data and were included in the final sample. Of these, 30 EPs showed greater than 20% improvement in Brief Psychiatric Rating Scale (BPRS) total score at follow-up and were classified as "Improvers.", Study Results: The overall logistic regression predicting Improver status was significant (χ2 = 23.66, Nagelkerke's R2 = 0.45, P < .001, with 85% concordance). Significant individual predictors of Improver status included higher default mode within-network connectivity, higher attention-default mode between-network connectivity, and higher attention-salience between-network connectivity. Including baseline BPRS as a predictor increased model significance and concordance to 92%, and the model was not significantly influenced by the dose of antipsychotic medication (chlorpromazine equivalents). Linear regression models predicting percent change in BPRS were also significant., Conclusions: Overall, these results suggest that resting-state functional magnetic resonance imaging connectivity may serve as a useful biomarker of clinical outcomes in recent-onset psychosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Psychotic symptoms (hallucinations and delusions) are a type of neuropsychiatric symptom found during Alzheimer's Disease (AD)., Objective: This systematic review aims to comprehensively capture, analyse, and evaluate the body of evidence that has investigated associations between brain regions/networks and psychotic symptoms in AD., Methods: The protocol, created according to the PRISMA guidelines, was pre-registered on OSF (https://osf.io/tg8xp/). Searches were performed using PubMed, Web of Science and PsycInfo. A partial coordinate-based meta-analysis (CBMA) was performed based on data availability., Results: Eighty-two papers were selected: delusions were found to be associated mainly with right fronto-temporal brain regions and the insula; hallucinations mainly with fronto-occipital areas; both were frequently associated with the anterior cingulate cortex. The CBMA, performed on the findings of fourteen papers on delusions, identified a cluster in the frontal lobe, one in the putamen, and a smaller one in the insula., Conclusions: The available evidence highlights that key brain regions, predominantly in the right frontal lobe, the anterior cingulate cortex, and temporo-occipital areas, appear to underpin the different manifestations of psychotic symptoms in AD and MCI. The fronto-temporal areas identified in relation to delusions may underpin a failure to assimilate correct information and consider alternative possibilities (which might generate and maintain the delusional belief), and dysfunction within the salience network (anterior cingulate cortex and insula) may suggest a contribution for how internal and external stimuli are identified; the fronto-occipital areas linked to hallucinations may indicate diminished sensory processing and non-optimal predictive processing, that together contribute to misinterpretation of stimuli and misperceptions; the fronto-temporal and occipital areas, as well as the anterior cingulate cortex were linked to the psychotic cluster., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Altered mental status (AMS) and coma are terms used to describe disorders of arousal and content of consciousness. AMS may account for up to 4% to 10% of chief complaints in the emergency department setting and is a common accompanying symptom for other presentations. AMS is not a diagnosis, but rather a term for symptoms of acute or chronic disordered mentation, including confusion, disorientation, lethargy, drowsiness, somnolence, unresponsiveness, agitation, altered behavior, inattention, hallucinations, delusions, and psychosis. Some of the most common disorders associated with AMS are underlying medical conditions, substance use, and mental disorders. This document focuses on the appropriateness of neuroimaging in adult patients presenting with AMS changes including new onset delirium or new onset psychosis. In these cases, imaging is often expedited for initial stabilization and to exclude an intracranial process requiring intervention. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation., (Copyright © 2024 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Schizophrenia (SZ) is a highly heritable mental disorder, and language dysfunctions play a crucial role in diagnosing it. Although language-related symptoms such as disorganized speech were predicted by the polygenic risk for SZ which emphasized the common genetic liability for the disease, few studies investigated possible white matter integrity abnormalities in the language-related tracts in those at familial high-risk for SZ. Also, their results are not consistent. In this current study, we examined possible aberrations in language-related white matter tracts in patients with first-episode psychosis (FEP, N = 20), their siblings (SIB, N = 20), and healthy controls (CON, N = 20) by applying whole-brain Tract-Based Spatial Statistics and region-of-interest analyses. We also assessed language ability by Thought and Language Index (TLI) using Thematic Apperception Test (TAT) pictures and verbal fluency to see whether the scores of these language tests would predict the differences in these tracts. We found significant alterations in language-related tracts such as inferior longitudinal fasciculus (ILF) and uncinate fasciculus (UF) among three groups and between SIB and CON. We also proved partly their relationship with the language test as indicated by the significant correlation detected between TLI Impoverished thought/language sub-scale and ILF. We could not find any difference between FEP and CON. These results showed that the abnormalities, especially in the ILF and UF, could be important pathophysiological vulnerability indexes of schizophrenia. Further studies are required to understand better the role of language as a possible endophenotype in schizophrenia with larger samples., Competing Interests: Declaration of competing interest None of the authors has any conflicts of interest to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialised tools are used. Three tools have been proven useful to personalise drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging., Methods: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 45 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET))., Results: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings., Conclusion: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry.

Recent studies show that accelerated cortical gray matter (GM) volume reduction seen in anatomical MRI can help distinguish between individuals at clinical high risk (CHR) for psychosis who will develop psychosis and those who will not. This reduction is suggested to represent atypical developmental or degenerative changes accompanying an accumulation of microstructural changes, such as decreased spine density and dendritic arborization. Detecting the microstructural sources of these changes before they accumulate into volume loss is crucial. Our study aimed to detect these microstructural GM alterations using diffusion MRI (dMRI). We tested for baseline and longitudinal group differences in anatomical and dMRI data from 160 individuals at CHR and 96 healthy controls (HC) acquired in a single imaging site. Of the CHR individuals, 33 developed psychosis (CHR-P), while 127 did not (CHR-NP). Among all participants, longitudinal data was available for 45 HCs, 17 CHR-P, and 66 CHR-NP. Eight cortical lobes were examined for GM volume and GM microstructure. A novel dMRI measure, interstitial free water (iFW), was used to quantify GM microstructure by eliminating cerebrospinal fluid contribution. Additionally, we assessed whether these measures differentiated the CHR-P from the CHR-NP. In addition, for completeness, we also investigated changes in cortical thickness and in white matter (WM) microstructure. At baseline the CHR group had significantly higher iFW than HC in the prefrontal, temporal, parietal, and occipital lobes, while volume was reduced only in the temporal lobe. Neither iFW nor volume differentiated between the CHR-P and CHR-NP groups at baseline. However, in many brain areas, the CHR-P group demonstrated significantly accelerated changes (iFW increase and volume reduction) with time than the CHR-NP group. Cortical thickness provided similar results as volume, and there were no significant changes in WM microstructure. Our results demonstrate that microstructural GM changes in individuals at CHR have a wider extent than volumetric changes or microstructural WM changes, and they predate the acceleration of brain changes that occur around psychosis onset. Microstructural GM changes, as reflected by the increased iFW, are thus an early pathology at the prodromal stage of psychosis that may be useful for a better mechanistic understanding of psychosis development., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Schizophrenia (SCZ) and psychotic bipolar disorder (PBD) are two major psychotic disorders with similar symptoms and tight associations on the psychopathological level, posing a clinical challenge for their differentiation. This study aimed to investigate and compare the structural connectivity patterns of the limbic system between SCZ and PBD, and to identify specific regional disruptions associated with psychiatric symptoms., Methods: Using sMRI data from 146 SCZ, 160 PBD, and 145 healthy control (HC) participants, we employed a data-driven approach to segment the hippocampus, thalamus, hypothalamus, amygdala, and cingulate cortex into subregions. We then investigated the structural connectivity patterns between these subregions at the global and nodal levels. Additionally, we assessed psychotic symptoms by utilizing the subscales of the Brief Psychiatric Rating Scale (BPRS) to examine correlations between symptom severity and network metrics between groups., Results: Patients with SCZ and PBD had decreased global efficiency (E glob ) (SCZ: adjusted P<0.001; PBD: adjusted P = 0.003), local efficiency (E loc ) (SCZ and PBD: adjusted P<0.001), and clustering coefficient (Cp) (SCZ and PBD: adjusted P<0.001), and increased path length (Lp) (SCZ: adjusted P<0.001; PBD: adjusted P = 0.004) compared to HC. Patients with SCZ showed more pronounced decreases in E glob (adjusted P<0.001), E loc (adjusted P<0.001), and Cp (adjusted P = 0.029), and increased Lp (adjusted P = 0.024) compared to patients with PBD. The most notable structural disruptions were observed in the hippocampus and thalamus, which correlated with different psychotic symptoms, respectively., Conclusion: This study provides evidence of distinct structural connectivity disruptions in the limbic system of patients with SCZ and PBD. These findings might contribute to our understanding of the neuropathological basis for distinguishing SCZ and PBD., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Psychosis implicates changes across a broad range of cognitive functions. These functions are cortically organized in the form of a hierarchy ranging from primary sensorimotor (unimodal) to higher-order association cortices, which involve functions such as language (transmodal). Language has long been documented as undergoing structural changes in psychosis. We hypothesized that these changes as revealed in spontaneous speech patterns may act as readouts of alterations in the configuration of this unimodal-to-transmodal axis of cortical organization in psychosis. Results from 29 patients with first-episodic psychosis (FEP) and 29 controls scanned with 7 T resting-state fMRI confirmed a compression of the cortical hierarchy in FEP, which affected metrics of the hierarchical distance between the sensorimotor and default mode networks, and of the hierarchical organization within the semantic network. These organizational changes were predicted by graphs representing semantic and syntactic associations between meaningful units in speech produced during picture descriptions. These findings unite psychosis, language, and the cortical hierarchy in a single conceptual scheme, which helps to situate language within the neurocognition of psychosis and opens the clinical prospect for mental dysfunction to become computationally measurable in spontaneous speech., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Negative symptoms are often found in youth at clinical high risk (CHR) for psychosis. The present study explored the feasibility of using tDCS in conjunction with CBT in the treatment of negative symptoms in 5 youths at CHR. We sought to determine whether the protocol was feasible given the requirement for repeated visits over a three-week period, and to determine if measures of neurobiological change could be included, both acutely and following three weeks of stimulation. The results from this study suggest that the protocol is feasible for these youth, and the inclusion of MRI scanning sessions yielded good quality data., Competing Interests: Declaration of competing interest P.D.M., M.M.D., K.B., S.B., F.M., A.H., and J.A. have nothing to declare. A.M. is founder and shareholder of MCGRx Corp., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Chronic low-grade inflammation is observed across mental disorders and is associated with difficult-to-treat-symptoms of anhedonia and functional brain changes, reflecting a potential transdiagnostic dimension. Previous investigations have focused on distinct illness categories in people with enduring illness, but few have explored inflammatory changes. We sought to identify an inflammatory signal and the associated brain function underlying anhedonia among young people with recent-onset psychosis and recent-onset depression., Methods: Resting-state functional magnetic resonance imaging, inflammatory markers, and anhedonia symptoms were collected from 108 (mean [SD] age = 26.2 [6.2] years; female = 50) participants with recent-onset psychosis (n = 53) and recent-onset depression (n = 55) from the European Union/Seventh Framework Programme-funded PRONIA (Personalised Prognostic Tools for Early Psychosis Management) study. Time series were extracted using the Schaefer atlas, defining 100 cortical regions of interest. Using advanced multimodal machine learning, an inflammatory marker model and a functional connectivity model were developed to classify participants into an anhedonic group or a normal hedonic group., Results: A repeated nested cross-validation model using inflammatory markers classified normal hedonic and anhedonic recent-onset psychosis/recent-onset depression groups with a balanced accuracy of 63.9% and an area under the curve of 0.61. The functional connectivity model produced a balanced accuracy of 55.2% and an area under the curve of 0.57. Anhedonic group assignment was driven by higher levels of interleukin 6, S100B, and interleukin 1 receptor antagonist and lower levels of interferon gamma, in addition to connectivity within the precuneus and posterior cingulate., Conclusions: We identified a potential transdiagnostic anhedonic subtype that was accounted for by an inflammatory profile and functional connectivity. Results have implications for anhedonia as an emerging transdiagnostic target across emerging mental disorders., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Multiple hypotheses exist about the pathophysiology of Postictal Psychosis (PIP). As the clinical manifestations of PIP are roughly stereotyped, we assumed the existence of a common neurological pathway. This study aimed to determine if a specific brain network sustained the psychotic episode, regardless of the localization of the epileptogenic zone. We conducted a systematic review following the PRISMA guidelines. We included a total of 24 studies providing electrophysiological results(n=22) and metabolic imaging performed during the PIP(n=5). Temporal and frontal lobes seemed frequently involved, without clear evidence for lateralization. The EEG patterns were heterogenous, varying from unchanged to diffuse slowing. Metabolic pattern showed an increased perfusion within temporal and frontal lobes during PIP. These results correspond to the patterns described during postictal state, but they persisted throughout PIP, within regions larger than the epileptogenic zone and resolved with the recovery. PIP symptoms are associated with an excessive persistence of postictal changes within extended frontotemporal networks. A hypothesis could be that PIP results from an abnormally prolonged and diffuse post-ictal dysregulation., Competing Interests: Declaration of competing interest None of the authors had any conflict of interest to disclose., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

A berrant connectivity in the cerebellum has been found in psychotic conditions such as schizophrenia corresponding with cognitive and motor deficits found in these conditions. Diffusion differences in the superior cerebellar peduncles, the white matter connecting the cerebellar circuitry to the rest of the brain, have also been found in schizophrenia and high-risk states. However, white matter diffusivity in the peduncles in individuals with sub-threshold psychotic experiences (PEs) but not reaching the threshold for a definitive diagnosis remains unstudied. This study investigates the cerebellar peduncles in adolescents with PEs but no formal psychiatric diagnosis.Sixteen adolescents with PEs and 17 age-matched controls recruited from schools underwent High-Angular-Resolution-Diffusion neuroimaging. Following constrained spherical deconvolution whole-brain tractography, the superior, inferior and middle peduncles were isolated and virtually dissected out using ExploreDTI. Differences for macroscopic and microscopic tract metrics were calculated using one-way between-group analyses of covariance controlling for age, sex and estimated Total Intracranial Volume (eTIV). Multiple comparisons were corrected using Bonferroni correction.A decrease in fractional anisotropy was identified in the right (p = 0.045) and left (p = 0.058) superior cerebellar peduncle; however, this did not survive strict Bonferroni multiple comparison correction. There were no differences in volumes or other diffusion metrics in either the middle or inferior peduncles.Our trend level changes in the superior cerebellar peduncle in a non-clinical sample exhibiting psychotic experiences complement similar but more profound changes previously found in ultra-high-risk individuals and those with psychotic disorders. This suggests that superior cerebellar peduncle circuitry perturbations may occur early along in the psychosis spectrum., (© 2023. The Author(s).)

A growing understanding of the nature of brain function has led to increased interest in interpreting the properties of large-scale brain networks. Methodological advances in network neuroscience provide means to decompose these networks into smaller functional communities and measure how they reconfigure over time as an index of their dynamic and flexible properties. Recent evidence has identified associations between flexibility and a variety of traits pertaining to complex cognition including creativity and working memory. The present study used measures of dynamic resting-state functional connectivity in data from the Human Connectome Project (n = 994) to test associations with Openness/Intellect, general intelligence, and psychoticism, three traits that involve flexible cognition. Using a machine-learning cross-validation approach, we identified reliable associations of intelligence with cohesive flexibility of parcels in large communities across the cortex, of psychoticism with disjoint flexibility, and of Openness/Intellect with overall flexibility among parcels in smaller communities. These findings are reasonably consistent with previous theories of the neural correlates of these traits and help to expand on previous associations of behavior with dynamic functional connectivity, in the context of broad personality dimensions., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Structural and functional neurobiological abnormalities have been observed in schizophrenia. Previous studies have concentrated on specific illness stages, obscuring relationships between functional/structural changes and disorder progression. The present study aimed to quantify structural and functional abnormalities across different clinical stages using functional near-infrared spectroscopy (fNIRS) and structural magnetic resonance imaging (sMRI)., Methods: Fifty-four participants with first-episode schizophrenia (FES), 120 with clinically high risk of psychosis (CHR), and 111 healthy controls (HCs) underwent functional near-infrared spectroscopy (fNIRS) to measure oxyhemoglobin (Oxy-Hb) during the verbal fluency task. Among them, 28FES, 64CHR and 55HC also finished sMRI. Oxy-Hb and gray matter volume (GMV) were compared among the three groups while controlling for covariates, including age, sex, years of education, and task performance. Mediation analysis was utilized to determine the mediating effect of GMV on Oxy-Hb and cognition., Results: Compared with the HC group, CHR and FES groups showed significantly reduced brain activity. However, there were no significant differences between the FES and CHR. Pronounced GMV increase in the right frontal pole area (F = 4.234, p = 0.016) was identified in the CHR and FES groups. Mediation analysis showed a significant mediation effect of the right frontal pole GMV between Channel 31 Oxy-Hb and processing speed (z = 2.105, p = 0.035) and attention/vigilance (z = 1.992, p = 0.046)., Conclusions: Brain activation and anatomical deficits were observed in different brain regions, suggesting that anatomical and functional abnormalities are dissociated in the early stages of psychosis. The relationship between neural activity and anatomy may reflect a specific pathophysiology related to cognitive deterioration in schizophrenia., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The profiles of cortical gyrification across schizophrenia, bipolar I disorder, and schizoaffective disorder have been studied to a limited extent, report discordant findings, and are rarely compared in the same study. Here we assess gyrification in a large dataset of psychotic disorder probands, categorized according to the DSM-IV. Furthermore, we explore gyrification changes with age across healthy controls and probands., Methods: Participants were recruited within the Bipolar-Schizophrenia Network of Intermediate Phenotypes study and received T1-MPRAGE and clinical assessment. Gyrification was measured using FreeSurfer 7.1.0. Pairwise t-tests were conducted in R, and age-related gyrification changes were analyzed in MATLAB. P values <0.05 after false discovery rate correction were considered significant., Results: Significant hypogyria in schizophrenia, bipolar disorder, and schizoaffective disorder probands compared to controls was found, with a significant difference bilaterally in the frontal lobe between schizophrenia and bipolar disorder probands. Verbal memory was associated with gyrification in the right frontal and right cingulate cortex in schizophrenia. Age-fitted gyrification curves differed significantly among psychotic disorders and controls., Conclusions: Findings indicate hypogyria in DSM-IV psychotic disorders compared to controls and suggest differential patterns of gyrification across the different diagnoses. The study extends age related models of gyrification to psychotic disorder probands and supports that age-related differences in gyrification may differ across diagnoses. Fitted gyrification curves among probands categorized by DSM-IV significantly deviate from controls, with the model capturing early hypergyria and later hypogyria in schizophrenia compared to controls; this suggests unique disease and age-related changes in gyrification across psychotic disorders., Competing Interests: Declaration of competing interest The authors Rychagov, Zeng, Oykhman, Dr. del Re, Dr. Yassin, Dr. Lizano, Dr. Sweeny, Dr. Gershon, Dr. Pearlson, Dr. McDowell, and Dr. Clementz reported no potential conflicts of interest. Dr. Keshavan reports serving as an advisor to Alkermes, Takeda, and Vanna Inc. Dr. Tamminga reports the following financial disclosures: American Psychiatric Association – Deputy Editor; Astellas – Ad Hoc Consultant; Autifony – Ad Hoc Consultant; The Brain and Behavior Foundation – Council Member; Eli Lilly Pharmaceuticals – Ad Hoc Consultant; Intra-cellular Therapies (ITI, Inc.) – Advisory Board, drug development; Institute of Medicine – Council Member; National Academy of Medicine – Council Member; Pfizer – Ad Hoc Consultant; Sunovion – Investigator Initiated grant funding., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Compared with conventional unimodal analysis, understanding how brain function and structure relate to one another opens a new biologically relevant assessment of neural mechanisms. However, how function-structure dependencies (FSDs) evolve throughout typical and abnormal neurodevelopment remains elusive. The 22q11.2 deletion syndrome (22q11.2DS) offers an important opportunity to study the development of FSDs and their specific association with the pathophysiology of psychosis., Methods: Previously, we used graph signal processing to combine brain activity and structural connectivity measures in adults, quantifying FSD. Here, we combined FSD with longitudinal multivariate partial least squares correlation to evaluate FSD alterations across groups and among patients with and without mild to moderate positive psychotic symptoms. We assessed 391 longitudinally repeated resting-state functional and diffusion-weighted magnetic resonance images from 194 healthy control participants and 197 deletion carriers (ages 7-34 years, data collected over a span of 12 years)., Results: Compared with control participants, patients with 22q11.2DS showed a persistent developmental offset from childhood, with regions of hyper- and hypocoupling across the brain. Additionally, a second deviating developmental pattern showed an exacerbation during adolescence, presenting hypocoupling in the frontal and cingulate cortices and hypercoupling in temporal regions for patients with 22q11.2DS. Interestingly, the observed aggravation during adolescence was strongly driven by the group with positive psychotic symptoms., Conclusions: These results confirm a central role of altered FSD maturation in the emergence of psychotic symptoms in 22q11.2DS during adolescence. The FSD deviations precede the onset of psychotic episodes and thus offer a potential early indication for behavioral interventions in individuals at risk., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Hippocampal volume (HV) is sensitive to environmental influences. Under normative conditions in humans, HV increases linearly into childhood and asymptotes in early adulthood. Studies of humans and nonhuman animals have provided evidence of inverse relationships between several measures of stress and HV., Methods: Using structural equation modeling, this study aimed to characterize the relationships of age, basal cortisol, biological sex, and lifetime perceived stress with bilateral HV in a sample of healthy adolescents and adolescents at clinical high risk for psychosis (CHR-P) (N = 571, 43% female; age range = 12-19.9 years). This sample included 469 individuals at CHR-P and 102 healthy comparison participants from the combined baseline cohorts of the second and third NAPLS (North American Prodrome Longitudinal Study)., Results: A structural model that constrained the individual effects of basal cortisol and perceived stress to single path coefficients, and freely estimated the effects of age and biological sex in group models, optimized model fit and parsimony relative to other candidate models. Significant inverse relationships between basal cortisol and bilateral HV were observed in adolescents at CHR-P and healthy comparison participants. Significant sex differences in bilateral HV were also observed, with females demonstrating smaller HV than males in both groups., Conclusions: Multigroup structural equation modeling revealed heterogeneity in the relationships of age and biological sex with basal cortisol, lifetime perceived stress, and bilateral HV in individuals at CHR-P and healthy comparison participants. Moreover, the findings support previous literature indicating that elevated basal cortisol is a nonspecific risk factor for reduced HV., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Despite longstanding interest in the central cholinergic system in schizophrenia (SCZ), cholinergic imaging studies with patients have been limited to receptors. Here, we conducted a proof-of-concept positron emission tomography study using [ 18 F]-VAT, a new radiotracer that targets the vesicular acetylcholine transporter as a proxy measure of acetylcholine transmission capacity, in patients with SCZ and explored relationships of vesicular acetylcholine transporter with clinical symptoms and cognition., Methods: A total of 18 adult patients with SCZ or schizoaffective disorder (the SCZ group) and 14 healthy control participants underwent a positron emission tomography scan with [ 18 F]-VAT. Distribution volume (V T ) for [ 18 F]-VAT was derived for each region of interest, and group differences in V T were assessed with 2-sample t tests. Functional significance was explored through correlations between V T and scores on the Positive and Negative Syndrome Scale and a computerized neurocognitive battery (PennCNB)., Results: No group differences in [ 18 F]-VAT V T were observed. However, within the SCZ group, psychosis symptom severity was positively associated with V T in multiple regions of interest, with the strongest effects in the hippocampus, thalamus, midbrain, cerebellum, and cortex. In addition, in the SCZ group, working memory performance was negatively associated with V T in the substantia innominata and several cortical regions of interest including the dorsolateral prefrontal cortex., Conclusions: In this initial study, the severity of 2 important features of SCZ-psychosis and working memory deficit-was strongly associated with [ 18 F]-VAT V T in several cortical and subcortical regions. These correlations provide preliminary evidence of cholinergic activity involvement in SCZ and, if replicated in larger samples, could lead to a more complete mechanistic understanding of psychosis and cognitive deficits in SCZ and the development of therapeutic targets., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Psychomotor disturbances are observed across psychiatric disorders and often manifest as psychomotor slowing, agitation, disorganized behavior, or catatonia. Psychomotor function includes both cognitive and motor components, but the neural circuits driving these subprocesses and how they relate to symptoms have remained elusive for centuries., Methods: We analyzed data from the HCP-EP (Human Connectome Project for Early Psychosis), a multisite study of 125 participants with early psychosis and 58 healthy participants with resting-state functional magnetic resonance imaging and clinical characterization. Psychomotor function was assessed using the 9-hole pegboard task, a timed motor task that engages mechanical and psychomotor components of action, and tasks assessing processing speed and task switching. We used multivariate pattern analysis of whole-connectome data to identify brain correlates of psychomotor function., Results: We identified discrete brain circuits driving the cognitive and motor components of psychomotor function. In our combined sample of participants with psychosis (n = 89) and healthy control participants (n = 52), the strongest correlates of psychomotor function (pegboard performance) (p < .005) were between a midline cerebellar region and left frontal region and presupplementary motor area. Psychomotor function was correlated with both cerebellar-frontal connectivity (r = 0.33) and cerebellar-presupplementary motor area connectivity (r = 0.27). However, the cognitive component of psychomotor performance (task switching) was correlated only with cerebellar-frontal connectivity (r = 0.19), whereas the motor component (processing speed) was correlated only with cerebellar-presupplementary motor area connectivity (r = 0.15), suggesting distinct circuits driving unique subprocesses of psychomotor function., Conclusions: We identified cerebellar-cortical circuits that drive distinct subprocesses of psychomotor function. Future studies should probe relationships between cerebellar connectivity and psychomotor performance using neuromodulation., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Elevated inflammation and impaired white matter (WM) microstructure have been observed in bipolar disorder (BD). The link between inflammation, WM integrity, and psychiatric symptoms in BD-II depression (BDII-D) remains unknown. We aimed to define BDII-D subgroups through the interplay of inflammation and WM microstructure, and to explore differences in psychiatric symptoms between subgroups, thus offering insight into elucidating the explanatory measures linked to BDII-D., Methods: WM differences were compared between 146 BDII-D individuals and 151 health controls (HCs) by Tract-Based Spatial Statistics. Partial correlation with multiple comparison corrections was used to explore associations between WM, inflammation, and psychiatric symptoms. The canonical correlation analysis metrics of WM and inflammation followed by k-means clustering were used to define WM microstructural-inflammation subgroups of BDII-D. The differences in clinical profiles were compared between the subgroups., Results: Compared with HCs, BDII-D showed significant WM alterations in the anterior thalamic radiation (ATR), cingulum, forceps, and inferior fronto-occipital fasciculus. In BDII-D, lower fraction anisotropy (FA) within the right ATR and cingulum were significantly associated with higher interleukin-6, while lower FA in the cingulum and lower axial diffusivity in the forceps major exhibited significant links with higher C-reactive protein. Among the subgroups identified, subgroup II characterized by elevated inflammation and impaired WM integrity displayed greater psychiatric symptoms., Conclusions: WM alterations are concentrated in emotional neurocircuits and are linked to inflammation in BDII-D. WM-inflammation subgroups exhibit distinct variations in psychiatric symptoms. Thus, WM alterations and inflammation might be an explanatory process in the pathophysiology of BDII-D., Competing Interests: Declaration of competing interest MW is a member of the advisory boards and gave presentations for the following companies: Boehringer Ingelheim, Germany; Bayer AG, Germany; and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and from Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with major depression unrelated to this investigation. All other authors report no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: A 34-year-old woman who presented with severe psychosis and clinical features of Cushing syndrome underwent 18 F-FDG PET/CT that revealed hypermetabolic lung lesion along with predominantly increased metabolism of bilateral basal ganglia, a scintigraphic correlate of acute psychosis. The lesion was surgically excised and histopathologically proven to be adrenocorticotropic hormone-producing lung carcinoid. Posttreatment 18 F-FDG PET scan showed restoration of normal brain metabolism with complete reversal of psychosis. Even though rare, one should be aware of psychosis as an initial presentation of Cushing syndrome and use of 18 F-FDG PET/CT for mapping brain metabolism as shown in this case., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Hypothesis: Abnormal thalamic nuclei volumes and their link to cognitive impairments have been observed in schizophrenia. However, whether and how this finding extends to the schizophrenia spectrum is unknown. We hypothesized a distinct pattern of aberrant thalamic nuclei volume across the spectrum and examined its potential associations with cognitive symptoms., Study Design: We performed a FreeSurfer-based volumetry of T1-weighted brain MRIs from 137 healthy controls, 66 at-risk mental state (ARMS) subjects, 89 first-episode psychosis (FEP) individuals, and 126 patients with schizophrenia to estimate thalamic nuclei volumes of six nuclei groups (anterior, lateral, ventral, intralaminar, medial, and pulvinar). We used linear regression models, controlling for sex, age, and estimated total intracranial volume, both to compare thalamic nuclei volumes across groups and to investigate their associations with positive, negative, and cognitive symptoms., Study Results: We observed significant volume alterations in medial and lateral thalamic nuclei. Medial nuclei displayed consistently reduced volumes across the spectrum compared to controls, while lower lateral nuclei volumes were only observed in schizophrenia. Whereas positive and negative symptoms were not associated with reduced nuclei volumes across all groups, higher cognitive scores were linked to lower volumes of medial nuclei in ARMS. In FEP, cognition was not linked to nuclei volumes. In schizophrenia, lower cognitive performance was associated with lower medial volumes., Conclusions: Results demonstrate distinct thalamic nuclei volume reductions across the schizophrenia spectrum, with lower medial nuclei volumes linked to cognitive deficits in ARMS and schizophrenia. Data suggest a distinctive trajectory of thalamic nuclei abnormalities along the course of schizophrenia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background and Hypothesis: Brain development/aging is not uniform across individuals, spawning efforts to characterize brain age from a biological perspective to model the effects of disease and maladaptive life processes on the brain. The brain age gap represents the discrepancy between estimated brain biological age and chronological age (in this case, based on structural magnetic resonance imaging, MRI). Structural MRI studies report an increased brain age gap (biological age > chronological age) in schizophrenia, with a greater brain age gap related to greater negative symptom severity. Less is known regarding the nature of this gap early in schizophrenia (ESZ), if this gap represents a psychosis conversion biomarker in clinical high-risk (CHR-P) individuals, and how altered brain development and/or aging map onto specific symptom facets., Study Design: Using structural MRI, we compared the brain age gap among CHR-P (n = 51), ESZ (n = 78), and unaffected comparison participants (UCP; n = 90), and examined associations with CHR-P psychosis conversion (CHR-P converters n = 10; CHR-P non-converters; n = 23) and positive and negative symptoms., Study Results: ESZ showed a greater brain age gap relative to UCP and CHR-P (Ps < .010). CHR-P individuals who converted to psychosis showed a greater brain age gap (P = .043) relative to CHR-P non-converters. A larger brain age gap in ESZ was associated with increased experiential (P = .008), but not expressive negative symptom severity., Conclusions: Consistent with schizophrenia pathophysiological models positing abnormal brain maturation, results suggest abnormal brain development is present early in psychosis. An increased brain age gap may be especially relevant to motivational and functional deficits in schizophrenia., (Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2024.)

Abnormal brain aging is suggested in epilepsy. Given the brain network dysfunction in epilepsy, the white matter tracts, which primarily interconnect brain regions, could be of special importance. We focused on white matter brain aging in diverse forms of epilepsy and comorbid psychosis. We obtained brain diffusion tensor imaging (DTI) data at 3 T-MRI in 257 patients with epilepsy and 429 healthy subjects. The tract-based fractional anisotropy values of the healthy subjects were used to build a brain-age prediction model, and we calculated the brain-predicted age difference (brain-PAD: predicted age-chronological age) of all subjects. As a result, almost all epilepsy categories showed significantly increased brain-PAD (p < 0.001), including temporal lobe epilepsy (TLE) with no MRI-lesion (+ 4.2 yr), TLE with hippocampal sclerosis (+ 9.1 yr), extratemporal focal epilepsy (+ 5.1 yr), epileptic encephalopathy or progressive myoclonus epilepsy (+ 18.4 yr), except for idiopathic generalized epilepsy (IGE). Patients with psychogenic non-epileptic seizures also presented increased brain-PAD. In TLE, interictal psychosis significantly raised brain-PAD by 8.7 years. In conclusion, we observed increased brain aging in most types of epilepsy, which was generally consistent with brain morphological aging results in previous studies. Psychosis may accelerate brain aging in TLE. These findings may suggest abnormal aging mechanisms in epilepsy and comorbid psychotic symptoms., (© 2024. The Author(s).)

Background: Psychosis involves a distortion of thought content, which is partly reflected in anomalous ways in which words are semantically connected into utterances in speech. We sought to explore how these linguistic anomalies are realized through putative circuit-level abnormalities in the brain's semantic network., Methods: Using a computational large-language model, Bidirectional Encoder Representations from Transformers (BERT), we quantified the contextual expectedness of a given word sequence (perplexity) across 180 samples obtained from descriptions of 3 pictures by patients with first-episode schizophrenia (FES) and controls matched for age, parental social status, and sex, scanned with 7 T ultra-high field functional magnetic resonance imaging (fMRI). Subsequently, perplexity was used to parametrize a spectral dynamic causal model (DCM) of the effective connectivity within (intrinsic) and between (extrinsic) 4 key regions of the semantic network at rest, namely the anterior temporal lobe, the inferior frontal gyrus (IFG), the posterior middle temporal gyrus (MTG), and the angular gyrus., Results: We included 60 participants, including 30 patients with FES and 30 controls. We observed higher perplexity in the FES group, indicating that speech was less predictable by the preceding context among patients. Results of Bayesian model comparisons showed that a DCM including the group by perplexity interaction best explained the underlying patterns of neural activity. We observed an increase of self-inhibitory effective connectivity within the IFG, as well as reduced self-inhibitory tone within the pMTG, in the FES group. An increase in self-inhibitory tone in the IFG correlated strongly and positively with inter-regional excitation between the IFG and posterior MTG, while self-inhibition of the posterior MTG was negatively correlated with this interregional excitation., Limitation: Our design did not address connectivity in the semantic network during tasks that selectively activated the semantic network, which could corroborate findings from this resting-state fMRI study. Furthermore, we do not present a replication study, which would ideally use speech in a different language., Conclusion: As an explanation for peculiar speech in psychosis, these results index a shift in the excitatory-inhibitory balance regulating information flow across the semantic network, confined to 2 regions that were previously linked specifically to the executive control of meaning. Based on our approach of combining a large language model with causal connectivity estimates, we propose loss in semantic control as a potential neurocognitive mechanism contributing to disorganization in psychosis., Competing Interests: Competing interests:: Maria Francisca Alonso-Sánchez is a member of the steering committee of the Discourse in Psychosis consortium. Rui He reports support meeting or travel support from the European Research Council and the Department of Science and Technology of Guangdong Province. Lena Palaniyappan reports speaker or consultant fees from Janssen Canada and Otsuka Canada, SPMM Course Limited, and the Canadian Psychiatric Association, book royalties from Oxford University Press, and investigator-initiated educational grants from Janssen Canada, Sunovion, and Otsuka Canada. No other competing interests were declared., (© 2024 CMA Impact Inc. or its licensors.)

People affected by psychotic, depressive and developmental disorders are at a higher risk for alcohol and tobacco use. However, the further associations between alcohol/tobacco use and symptoms/cognition in these disorders remain unexplored. We identified multimodal brain networks involving alcohol use (n = 707) and tobacco use (n = 281) via supervised multimodal fusion and evaluated if these networks affected symptoms and cognition in people with psychotic (schizophrenia/schizoaffective disorder/bipolar, n = 178/134/143), depressive (major depressive disorder, n = 260) and developmental (autism spectrum disorder/attention deficit hyperactivity disorder, n = 421/346) disorders. Alcohol and tobacco use scores were used as references to guide functional and structural imaging fusion to identify alcohol/tobacco use associated multimodal patterns. Correlation analyses between the extracted brain features and symptoms or cognition were performed to evaluate the relationships between alcohol/tobacco use with symptoms/cognition in 6 psychiatric disorders. Results showed that (1) the default mode network (DMN) and salience network (SN) were associated with alcohol use, whereas the DMN and fronto-limbic network (FLN) were associated with tobacco use; (2) the DMN and fronto-basal ganglia (FBG) related to alcohol/tobacco use were correlated with symptom and cognition in psychosis; (3) the middle temporal cortex related to alcohol/tobacco use was associated with cognition in depression; (4) the DMN related to alcohol/tobacco use was related to symptom, whereas the SN and limbic system (LB) were related to cognition in developmental disorders. In summary, alcohol and tobacco use were associated with structural and functional abnormalities in DMN, SN and FLN and had significant associations with cognition and symptoms in psychotic, depressive and developmental disorders likely via different brain networks. Further understanding of these relationships may assist clinicians in the development of future approaches to improve symptoms and cognition among psychotic, depressive and developmental disorders., (© 2024. The Author(s).)

Background: Intrinsic brain network connectivity is already altered in first-episode psychosis (FEP), but the longitudinal trajectories of network connectivity, especially in response to antipsychotic treatment, remain poorly understood. The goal of this study was to investigate how antipsychotic medications affect higher-order intrinsic brain network connectivity in FEP., Methods: Data from 87 antipsychotic medication-naïve patients with FEP and 87 healthy control participants were used. Medication-naïve patients received antipsychotic treatment for 16 weeks. Resting-state functional connectivity (FC) of the default mode, salience, dorsal attention, and executive control networks were assessed prior to treatment and at 6 and 16 weeks after treatment. We evaluated baseline and FC changes using linear mixed models to test group × time interactions within each network. Associations between FC changes after 16 weeks and response to treatment were also evaluated., Results: Prior to treatment, significant group differences in all networks were found. However, significant trajectory changes in FC were found only in the default mode and executive control networks. Changes in FC in these networks were associated with treatment response. Several sensitivity analyses showed a consistent normalization of executive control network FC in response to antipsychotic treatment., Conclusions: Here, we found that alterations in intrinsic brain network FC were not only alleviated with antipsychotic treatment, but the extent of this normalization was also associated with the degree of reduction in symptom severity. Taken together, our data suggest modulation of intrinsic brain network connectivity (mainly frontoparietal connectivity) as a mechanism underlying antipsychotic treatment response in FEP., (Copyright © 2024. Published by Elsevier Inc.)

Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, p FDR  < 0.001) and across its subfields (all p FDR  < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all p FDR  < 0.001) was significantly reduced (t(69) = -5.1, p FDR  < 0.001) and normalized to HC levels (F(1,41) = 0.4, p FDR  = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis., (© 2024. The Author(s).)

Background: Patients with psychosis and patients with depression exhibit widespread neurobiological abnormalities. The analysis of dynamic functional connectivity (dFC) allows for the detection of changes in complex brain activity patterns, providing insights into common and unique processes underlying these disorders., Methods: We report the analysis of dFC in a large sample including 127 patients at clinical high risk for psychosis, 142 patients with recent-onset psychosis, 134 patients with recent-onset depression, and 256 healthy control participants. A sliding window-based technique was used to calculate the time-dependent FC in resting-state magnetic resonance imaging data, followed by clustering to reveal recurrent FC states in each diagnostic group., Results: We identified 5 unique FC states, which could be identified in all groups with high consistency (mean r = 0.889 [SD = 0.116]). Analysis of dynamic parameters of these states showed a characteristic increase in the lifetime and frequency of a weakly connected FC state in patients with recent-onset depression (p < .0005) compared with the other groups and a common increase in the lifetime of an FC state characterized by high sensorimotor and cingulo-opercular connectivities in all patient groups compared with the healthy control group (p < .0002). Canonical correlation analysis revealed a mode that exhibited significant correlations between dFC parameters and clinical variables (r = 0.617, p < .0029), which was associated with positive psychosis symptom severity and several dFC parameters., Conclusions: Our findings indicate diagnosis-specific alterations of dFC and underline the potential of dynamic analysis to characterize disorders such as depression and psychosis and clinical risk states., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Individuals with schizophrenia (SZ) and auditory hallucinations (AHs) display a distorted sense of self and self-other boundaries. Alterations of activity in midline cortical structures such as the prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) during self-reference as well as in the superior temporal gyrus (STG) have been proposed as neuromarkers of SZ and AHs., Methods: In this randomized, participant-blinded, sham-controlled trial, 22 adults (18 males) with SZ spectrum disorders (SZ or schizoaffective disorder) and frequent medication-resistant AHs received one session of real-time fMRI neurofeedback (NFB) either from the STG (n = 11; experimental group) or motor cortex (n = 11; control group). During NFB, participants were instructed to upregulate their STG activity by attending to pre-recorded sentences spoken in their own voice and downregulate it by ignoring unfamiliar voices. Before and after NFB, participants completed a self-reference task where they evaluated if trait adjectives referred to themselves (self condition), Abraham Lincoln (other condition), or whether adjectives had a positive valence (semantic condition). FMRI activation analyses of self-reference task data tested between-group changes after NFB (self>semantic, post>pre-NFB, experimental>control). Analyses were pre-masked within a self-reference network., Results: Activation analyses revealed significantly (p < 0.001) greater activation increase in the experimental, compared to the control group, after NFB within anterior regions of the self-reference network (mPFC, ACC, superior frontal cortex)., Conclusions: STG-NFB was associated with activity increase in the mPFC, ACC, and superior frontal cortex during self-reference. Modulating the STG is associated with activation changes in other, not-directly targeted, regions subserving higher-level cognitive processes associated with self-referential processes and AHs psychopathology in SZ., Clinicaltrials: GOV: Rt-fMRI Neurofeedback and AH in Schizophrenia; https://clinicaltrials.gov/study/NCT03504579., Competing Interests: Declaration of competing interest All authors declare that they have no actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three (3) years of beginning the work submitted that could inappropriately influence, or be perceived to influence, their work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: Studies using human postmortem tissue and imaging with positron emission tomography (PET) support a low hippocampal availability of the α7 nicotinic acetylcholine receptor (α7-nAChR) in psychotic conditions, particularly in schizophrenia or schizoaffective disorder (nonaffective psychosis). If validated further, the finding may have implications for clinical diagnosis and treatment., Objective: To test for lower availability of the α7-nAChR in the hippocampus of individuals with recent-onset psychosis compared with healthy control individuals and its association with lower cognitive performance or higher psychotic symptom burden within recent-onset psychosis., Design, Setting, and Participants: In this cross-sectional study, healthy individuals without history of psychosis and patients within 10 years of a first onset of psychotic disorder were recruited from the greater Baltimore, Maryland, and Washington, DC, area. Fluorine 18-labeled ASEM ([18F] ASEM) PET data were acquired from participants enrolled between March 1, 2014, and July 31, 2023, from an academic research institution. Data acquired between March 1, 2014, and January 31, 2018 (n = 26), were published as a pilot study and were combined with new data acquired between January 1, 2019, and July 31, 2023 (n = 33)., Main Outcome and Measures: Regional [18F]ASEM total distribution volume (VT) that measures α7-nAChR availability, global cognition composite score, and total scores on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms., Results: A total of 59 participants (30 women [51%]; mean [SD] age, 25.5 [5.2] years), including 35 with recent-onset psychosis and 24 healthy controls, completed the study. In age-adjusted analyses, lower hippocampal [18F]ASEM VT was found in individuals with recent-onset psychosis (mean [SE], 17.87 [0.60]) compared with healthy controls (mean [SE], 19.82 [0.73]) (P = .04). In addition, [18F]ASEM VT was lower in individuals with nonaffective psychosis (mean [SE], 16.30 [0.83]) compared with healthy controls (P = .006) or those with affective psychosis (mean [SE], 19.34 [0.80]) (P = .03). Across recent-onset psychosis and after controlling for age, lower hippocampal [18F]ASEM VT was associated with more positive (r = -0.44; P = .009) but not negative symptoms, and higher hippocampal VT was associated with better global cognition composite score (r = 0.38; P = .03)., Conclusions and Relevance: In this cross-sectional study of individuals with recent-onset psychosis compared with healthy controls, a lower hippocampal α7-nAChR availability was found in recent-onset psychosis, and its availability was lower in those with nonaffective vs affective psychosis. Further study of the association between low availability of the α7-nAChR and recent-onset psychosis is warranted toward informing diagnostic or therapeutic strategies related to these findings.

Background: Recent research has demonstrated that the dorsal striatum is directly associated with the integration of cognitive, sensory-motor, and motivational/emotional data. Disruptions in the corticostriatal circuit have been implicated in the pathophysiology of psychosis. The dorsal striatum was reported to show lateralized pathology in psychotic disorders. In this study, we aimed to analyze the laterality of the dorsal striatum with texture analysis of T2-weighted magnetic resonance imaging (MRI) images from schizoaffective disorder (SAD) patients., Methods: Twenty SAD patients, met the inclusion criteria and had available cranial MRI data were assigned as the patient group. Twenty healthy individuals were determined as the control group. Texture analysis values were obtained from striatum region of interests (ROI) generated from T2-weighted MRI images. Data are presented as mean and standard deviation. The suitability of the data for normal distribution was analyzed with the Kolmogorov-Smirnov test. Analysis of variance (ANOVA) test (Post Hoc TUKEY) was employed to compare the group data based on test findings., Results: There was no significant difference between the groups in terms of gender and age. There were differences in the values of texture analysis parameters of both caudate and putamen nuclei in comparison to controls. We identified differences in the left dorsal striatum nuclei in SAD. The differences in the putamen were more and more pronounced than in the caudate., Conclusions: Texture analyses suggest that the left dorsal striatum nuclei may be different in SAD patients. Further studies are needed to determine the pathophysiology of SAD and how it may affect disease treatment.

We aimed to examine the hippocampus and amygdala volumes in patients with schizoaffective disorder with the notion that schizoaffective disorder has strong resemblance of clinical presentation with schizophrenia and bipolar disorder and that there have been studies on regions of interest volumes in patients with schizophrenia and bipolar disorder but not in patients with schizoaffective disorder. Eighteen patients with schizoaffective disorder and nineteen healthy controls were included into the study. Hippocampus and amygdala volumes were examined by using the MRI. Both hippocampus and amygdala volumes were statistically significantly reduced in patients with schizoaffective disorder compared to those of the healthy control comparisons (p<0.001 for the hippocampus and p<0.001 for the amygdala). In summary, our findings of the present study suggest that patients with schizoaffective disorder seem to have smaller volumes of the hippocampus and amygdala regions and that our results were in accordance with those obtained both in patients with schizophrenia and bipolar disorder, considering that schizoaffective disorder might have neuroanatomic similarities with both schizophrenia and bipolar disorder. Beacuse of some limitations aforementioned especially age, it is required to replicate our present results in this patient group., Competing Interests: Declaration of competing interest The authors have confirmed that there are not any conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cortical thickness (CT) alterations, mismatch negativity (MMN) reductions, and cognitive deficits are robust findings in first-episode psychosis (FEP). However, most studies focused on medicated patients, leaving gaps in our understanding of the interrelationships between CT, MMN, neurocognition, and psychosocial functioning in unmedicated FEP. This study aimed to employ multiple mediation analysis to investigate potential pathways among these variables in unmedicated drug-naïve FEP., Methods: We enrolled 28 drug-naïve FEP and 34 age and sex-matched healthy controls. Clinical symptoms, neurocognition, psychosocial functioning, auditory duration MMN, and T1 structural magnetic resonance imaging data were collected. We measured CT in the superior temporal gyrus (STG), a primary MMN-generating region., Results: We found a significant negative correlation between MMN amplitude and bilateral CT of STG (CT&#95;STG) in FEP (left: r = -.709, P < .001; right: r = -.612, P = .008). Multiple mediation models revealed that a thinner left STG cortex affected functioning through both direct (24.66%) and indirect effects (75.34%). In contrast, the effects of the right CT&#95;STG on functioning were mainly mediated through MMN and neurocognitive pathways., Conclusions: Bilateral CT&#95;STG showed significant association with MMN, and MMN plays a mediating role between CT and cognition. Both MMN alone and its interaction with cognition mediated the effects of structural alterations on psychosocial function. The decline in overall function in FEP may stem from decreased CT&#95;STG, leading to subsequent MMN deficits and neurocognitive dysfunction. These findings underline the crucial role of MMN in elucidating how subtle structural alterations can impact neurocognition and psychosocial function in FEP., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Heterogeneity in the etiology, pathophysiology, and clinical features of schizophrenia challenges clinicians and researchers. A helpful approach could be stratifying patients according to the presence or absence of clinical features of the deficit syndrome (DS). DS is characterized by enduring and primary negative symptoms, a clinically less heterogeneous subtype of the illness, and patients with features of DS are thought to present abnormal brain network characteristics, however, this idea has received limited attention. We investigated functional brain network topology in patients displaying deficit features and those who do not., Design: We applied graph theory analytics to resting-state functional magnetic resonance imaging data of 61 antipsychotic medication-naïve first episode psychosis patients, 18 DS and 43 non-deficit schizophrenia (NDS), and 72 healthy controls (HC). We quantified small-worldness, global and nodal efficiency measures, shortest path length, nodal local efficiency, and synchronization and contrasted them among the 3 groups., Results: DS presented decreased network integration and segregation compared to HC and NDS. DS showed lower global efficiency, longer global path lengths, and lower global local efficiency. Nodal efficiency was lower and the shortest path length was longer in DS in default mode, ventral attention, dorsal attention, frontoparietal, limbic, somatomotor, and visual networks compared to HC. Compared to NDS, DS showed lower efficiency and longer shortest path length in default mode, limbic, somatomotor, and visual networks., Conclusions: Our data supports increasing evidence, based on topological perturbations of the functional connectome, that deficit syndrome may be a distinct form of the illness., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Hypothesis: Structural brain alterations are well-established features of schizophrenia but they do not effectively predict disease/disease risk. Similar to polygenic risk scores in genetics, we integrated multifactorial aspects of brain structure into a summary "Neuroscore" and examined its potential as a marker of disease., Study Design: We extracted measures from T1-weighted scans and diffusion tensor imaging (DTI) models from three studies with schizophrenia and healthy individuals. We calculated individual-level summary scores (Neuroscores) for T1-weighted and DTI measures and a combined score (Multimodal Neuroscore-MM). We assessed each score's ability to differentiate schizophrenia cases from controls and its relationship to clinical symptomatology, intelligence quotient (IQ), and medication dosage. We assessed Neuroscore specificity by performing all analyses in a more inclusive psychosis sample and by using scores generated from MDD effect sizes., Study Results: All Neuroscores significantly differentiated schizophrenia cases from controls (T1 d = 0.56, DTI d = 0.29, MM d = 0.64) to a greater degree than individual brain regions. Higher Neuroscores (ie, increased liability) were associated with lower IQ (T1 β = -0.26, DTI β = -0.15, MM β = -0.30). Higher T1-weighted Neuroscores were associated with higher positive and negative symptom severity (Positive β = 0.21, Negative β = 0.16); Higher Multimodal Neuroscores were associated with higher positive symptom severity (β = 0.30). SZ Neuroscores outperformed MDD Neuroscores in predicting IQ (T1: z = 3.5, q = 0.0007; MM: z = 1.8, q = 0.05)., Conclusions: Neuroscores are a step toward leveraging widespread structural brain alterations in psychosis to identify robust neurobiological markers of disease. Future studies will assess ways to improve neuroscore calculation, including developing the optimal methods to calculate neuroscores and considering disorder overlap., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Theories of psychotic illness suggest that abnormal intrinsic functional connectivity may explain its characteristic positive and disorganization symptoms as well as lead to impaired general functioning. Here we used resting state functional magnetic resonance imaging (fMRI) to evaluate associations between these symptoms and the degree to which global connectivity is abnormal in early psychosis (EP). Eighty-six healthy controls (HCs) and 108 individuals with EP with resting state fMRI data were included in primary analyses. The EP group included 83 participants with schizophrenia-spectrum disorders and 25 with bipolar disorder type I with psychotic features. A global intrinsic connectivity "similarity index" for each EP individual was determined by calculating its correlation with the average HC connectivity matrix extracted using Schaefer atlases of multiple parcellations (100, 200, 300, and 400 region parcellations). As hypothesized, connectivity similarity with the average HC matrix was negatively associated with Brief Psychiatric Rating Scale total score, Scale for the Assessment of Positive Symptoms total score, and disorganization symptoms. Similarity was also positively associated with Global Assessment of Functioning score. Results were not driven by sex or diagnosis effects and were consistent across parcellation schemes. These results support the hypothesis that changes in whole-brain connectivity patterns are associated with psychosis symptoms and support the use of functional connectivity as a biomarker for these symptoms in EP., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Cerebellar alterations, including both volumetric changes in the cerebellar vermis and dysfunctions of the corticocerebellar connections, have been documented in psychotic disorders. Starting from the clinical observation of a bipolar patient with cerebellar hypoplasia, the purpose of this review is to summarize the data in the literature about the association between hypoplasia of the cerebellar vermis and psychotic disorders [schizophrenia (SCZ) and bipolar disorder (BD)]., Methods: A bibliographic search on PubMed has been conducted, and 18 articles were finally included in the review: five used patients with BD, 12 patients with SCZ and one subject at psychotic risk., Results: For SCZ patients and subjects at psychotic risk, the results of most of the reviewed studies seem to suggest a gray matter volume reduction coupled with an increase in white matter volumes in the cerebellar vermis, compared to healthy controls. Instead, the results of the studies on BD patients are more heterogeneous with evidence showing a reduction, no difference or even an increase in cerebellar vermis volume compared to healthy controls., Conclusions: From the results of the reviewed studies, a possible correlation emerged between cerebellar vermis hypoplasia and psychotic disorders, especially SCZ, ultimately supporting the hypothesis of psychotic disorders as neurodevelopmental disorders., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Decreased white matter (WM) integrity and disturbance in fatty acid composition have been reported in individuals at ultra-high risk of psychosis (UHR). The current study is the first to investigate both WM integrity and erythrocyte membrane polyunsaturated fatty acid (PUFA) levels as potential risk biomarkers for persistent UHR status, and global functioning in UHR individuals. Forty UHR individuals were analysed at baseline for erythrocyte membrane PUFA concentrates. Tract-based spatial statistics (TBSS) was used to analyse fractional anisotropy (FA) and diffusivity measures. Measures of global functioning and psychiatric symptoms were evaluated at baseline and at 12-months. Fatty acids and WM indices did not predict functional outcomes at baseline or 12-months. Significant differences were found in FA between UHR remitters and non-remitters (individuals who no longer met UHR criteria versus those who continued to meet criteria at 12-months). Docosahexaenoic acid (DHA) was found to be a significant predictor of UHR status at 12-months, as was the interaction between the sum of ώ-3 and whole brain FA, and the interaction between the right anterior limb of the internal capsule and the sum of ώ-3. The results confirm that certain fatty acids have a unique relationship with WM integrity in UHR individuals., Competing Interests: Declaration of competing interest The other authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Functional network connectivity (FNC) has previously been shown to distinguish patient groups from healthy controls (HC). However, the overlap across psychiatric disorders such as schizophrenia (SZ), bipolar (BP), and schizoaffective disorder (SAD) is not evident yet. This study focuses on studying the overlap across these three psychotic disorders in both dynamic and static FNC (dFNC/sFNC). We used resting-state fMRI, demographics, and clinical information from the Bipolar-Schizophrenia Network on Intermediate Phenotypes cohort (BSNIP). The data includes three groups of patients with schizophrenia (SZ, N = 181), bipolar (BP, N = 163), and schizoaffective (SAD, N = 130) and HC (N = 238) groups. After estimating each individual's dFNC, we group them into three distinct states. We evaluated two dFNC features, including occupancy rate (OCR) and distance travelled over time. Finally, the extracted features, including both sFNC and dFNC, are tested statistically across patients and HC groups. In addition, we explored the link between the clinical scores and the extracted features. We evaluated the connectivity patterns and their overlap among SZ, BP, and SAD disorders (false discovery rate or FDR corrected p < 0.05). Results showed dFNC captured unique information about overlap across disorders where all disorder groups showed similar pattern of activity in state 2. Moreover, the results showed similar patterns between SZ and SAD in state 1 which was different than BP. Finally, the distance travelled feature of SZ (average R = 0.245, p < 0.01) and combined distance travelled from all disorders was predictive of the PANSS symptoms scores (average R = 0.147, p < 0.01)., Competing Interests: Declaration of competing interest Mohammad Sendi has served as a consultant for Niji Corp. Thomas RomsØy is the CEO of Neurons Inc., (Copyright © 2024 Elsevier B.V. All rights reserved.)

N-acetylasparate and lactate are two prominent brain metabolites closely related to mitochondrial functioning. Prior research revealing lower levels of NAA and higher levels of lactate in the cerebral cortex of patients with schizophrenia suggest possible abnormalities in the energy supply pathway necessary for brain function. Given that stress and adversity are a strong risk factor for a variety of mental health problems, including psychotic disorders, we investigated the hypothesis that stress contributes to abnormal neuroenergetics in patients with schizophrenia. To test this hypothesis, we used the Stress and Adversity Inventory (STRAIN) to comprehensively assess the lifetime stressor exposure profiles of 35 patients with schizophrenia spectrum disorders and 33 healthy controls who were also assessed with proton magnetic resonance spectroscopy at the anterior cingulate cortex using 3 Tesla scanner. Consistent with the hypothesis, greater lifetime stressor exposure was significantly associated with lower levels of N-acetylasparate (β = -0.36, p = .005) and higher levels of lactate (β = 0.43, p = .001). Moreover, these results were driven by patients, as these associations were significant for the patient but not control group. Though preliminary, these findings suggest a possible role for stress processes in the pathophysiology of abnormal neuroenergetics in schizophrenia., Competing Interests: Declaration of competing interest LEH has received, or plans to receive, research funding or consulting fees on research projects from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho, Heptares, Pfizer, Luye Pharma, IGC Pharma, Sound Pharma, Regeneron, and Takeda. Other authors declare no conflicts of interest with respect to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Sensory prediction allows the brain to anticipate and parse incoming self-generated sensory information from externally generated signals. Sensory prediction breakdowns may contribute to perceptual and agency abnormalities in psychosis (hallucinations, delusions). The pons, a central node in a cortico-ponto-cerebellar-thalamo-cortical circuit, is thought to support sensory prediction. Examination of pons connectivity in schizophrenia and its role in sensory prediction abnormalities is lacking., Methods: We examined these relationships using resting-state functional magnetic resonance imaging and the electroencephalography-based auditory N1 event-related potential in 143 participants with psychotic spectrum disorders (PSPs) (with schizophrenia, schizoaffective disorder, or bipolar disorder); 63 first-degree relatives of individuals with psychosis; 45 people at clinical high risk for psychosis; and 124 unaffected comparison participants. This unique sample allowed examination across the psychosis spectrum and illness trajectory. Seeding from the pons, we extracted average connectivity values from thalamic and cerebellar clusters showing differences between PSPs and unaffected comparison participants. We predicted N1 amplitude attenuation during a vocalization task from pons connectivity and group membership. We correlated participant-level connectivity in PSPs and people at clinical high risk for psychosis with hallucination and delusion severity., Results: Compared to unaffected comparison participants, PSPs showed pons hypoconnectivity to 2 cerebellar clusters, and first-degree relatives of individuals with psychosis showed hypoconnectivity to 1 of these clusters. Pons-to-cerebellum connectivity was positively correlated with N1 attenuation; only PSPs with heightened pons-to-postcentral gyrus connectivity showed this pattern, suggesting a possible compensatory mechanism. Pons-to-cerebellum hypoconnectivity was correlated with greater hallucination severity specifically among PSPs with schizophrenia., Conclusions: Deficient pons-to-cerebellum connectivity linked sensory prediction network breakdowns with perceptual abnormalities in schizophrenia. Findings highlight shared features and clinical heterogeneity across the psychosis spectrum., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Psychotic disorders have long been considered neurodevelopmental disorders where excessive synaptic pruning and cortical volume loss are central to disease pathology. We conducted a systematic review of the literature to identify neuroimaging studies specifically examining synaptic density across the psychosis spectrum., Methods: PRISMA guidelines on reporting were followed. We systematically searched MEDLINE, Embase, APA PsycINFO, Web of Science and The Cochrane Library from inception to December 8, 2023, and included all original peer-reviewed articles or completed clinical neuroimaging studies of any modality measuring synaptic density in participants with a diagnosis of psychosis spectrum disorder as well as individuals with psychosis-risk states. The NIH quality assessment tool for observational cohort and cross-sectional studies was used for the risk of bias assessment., Results: Five studies (k = 5) met inclusion criteria, comprising n = 128 adults (psychotic disorder; n = 61 and healthy volunteers; n = 67 and specifically measuring synaptic density via positron emission tomography (PET) imaging of the synaptic vesicle glycoprotein 2 A (SV2A). Three studies were included in our primary meta-analysis sharing the same outcome measure of SV2A binding, volume of distribution (V T ). Regional SV2A V T was reduced in psychotic disorder participants in comparison to healthy volunteers, including the occipital lobe (Mean Difference (MD)= -2.17; 95% CI: -3.36 to -0.98; P < 0.001 ), temporal lobe (MD: -2.03; 95% CI: -3.19 to -0.88; P < 0.001 ), parietal lobe (MD:-1.61; 95% CI: -2.85 to -0.37; P = 0.01), anterior cingulate cortex (MD= -1.47; 95% CI: -2.45 to -0.49; P = 0.003), frontal cortex (MD: -1.16; 95% CI: -2.18 to -0.15; P = 0.02), amygdala (MD: -1.36; 95% CI: -2.20 to -0.52, p = 0.002), thalamus (MD:-1.46; 95% CI:-2.46 to -0.46, p = 0.004) and hippocampus (MD= -0.96; 95% CI: -1.59 to -0.33; P = 0.003)., Conclusions: Preliminary studies provide in vivo evidence for reduced synaptic density in psychotic disorders. However, replication of findings in larger samples is required prior to definitive conclusions being drawn., Prospero: CRD42022359018., (© 2024. The Author(s).)

Background: Individuals with schizophrenia spectrum disorders (SSD) often demonstrate cognitive impairments, associated with poor functional outcomes. While neurobiological heterogeneity has posed challenges when examining social cognition in SSD, it provides a unique opportunity to explore brain-behavior relationships. The aim of this study was to investigate the relationship between individual variability in functional connectivity during resting state and the performance of a social task and social and non-social cognition in a large sample of controls and individuals diagnosed with SSD., Methods: Neuroimaging and behavioral data were analyzed for 193 individuals with SSD and 155 controls (total n = 348). Individual variability was quantified through mean correlational distance (MCD) of functional connectivity between participants; MCD was defined as a global 'variability score'. Pairwise correlational distance was calculated as 1 - the correlation coefficient between a given pair of participants, and averaging distance from one participant to all other participants provided the mean correlational distance metric. Hierarchical regressions were performed on variability scores derived from resting state and Empathic Accuracy (EA) task functional connectivity data to determine potential predictors (e.g., age, sex, neurocognitive and social cognitive scores) of individual variability., Results: Group comparison between SSD and controls showed greater SSD MCD during rest (p = 0.00038), while no diagnostic differences were observed during task (p = 0.063). Hierarchical regression analyses demonstrated the persistence of a significant diagnostic effect during rest (p = 0.008), contrasting with its non-significance during the task (p = 0.50), after social cognition was added to the model. Notably, social cognition exhibited significance in both resting state and task conditions (both p = 0.01)., Conclusions: Diagnostic differences were more prevalent during unconstrained resting scans, whereas the task pushed participants into a more common pattern which better emphasized transdiagnostic differences in cognitive abilities. Focusing on variability may provide new opportunities for interventions targeting specific cognitive impairments to improve functional outcomes., Competing Interests: Declaration of competing interest LDO receives grant support from the Brain & Behavior Research Foundation (BBRF). EWD has received funding from BBRF, National Institute of Mental Health (NIMH), Canadian Institutes of Health Research (CIHR), and Centre for Addiction and Mental Health (CAMH) Foundation. GF currently receives funding from the CIHR, the CAMH Foundation, and the University of Toronto, and has served on an advisory board for AbbVie. AKM receives grant support from the NIMH (R01 MH109508, R01 MH108654, R61 MH120188). RWB has consulted for Boehringer-Ingelheim, serves on the Data Safety and Monitoring Boards of Roche, Merck, and Newron, and has served on the Advisory Boards of Merck, Acadia, Karuna, and Neurocrine. ANV currently receives funding from the NIMH (1/3R01 MH102324, 1/5R01 MH114970), CIHR, Canada Foundation for Innovation, CAMH Foundation, and University of Toronto. CH receives grant support from the NIMH, CIHR, and the CAMH Foundation. All other authors have no interests to declare., (Copyright © 2023. Published by Elsevier Inc.)

There is a lack of knowledge regarding the relationship between proneness to dimensional psychopathological syndromes and the underlying pathogenesis across major psychiatric disorders, i.e., Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizoaffective Disorder (SZA), and Schizophrenia (SZ). Lifetime psychopathology was assessed using the OPerational CRITeria (OPCRIT) system in 1,038 patients meeting DSM-IV-TR criteria for MDD, BD, SZ, or SZA. The cohort was split into two samples for exploratory and confirmatory factor analyses. All patients were scanned with 3-T MRI, and data was analyzed with the CAT-12 toolbox in SPM12. Psychopathological factor scores were correlated with gray matter volume (GMV) and cortical thickness (CT). Finally, factor scores were used for exploratory genetic analyses including genome-wide association studies (GWAS) and polygenic risk score (PRS) association analyses. Three factors (paranoid-hallucinatory syndrome, PHS; mania, MA; depression, DEP) were identified and cross-validated. PHS was negatively correlated with four GMV clusters comprising parts of the hippocampus, amygdala, angular, middle occipital, and middle frontal gyri. PHS was also negatively associated with the bilateral superior temporal, left parietal operculum, and right angular gyrus CT. No significant brain correlates were observed for the two other psychopathological factors. We identified genome-wide significant associations for MA and DEP. PRS for MDD and SZ showed a positive effect on PHS, while PRS for BD showed a positive effect on all three factors. This study investigated the relationship of lifetime psychopathological factors and brain morphometric and genetic markers. Results highlight the need for dimensional approaches, overcoming the limitations of the current psychiatric nosology., (© 2024. The Author(s).)

Increasing evidence points toward the role of the extracellular matrix, specifically matrix metalloproteinase 9 (MMP-9), in the pathophysiology of psychosis. MMP-9 is a critical regulator of the crosstalk between peripheral and central inflammation, extracellular matrix remodeling, hippocampal development, synaptic pruning, and neuroplasticity. Here, we aim to characterize the relationship between plasma MMP-9 activity, hippocampal microstructure, and cognition in healthy individuals and individuals with early phase psychosis. We collected clinical, blood, and structural and diffusion-weighted magnetic resonance imaging data from 39 individuals with early phase psychosis and 44 age and sex-matched healthy individuals. We measured MMP-9 plasma activity, hippocampal extracellular free water (FW) levels, and hippocampal volumes. We used regression analyses to compare MMP-9 activity, hippocampal FW, and volumes between groups. We then examined associations between MMP-9 activity, FW levels, hippocampal volumes, and cognitive performance assessed with the MATRICS battery. All analyses were controlled for age, sex, body mass index, cigarette smoking, and years of education. Individuals with early phase psychosis demonstrated higher MMP-9 activity (p < 0.0002), higher left (p < 0.05) and right (p < 0.05) hippocampal FW levels, and lower left (p < 0.05) and right (p < 0.05) hippocampal volume than healthy individuals. MMP-9 activity correlated positively with hippocampal FW levels (all participants and individuals with early phase psychosis) and negatively with hippocampal volumes (all participants and healthy individuals). Higher MMP-9 activity and higher hippocampal FW levels were associated with slower processing speed and worse working memory performance in all participants. Our findings show an association between MMP-9 activity and hippocampal microstructural alterations in psychosis and an association between MMP-9 activity and cognitive performance. Further, more extensive longitudinal studies should examine the therapeutic potential of MMP-9 modulators in psychosis., (© 2024. The Author(s).)

Psychosis in Alzheimer's Disease (AD) is prevalent and indicates poor prognosis. However, the neuropathological, cognitive and brain atrophy patterns underlying these symptoms have not been fully elucidated. In this study, we evaluated 178 patients with AD neuropathological change (ADNC) and ante-mortem volumetric brain magnetic resonance imaging (MRI). Presence of psychosis was determined using the Neuropsychiatric Inventory Questionnaire. Clinical Dementia Rating Sum-of-boxes (CDR-SB) was longitudinally compared between groups with a follow-up of 3000 days using mixed-effects multiple linear regression. Neuropsychological tests closest to the time of MRI and brain regional volumes were cross-sectionally compared. Psychosis was associated with lower age of death, higher longitudinal CDR-SB scores, multi-domain cognitive deficits, higher neuritic plaque severity, Braak stage, Lewy Body pathology (LB) and right temporal lobe regional atrophy. Division according to the presence of LB showed differential patterns of AD-typical pathology, cognitive deficits and regional atrophy. In conclusion, psychosis in ADNC with and without LB has clinical value and associates with subgroup patterns of neuropathology, cognition and regional atrophy., (Copyright © 2024. Published by Elsevier Inc.)