Using brain structural neuroimaging measures to predict psychosis onset for individuals at clinical high-risk.

Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.

Mapping gray and white matter volume abnormalities in early-onset psychosis: an ENIGMA multicenter voxel-based morphometry study.

INTRODUCTION: Regional gray matter (GM) alterations have been reported in early-onset psychosis (EOP, onset before age 18), but previous studies have yielded conflicting results, likely due to small sample sizes and the different brain regions examined. In this study, we conducted a whole brain voxel-based morphometry (VBM) analysis in a large sample of individuals with EOP, using the newly developed ENIGMA-VBM tool. METHODS: 15 independent cohorts from the ENIGMA-EOP working group participated in the study. The overall sample comprised T1-weighted MRI data from 482 individuals with EOP and 469 healthy controls. Each site performed the VBM analysis locally using the standardized ENIGMA-VBM tool. Statistical parametric T-maps were generated from each cohort and meta-analyzed to reveal voxel-wise differences between EOP and healthy controls as well as the individual-based association between GM volume and age of onset, chlorpromazine (CPZ) equivalent dose, and other clinical variables. RESULTS: Compared with healthy controls, individuals with EOP showed widespread lower GM volume encompassing most of the cortex, with the most marked effect in the left median cingulate (Hedges' g = 0.55, p = 0.001 corrected), as well as small clusters of lower white matter (WM), whereas no regional GM or WM volumes were higher in EOP. Lower GM volume in the cerebellum, thalamus and left inferior parietal gyrus was associated with older age of onset. Deficits in GM in the left inferior frontal gyrus, right insula, right precentral gyrus and right superior frontal gyrus were also associated with higher CPZ equivalent doses. CONCLUSION: EOP is associated with widespread reductions in cortical GM volume, while WM is affected to a smaller extent. GM volume alterations are associated with age of onset and CPZ equivalent dose but these effects are small compared to case-control differences. Mapping anatomical abnormalities in EOP may lead to a better understanding of the role of psychosis in brain development during childhood and adolescence.

Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders.

Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits.

Changes in the structure of spontaneous speech predict the disruption of hierarchical brain organization in first-episode psychosis.

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.

Enlarged pituitary gland volume: a possible state rather than trait marker of psychotic disorders.

BACKGROUND: Enlarged pituitary gland volume could be a marker of psychotic disorders. However, previous studies report conflicting results. To better understand the role of the pituitary gland in psychosis, we examined a large transdiagnostic sample of individuals with psychotic disorders. METHODS: The study included 751 participants (174 with schizophrenia, 114 with schizoaffective disorder, 167 with psychotic bipolar disorder, and 296 healthy controls) across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Structural magnetic resonance images were obtained, and pituitary gland volumes were measured using the MAGeT brain algorithm. Linear mixed models examined between-group differences with controls and among patient subgroups based on diagnosis, as well as how pituitary volumes were associated with symptom severity, cognitive function, antipsychotic dose, and illness duration. RESULTS: Mean pituitary gland volume did not significantly differ between patients and controls. No significant effect of diagnosis was observed. Larger pituitary gland volume was associated with greater symptom severity (F = 13.61, p = 0.0002), lower cognitive function (F = 4.76, p = 0.03), and higher antipsychotic dose (F = 5.20, p = 0.02). Illness duration was not significantly associated with pituitary gland volume. When all variables were considered, only symptom severity significantly predicted pituitary gland volume (F = 7.54, p = 0.006). CONCLUSIONS: Although pituitary volumes were not increased in psychotic disorders, larger size may be a marker associated with more severe symptoms in the progression of psychosis. This finding helps clarify previous inconsistent reports and highlights the need for further research into pituitary gland-related factors in individuals with psychosis.

A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup.

Psychosis onset is a transdiagnostic event that leads to a range of psychiatric disorders, which are currently diagnosed through clinical observation. The integration of multimodal biological data could reveal different subtypes of psychosis onset to target for the personalization of care. In this study, we tested the existence of subgroups of patients affected by first-episode psychosis (FEP) with a possible immunopathogenic basis. To do this, we designed a data-driven unsupervised machine learning model to cluster a sample of 127 FEP patients and 117 healthy controls (HC), based on the peripheral blood expression levels of 12 psychosis-related immune gene transcripts. To validate the model, we applied a resampling strategy based on the half-splitting of the total sample with random allocation of the cases. Further, we performed a post-hoc univariate analysis to verify the clinical, cognitive, and structural brain correlates of the subgroups identified. The model identified and validated two distinct clusters: 1) a FEP cluster characterized by the high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A and CXCR3); 2) a cluster consisting of an equal number of FEP and HC subjects, which did not show a relative over or under expression of any immune marker (balanced subgroup). None of the subgroups was related to specific symptoms dimensions or longitudinal diagnosis of affective vs non-affective psychosis. FEP patients included in the balanced immune subgroup showed a thinning of the left supramarginal and superiorfrontal cortex (FDR-adjusted p-values < 0.05). Our results demonstrated the existence of a FEP patients' subgroup identified by a multivariate pattern of immunomarkers involved in inflammatory activation. This evidence may pave the way to sample stratification in clinical studies aiming to develop diagnostic tools and therapies targeting specific immunopathogenic pathways of psychosis.

The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis.

BACKGROUND: Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography. METHODS: Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively. RESULTS: We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right (p = 0.03), but not left (p = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p = .00023; p = .00023) originating in selective PFC subregions. CONCLUSIONS: In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.

The neurobiology of duration of untreated psychosis: a comprehensive review.

Duration of untreated psychosis (DUP) is defined as the time from the onset of psychotic symptoms until the first treatment. Studies have shown that longer DUP is associated with poorer response rates to antipsychotic medications and impaired cognition, yet the neurobiologic correlates of DUP are poorly understood. Moreover, it has been hypothesized that untreated psychosis may be neurotoxic. Here, we conducted a comprehensive review of studies that have examined the neurobiology of DUP. Specifically, we included studies that evaluated DUP using a range of neurobiologic and imaging techniques and identified 83 articles that met inclusion and exclusion criteria. Overall, 27 out of the total 83 studies (32.5%) reported a significant neurobiological correlate with DUP. These results provide evidence against the notion of psychosis as structurally or functionally neurotoxic on a global scale and suggest that specific regions of the brain, such as temporal regions, may be more vulnerable to the effects of DUP. It is also possible that current methodologies lack the resolution needed to more accurately examine the effects of DUP on the brain, such as effects on synaptic density. Newer methodologies, such as MR scanners with stronger magnets, PET imaging with newer ligands capable of measuring subcellular structures (e.g., the PET ligand [11C]UCB-J) may be better able to capture these limited neuropathologic processes. Lastly, to ensure robust and replicable results, future studies of DUP should be adequately powered and specifically designed to test for the effects of DUP on localized brain structure and function with careful attention paid to potential confounds and methodological issues.

The interplay of psychosis and non-compliance with fatal outcome in an adult with MSUD.

Significant progress has been achieved in enhancing early outcomes for individuals with maple syrup urine disease (MSUD), a rare metabolic disorder that leads to the accumulation of branched-chain amino acids leucine, isoleucine, and valine, where leucine is known as the primary neurotoxic metabolite. Newborn screening is helpful in early diagnosis and implementation of dietary treatment, thus reducing neurological deterioration and complications in young children. However, patients face the life-long challenge of maintaining metabolic control through adherence to a strict low-leucine diet to avoid long-term consequences of chronic hyperleucinemia, which include cognitive deficits, mood disorders, and movement disorders. This case report exemplifies the complex involvement of MSUD in adult survivors. Despite presenting early in life, the patient thrived until the onset of psychiatric symptoms. The subject of this case is a 25-year-old woman with MSUD, who remained in her usual state of health until presentation to the emergency department (ED) with psychosis and altered mental status. However, due to a lack of medical records and poor communication, there was a delay in considering MSUD as a primary cause of her psychiatric symptoms. Although a genetics consultation was later arranged and efforts were made to decrease plasma leucine to the therapeutic range, these interventions proved inadequate in halting her deterioration in health. Her condition worsened within 72 h, culminating in her untimely death. This case emphasizes the comorbidity of psychiatric involvement in MSUD, which contributes to metabolic decompensation that can lead to cerebral edema and death. This case also highlights the pressing need for enhanced strategies for the acute management and long-term care of MSUD patients with psychiatric involvement, particularly in scenarios where mental disturbance could lead to noncompliance.

Presenilin Gene Mutation-associated Psychosis: Phenotypic Characteristics and Clinical Implications.

Although psychotic symptoms have been described in association with rare presenilin ( PSEN ) gene mutations underlying early-onset Alzheimer disease (AD), no contemporary reviews on this topic exist. The purpose of this review is to characterize the psychiatric phenotype (specifically with respect to psychosis) of PSEN1 and PSEN2 variant-associated AD. A PubMed search was completed in July 2023. Only articles that described individuals harboring a PSEN1 or PSEN2 mutation who experienced symptoms of psychosis were included in the review. Thirty-three articles describing 52 individuals were included in the review, as well as one other study that provided limited information pertaining to an additional 21 cases. While visual hallucinations were the most common psychotic symptom, followed by persecutory delusions, auditory hallucinations occurred in ~17% of individuals. In ~33% of the reviewed cases psychotic symptoms were present at or near disease onset, and 9 of these individuals experienced auditory hallucinations and/or delusions in the absence of visual hallucinations (~17% of all cases). In many cases, symptoms developed at a relatively young age. As presenilin gene variant-associated psychosis may resemble a primary psychotic disorder, clinicians should be vigilant with respect to screening for signs/symptoms suggestive of neurodegeneration in first-episode psychosis.

A systematic review and meta-analysis of neuroimaging studies examining synaptic density in individuals with psychotic spectrum disorders.

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 (VT). Regional SV2A VT 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.

Differential longitudinal changes of hippocampal subfields in patients with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) is a mental disorder characterized by dietary restriction, fear of gaining weight, and distorted body image. Recent studies indicate that the hippocampus, crucial for learning and memory, may be affected in AN, yet subfield-specific effects remain unclear. We investigated hippocampal subfield alterations in acute AN, changes following weight restoration, and their associations with leptin levels. METHODS: T1-weighted magnetic resonance imaging scans were processed using FreeSurfer. We compared 22 left and right hemispheric hippocampal subfield volumes cross-sectionally and longitudinally in females with acute AN (n = 165 at baseline, n = 110 after partial weight restoration), healthy female controls (HCs; n = 271), and females after long-term recovery from AN (n = 79) using linear models. RESULTS: We found that most hippocampal subfield volumes were significantly reduced in patients with AN compared with HCs (~-3.9%). Certain areas such as the subiculum exhibited no significant reduction in the acute state of AN, while other areas, such as the hippocampal tail, showed strong decreases (~-9%). Following short-term weight recovery, most subfields increased in volume. Comparisons between participants after long-term weight-recovery and HC yielded no differences. The hippocampal tail volume was positively associated with leptin levels in AN independent of body mass index. CONCLUSIONS: Our study provides evidence of differential volumetric differences in hippocampal subfields between individuals with AN and HC and almost complete normalization after weight rehabilitation. These alterations are spatially inhomogeneous and more pronounced compared with other major mental disorders (e.g. major depressive disorder and schizophrenia). We provide novel insights linking hypoleptinemia to hippocampal subfield alterations hinting towards clinical relevance of leptin normalization in AN recovery.

A preliminary choroid plexus volumetric study in individuals with psychosis.

The choroid plexus (ChP) is part of the blood-cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging-based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.

Brain morphometry points to emerging patterns of psychosis, depression, and anxiety vulnerability over a 2-year period in childhood.

BACKGROUND: Gray matter morphometry studies have lent seminal insights into the etiology of mental illness. Existing research has primarily focused on adults and then, typically on a single disorder. Examining brain characteristics in late childhood, when the brain is preparing to undergo significant adolescent reorganization and various forms of serious psychopathology are just first emerging, may allow for a unique and highly important perspective of overlapping and unique pathogenesis. METHODS: A total of 8645 youth were recruited as part of the Adolescent Brain and Cognitive Development study. Magnetic resonance imaging scans were collected, and psychotic-like experiences (PLEs), depressive, and anxiety symptoms were assessed three times over a 2-year period. Cortical thickness, surface area, and subcortical volume were used to predict baseline symptomatology and symptom progression over time. RESULTS: Some features could possibly signal common vulnerability, predicting progression across forms of psychopathology (e.g. superior frontal and middle temporal regions). However, there was a specific predictive value for emerging PLEs (lateral occipital and precentral thickness), anxiety (parietal thickness/area and cingulate), and depression (e.g. parahippocampal and inferior temporal). CONCLUSION: Findings indicate common and distinct patterns of vulnerability for varying forms of psychopathology are present during late childhood, before the adolescent reorganization, and have direct relevance for informing novel conceptual models along with early prevention and intervention efforts.

Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response.

BACKGROUND: Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. METHODS: We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). RESULTS: There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). CONCLUSIONS: These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

Shared and distinct white matter abnormalities in adolescent-onset schizophrenia and adolescent-onset psychotic bipolar disorder.

BACKGROUND: While adolescent-onset schizophrenia (ADO-SCZ) and adolescent-onset bipolar disorder with psychosis (psychotic ADO-BPD) present a more severe clinical course than their adult forms, their pathophysiology is poorly understood. Here, we study potentially state- and trait-related white matter diffusion-weighted magnetic resonance imaging (dMRI) abnormalities along the adolescent-onset psychosis continuum to address this need. METHODS: Forty-eight individuals with ADO-SCZ (20 female/28 male), 15 individuals with psychotic ADO-BPD (7 female/8 male), and 35 healthy controls (HCs, 18 female/17 male) underwent dMRI and clinical assessments. Maps of extracellular free-water (FW) and fractional anisotropy of cellular tissue (FAT) were compared between individuals with psychosis and HCs using tract-based spatial statistics and FSL's Randomise. FAT and FW values were extracted, averaged across all voxels that demonstrated group differences, and then utilized to test for the influence of age, medication, age of onset, duration of illness, symptom severity, and intelligence. RESULTS: Individuals with adolescent-onset psychosis exhibited pronounced FW and FAT abnormalities compared to HCs. FAT reductions were spatially more widespread in ADO-SCZ. FW increases, however, were only present in psychotic ADO-BPD. In HCs, but not in individuals with adolescent-onset psychosis, FAT was positively related to age. CONCLUSIONS: We observe evidence for cellular (FAT) and extracellular (FW) white matter abnormalities in adolescent-onset psychosis. Although cellular white matter abnormalities were more prominent in ADO-SCZ, such alterations may reflect a shared trait, i.e. neurodevelopmental pathology, present across the psychosis spectrum. Extracellular abnormalities were evident in psychotic ADO-BPD, potentially indicating a more dynamic, state-dependent brain reaction to psychosis.

Decreased basal ganglia and thalamic iron in early psychotic spectrum disorders are associated with increased psychotic and schizotypal symptoms.

Iron deficits have been reported as a risk factor for psychotic spectrum disorders (PSD). However, examinations of brain iron in PSD remain limited. The current study employed quantitative MRI to examine iron content in several iron-rich subcortical structures in 49 young adult individuals with PSD (15 schizophrenia, 17 schizoaffective disorder, and 17 bipolar disorder with psychotic features) compared with 35 age-matched healthy controls (HC). A parametric approach based on a two-pool magnetization transfer model was applied to estimate longitudinal relaxation rate (R1), which reflects both iron and myelin, and macromolecular proton fraction (MPF), which is specific to myelin. To describe iron content, a synthetic effective transverse relaxation rate (R2*) was modeled using a linear fitting of R1 and MPF. PSD patients compared to HC showed significantly reduced R1 and synthetic R2* across examined regions including the pallidum, ventral diencephalon, thalamus, and putamen areas. This finding was primarily driven by decreases in the subgroup with schizophrenia, followed by schizoaffective disorder. No significant group differences were noted for MPF between PSD and HC while for regional volume, significant reductions in patients were only observed in bilateral caudate, suggesting that R1 and synthetic R2* reductions in schizophrenia and schizoaffective patients likely reflect iron deficits that either occur independently or precede structural and myelin changes. Subcortical R1 and synthetic R2* were also found to be inversely related to positive symptoms within the PSD group and to schizotypal traits across the whole sample. These findings that decreased iron in subcortical regions are associated with PSD risk and symptomatology suggest that brain iron deficiencies may play a role in PSD pathology and warrant further study.

Longitudinal trajectories of cortical development in 22q11.2 copy number variants and typically developing controls.

Probing naturally-occurring, reciprocal genomic copy number variations (CNVs) may help us understand mechanisms that underlie deviations from typical brain development. Cross-sectional studies have identified prominent reductions in cortical surface area (SA) and increased cortical thickness (CT) in 22q11.2 deletion carriers (22qDel), with the opposite pattern in duplication carriers (22qDup), but the longitudinal trajectories of these anomalies-and their relationship to clinical symptomatology-are unknown. Here, we examined neuroanatomic changes within a longitudinal cohort of 261 22q11.2 CNV carriers and demographically-matched typically developing (TD) controls (84 22qDel, 34 22qDup, and 143 TD; mean age 18.35, ±10.67 years; 50.47% female). A total of 431 magnetic resonance imaging scans (164 22qDel, 59 22qDup, and 208 TD control scans; mean interscan interval = 20.27 months) were examined. Longitudinal FreeSurfer analysis pipelines were used to parcellate the cortex and calculate average CT and SA for each region. First, general additive mixed models (GAMMs) were used to identify regions with between-group differences in developmental trajectories. Secondly, we investigated whether these trajectories were associated with clinical outcomes. Developmental trajectories of CT were more protracted in 22qDel relative to TD and 22qDup. 22qDup failed to show normative age-related SA decreases. 22qDel individuals with psychosis spectrum symptoms showed two distinct periods of altered CT trajectories relative to 22qDel without psychotic symptoms. In contrast, 22q11.2 CNV carriers with autism spectrum diagnoses showed early alterations in SA trajectories. Collectively, these results provide new insights into altered neurodevelopment in 22q11.2 CNV carriers, which may shed light on neural mechanisms underlying distinct clinical outcomes.

Magnetic Resonance Spectroscopy Studies of Brain Energy Metabolism in Schizophrenia: Progression from Prodrome to Chronic Psychosis.

PURPOSE OF REVIEW: Schizophrenia (SZ) is a debilitating mental illness; existing treatments are partially effective and associated with significant side effect burden, largely due to our limited understanding of disease mechanisms and the trajectory of disease progression. Accumulating evidence suggests that metabolic changes associated with glucose metabolism, mitochondrial dysfunction, and redox imbalance play an important role in the pathophysiology of schizophrenia. However, the molecular mechanisms associated with these abnormalities in the brains of schizophrenia patients and the ways in which they change over time remain unclear. This paper aims to review the current literature on molecular mechanisms and in vivo magnetic resonance spectroscopy (MRS) studies of impaired energy metabolism in patients at clinical high risk for psychosis, with first-episode SZ, and with chronic SZ. Our review covers research related to high-energy phosphate metabolism, lactate, intracellular pH, redox ratio, and the antioxidant glutathione. RECENT FINDINGS: Both first-episode and chronic SZ patients display a significant reduction in creatine kinase reaction activity and redox (NAD + /NADH) ratio in the prefrontal cortex. Chronic, but not first-episode, SZ patients also show a trend toward increased lactate levels and decreased pH value. These findings suggest a progressive shift from oxidative phosphorylation to glycolysis for energy production over the course of SZ, which is associated with redox imbalance and mitochondrial dysfunction. Accumulating evidence indicates that aberrant brain energy metabolism associated with mitochondrial dysfunction and redox imbalance plays a critical role in SZ and will be a promising target for future treatments.

Magnetic resonance advanced imaging analysis in adolescents: cortical thickness study to identify attenuated psychosis syndrome.

PURPOSE: Psychosis is a symptom common to several mental illnesses and a defining feature of schizophrenia spectrum disorders, whose onset typically occurs in adolescence. Neuroradiological studies have reported evidence of brain structural abnormalities in patients with overt psychosis. However, early identification of brain structural changes in young subjects at risk for developing psychosis (such as those with Attenuated Psychosis Syndrome -APS) is currently lacking. METHODS: Brain 3D T1-weighted and 64 directions diffusion-weighted images were acquired on 55 help-seeking adolescents (12-17 years old) with psychiatric disorders who referred to our Institute. Patients were divided into three groups: non-APS (n = 20), APS (n = 20), and Early-Onset Psychosis (n = 15). Cortical thickness was calculated from T1w images, and Tract-Based Spatial Statistics analysis was performed to study the distribution of white matter fractional anisotropy and all diffusivity metrics. A thorough neuropsychological test battery was adopted to investigate cognitive performance in several domains. RESULTS: In patients with Attenuated Psychotic Syndrome, the left superior frontal gyrus was significantly thinner compared to patients with non-APS (p = 0.048), and their right medial orbitofrontal cortex thickness was associated with lower working memory scores (p = 0.0025, r = -0.668 for the working memory index and p = 0.001, r = -0.738 for the digit span). Early-Onset Psychosis patients showed thinner left pars triangularis compared to non-APS individuals (p = 0.024), and their left pars orbitalis was associated with impaired performance at the symbol search test (p = 0.005, r = -0.726). No differences in diffusivity along main tracts were found between sub-groups (p > 0.05). CONCLUSION: This study showed specific associations between structural imaging features and cognitive performance in patients with APS. Characterizing this disorder using neuroimaging could reveal useful information that may aid in the development and evaluation of preventive strategies in these individuals.