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.

Brain-age prediction: Systematic evaluation of site effects, and sample age range and size.

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.

Sex differences in predictors and regional patterns of brain age gap estimates.

The brain-age-gap estimate (brainAGE) quantifies the difference between chronological age and age predicted by applying machine-learning models to neuroimaging data and is considered a biomarker of brain health. Understanding sex differences in brainAGE is a significant step toward precision medicine. Global and local brainAGE (G-brainAGE and L-brainAGE, respectively) were computed by applying machine learning algorithms to brain structural magnetic resonance imaging data from 1113 healthy young adults (54.45% females; age range: 22-37 years) participating in the Human Connectome Project. Sex differences were determined in G-brainAGE and L-brainAGE. Random forest regression was used to determine sex-specific associations between G-brainAGE and non-imaging measures pertaining to sociodemographic characteristics and mental, physical, and cognitive functions. L-brainAGE showed sex-specific differences; in females, compared to males, L-brainAGE was higher in the cerebellum and brainstem and lower in the prefrontal cortex and insula. Although sex differences in G-brainAGE were minimal, associations between G-brainAGE and non-imaging measures differed between sexes with the exception of poor sleep quality, which was common to both. While univariate relationships were small, the most important predictor of higher G-brainAGE was self-identification as non-white in males and systolic blood pressure in females. The results demonstrate the value of applying sex-specific analyses and machine learning methods to advance our understanding of sex-related differences in factors that influence the rate of brain aging and provide a foundation for targeted interventions.

The clinical relevance of formal thought disorder in the early stages of psychosis: results from the PRONIA study.

BACKGROUND: Formal thought disorder (FTD) has been associated with more severe illness courses and functional deficits in patients with psychotic disorders. However, it remains unclear whether the presence of FTD characterises a specific subgroup of patients showing more prominent illness severity, neurocognitive and functional impairments. This study aimed to identify stable and generalizable FTD-subgroups of patients with recent-onset psychosis (ROP) by applying a comprehensive data-driven clustering approach and to test the validity of these subgroups by assessing associations between this FTD-related stratification, social and occupational functioning, and neurocognition. METHODS: 279 patients with ROP were recruited as part of the multi-site European PRONIA study (Personalised Prognostic Tools for Early Psychosis Management; www.pronia.eu). Five FTD-related symptoms (conceptual disorganization, poverty of content of speech, difficulty in abstract thinking, increased latency of response and poverty of speech) were assessed with Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). RESULTS: The results with two patient subgroups showing different levels of FTD were the most stable and generalizable clustering solution (predicted clustering strength value = 0.86). FTD-High subgroup had lower scores in social (pfdr < 0.001) and role (pfdr < 0.001) functioning, as well as worse neurocognitive performance in semantic (pfdr < 0.001) and phonological verbal fluency (pfdr < 0.001), short-term verbal memory (pfdr = 0.002) and abstract thinking (pfdr = 0.010), in comparison to FTD-Low group. CONCLUSIONS: Clustering techniques allowed us to identify patients with more pronounced FTD showing more severe deficits in functioning and neurocognition, thus suggesting that FTD may be a relevant marker of illness severity in the early psychosis pathway.

BrainAGE, brain health, and mental disorders: A systematic review.

The imaging-based method of brainAGE aims to characterize an individual's vulnerability to age-related brain changes. The present study systematically reviewed brainAGE findings in neuropsychiatric conditions and discussed the potential of brainAGE as a marker for biological age. A systematic PubMed search (from inception to March 6th, 2023) identified 273 articles. The 30 included studies compared brainAGE between neuropsychiatric and healthy groups (n≥50). We presented results qualitatively and adapted a bias risk assessment questionnaire. The imaging modalities, design, and input features varied considerably between studies. While the studies found higher brainAGE in neuropsychiatric conditions (11 mild cognitive impairment/ dementia, 11 schizophrenia spectrum/ other psychotic and bipolar disorder, six depression/ anxiety, two multiple groups), the associations with clinical characteristics were mixed. While brainAGE is sensitive to group differences, limitations include the lack of diverse training samples, multi-modal studies, and external validation. Only a few studies obtained longitudinal data, and all have used algorithms built solely to predict chronological age. These limitations impede the validity of brainAGE as a biological age marker.

Brain responses to intermittent fasting and the healthy living diet in older adults.

Diet may promote brain health in metabolically impaired older individuals. In an 8-week randomized clinical trial involving 40 cognitively intact older adults with insulin resistance, we examined the effects of 5:2 intermittent fasting and the healthy living diet on brain health. Although intermittent fasting induced greater weight loss, the two diets had comparable effects in improving insulin signaling biomarkers in neuron-derived extracellular vesicles, decreasing the brain-age-gap estimate (reflecting the pace of biological aging of the brain) on magnetic resonance imaging, reducing brain glucose on magnetic resonance spectroscopy, and improving blood biomarkers of carbohydrate and lipid metabolism, with minimal changes in cerebrospinal fluid biomarkers for Alzheimer's disease. Intermittent fasting and healthy living improved executive function and memory, with intermittent fasting benefiting more certain cognitive measures. In exploratory analyses, sex, body mass index, and apolipoprotein E and SLC16A7 genotypes modulated diet effects. The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization. For further information, please see ClinicalTrials.gov registration: NCT02460783.

Transdiagnostic subgroups of cognitive impairment in early affective and psychotic illness.

Cognitively impaired and spared patient subgroups were identified in psychosis and depression, and in clinical high-risk for psychosis (CHR). Studies suggest differences in underlying brain structural and functional characteristics. It is unclear whether cognitive subgroups are transdiagnostic phenomena in early stages of psychotic and affective disorder which can be validated on the neural level. Patients with recent-onset psychosis (ROP; N = 140; female = 54), recent-onset depression (ROD; N = 130; female = 73), CHR (N = 128; female = 61) and healthy controls (HC; N = 270; female = 165) were recruited through the multi-site study PRONIA. The transdiagnostic sample and individual study groups were clustered into subgroups based on their performance in eight cognitive domains and characterized by gray matter volume (sMRI) and resting-state functional connectivity (rsFC) using support vector machine (SVM) classification. We identified an impaired subgroup (NROP = 79, NROD = 30, NCHR = 37) showing cognitive impairment in executive functioning, working memory, processing speed and verbal learning (all p < 0.001). A spared subgroup (NROP = 61, NROD = 100, NCHR = 91) performed comparable to HC. Single-disease subgroups indicated that cognitive impairment is stronger pronounced in impaired ROP compared to impaired ROD and CHR. Subgroups in ROP and ROD showed specific symptom- and functioning-patterns. rsFC showed superior accuracy compared to sMRI in differentiating transdiagnostic subgroups from HC (BACimpaired = 58.5%; BACspared = 61.7%, both: p < 0.01). Cognitive findings were validated in the PRONIA replication sample (N = 409). Individual cognitive subgroups in ROP, ROD and CHR are more informative than transdiagnostic subgroups as they map onto individual cognitive impairment and specific functioning- and symptom-patterns which show limited overlap in sMRI and rsFC. CLINICAL TRIAL REGISTRY NAME: German Clinical Trials Register (DRKS). Clinical trial registry URL: https://www.drks.de/drks_web/ . Clinical trial registry number: DRKS00005042.

Alterations of Functional Connectivity Dynamics in Affective and Psychotic Disorders.

BACKGROUND: Psychosis and depression patients 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: In the present study, we report the analysis of dFC in a large patient sample including 127 clinical high-risk patients (CHR), 142 recent-onset psychosis (ROP) patients, 134 recent-onset depression (ROD) patients, and 256 healthy controls (HC). A sliding window-based technique was used to calculate the time-dependent FC in resting-state MRI data, followed by clustering to reveal recurrent FC states in each diagnostic group. RESULTS: We identified five unique FC states, which could be identified in all groups with high consistency (rmean = 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 ROD patients (p < 0.0005) compared to most other groups, and a common increase in the lifetime of a FC state characterised by high sensorimotor and cingulo-opercular connectivities in all patient groups compared to the HC group (p < 0.0002). Canonical correlation analysis revealed a mode which exhibited significant correlations between dFC parameters and clinical variables (r = 0.617, p < 0.0029), 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, psychosis and clinical risk states.

Anhedonia as a potential transdiagnostic phenotype with immune-related changes in recent onset mental health disorders.

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 those with enduring illness, with few exploring inflammatory changes. We sought to identify an inflammatory signal and associated brain function underlying anhedonia among young people with recent onset psychosis (ROP) and recent onset depression (ROD). METHOD: Resting-state functional magnetic resonance imaging, inflammatory markers, and anhedonia symptoms were collected from N=108 (M age=26.2[SD 6.2]years; Female =50) participants with ROP (n=53) and ROD (n=55) from the EU-FP7-funded PRONIA 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 functional connectivity model were developed to classify an anhedonic group, compared to a normal hedonic group. RESULTS: A repeated nested cross-validation model using inflammatory markers classified normal hedonic and anhedonic ROP/ROD groups with a balanced accuracy (BAC) of 63.9%, and an area under the curve (AUC) of 0.61. The functional connectivity model produced a BAC of 55.2% and an AUC 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. CONCLUSION: 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.

Normative modelling of brain morphometry across the lifespan with CentileBrain: algorithm benchmarking and model optimisation.

The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3-90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Reduced neural connectivity in the caudate anterior head predicts hallucination severity in schizophrenia.

BACKGROUND: Caudate functional abnormalities have been identified as one critical neural substrate underlying sensory gating impairments that lead to auditory phantom hallucinations in both patients with schizophrenia (SZ) and tinnitus, characterized by the perception of internally generated sounds in the absence of external environmental auditory stimuli. In this study, we tested the hypothesis as to whether functional connectivity abnormalities in distinct caudate subdivisions implicated in sensory gating and auditory phantom percepts in tinnitus, which are currently being localized for neuromodulation targeting using deep brain stimulation techniques, would be associated with auditory phantom hallucination severity in SZ. METHODS: Twenty five SZ and twenty eight demographically-matched healthy control (HC) participants, completed this fMRI resting-state study and clinical assessments. RESULTS: Between-group seed-to-voxel analyses revealed only one region, the caudate anterior head, which showed reduced functional connectivity with the thalamus that survived whole-brain multiple comparison corrections. Importantly, connectivity between the caudate anterior head with thalamus negatively correlated with hallucination severity. CONCLUSIONS: In the present study, we deliver the first evidence of caudate subdivision specificity for the neural pathophysiology underlying hallucinations in schizophrenia within a sensory gating framework that has been developed for auditory phantoms in patients with tinnitus. Our findings provide transdiagnostic convergent evidence for the role of the caudate in the gating of auditory phantom hallucinations, observed across patients with SZ and tinnitus by specifying the anterior caudate division is key to mediation of hallucinations, and creating a path towards personalized treatment approaches to arrest auditory phantom hallucinations from reaching perceptual awareness.

Structural and Functional Brain Patterns Predict Formal Thought Disorder's Severity and Its Persistence in Recent-Onset Psychosis: Results From the PRONIA Study.

BACKGROUND: Formal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level. METHODS: Two hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up. RESULTS: Cross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BACslow-5 = 73.2%, BACslow-4 = 72.9%, BACslow-3 = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%. CONCLUSIONS: We report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes.

Normative modeling of brain morphometry in Clinical High-Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in the majority of individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high-risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design Setting and Participants: Clinical, IQ and FreeSurfer-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1,340 CHR-P individuals [47.09% female; mean age: 20.75 (4.74) years] and 1,237 healthy individuals [44.70% female; mean age: 22.32 (4.95) years] from 29 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. Main Outcomes and Measures: For each regional morphometric measure, z-scores were computed that index the degree of deviation from the normative means of that measure in a healthy reference population (N=37,407). Average deviation scores (ADS) for CT, SA, SV, and globally across all measures (G) were generated by averaging the respective regional z-scores. Regression analyses were used to quantify the association of deviation scores with clinical severity and cognition and two-proportion z-tests to identify case-control differences in the proportion of individuals with infranormal (z<-1.96) or supranormal (z>1.96) scores. Results: CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z-scores, and all ADS vales. The proportion of CHR-P individuals with infranormal or supranormal values in any metric was low (<12%) and similar to that of healthy individuals. CHR-P individuals who converted to psychosis compared to those who did not convert had a higher percentage of infranormal values in temporal regions (5-7% vs 0.9-1.4%). In the CHR-P group, only the ADSSA showed significant but weak associations (|ß|<0.09; PFDR<0.05) with positive symptoms and IQ. Conclusions and Relevance: The study findings challenge the usefulness of macroscale neuromorphometric measures as diagnostic biomarkers of psychosis risk and suggest that such measures do not provide an adequate explanation for psychosis risk.

Normative Modeling of Brain Morphometry Across the Lifespan Using CentileBrain: Algorithm Benchmarking and Model Optimization.

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

Lower functional hippocampal connectivity in healthy adults is jointly associated with higher levels of leptin and insulin resistance.

BACKGROUND: Metabolic dysregulation is currently considered a major risk factor for hippocampal pathology. The aim of the present study was to characterize the influence of key metabolic drivers on functional connectivity of the hippocampus in healthy adults. METHODS: Insulin resistance was directly quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test and fasting levels of insulin, glucose, leptin, and cortisol, and measurements of body mass index and waist circumference were obtained in a sample of healthy cognitively intact adults (n = 104). Resting-state neuroimaging data were also acquired for the quantification of hippocampal functional cohesiveness and integration with the major resting-state networks (RSNs). Data-driven analysis using unsupervised machine learning (k-means clustering) was then employed to identify clusters of individuals based on their metabolic and functional connectivity profiles. RESULTS: K-means clustering identified two clusters of increasing metabolic deviance evidenced by cluster differences in the plasma levels of leptin (40.36 (29.97) vs. 27.59 (25.58) µg/L) and the degree of insulin resistance (SSPG concentration: 161.63 (65.27) vs. 125.72 (66.81) mg/dL). Individuals in the cluster with higher metabolic deviance showed lower functional cohesiveness within each hippocampus and lower integration of posterior and anterior components of the left and right hippocampus with the major RSNs. The two clusters did not differ in general intellectual ability or episodic memory. CONCLUSIONS: We identified two clusters of individuals differentiated by abnormalities in insulin resistance, leptin levels, and hippocampal connectivity, with one of the clusters showing greater deviance. These findings support the link between metabolic dysregulation and hippocampal function even in nonclinical samples.

Accelerated Global and Local Brain Aging Differentiate Cognitively Impaired From Cognitively Spared Patients With Schizophrenia.

Background: Accelerated aging has been proposed as a mechanism underlying the clinical and cognitive presentation of schizophrenia. The current study extends the field by examining both global and regional patterns of brain aging in schizophrenia, as inferred from brain structural data, and their association with cognitive and psychotic symptoms. Methods: Global and local brain-age-gap-estimates (G-brainAGE and L-brainAGE) were computed using a U-Net Model from T1-weighted structural neuroimaging data from 84 patients (aged 16-35 years) with early-stage schizophrenia (illness duration <5 years) and 1,169 healthy individuals (aged 16-37 years). Multidomain cognitive data from the patient sample were submitted to Heterogeneity through Discriminative Analysis (HYDRA) to identify cognitive clusters. Results: HYDRA classified patients into a cognitively impaired cluster (n = 69) and a cognitively spared cluster (n = 15). Compared to healthy individuals, G-brainAGE was significantly higher in the cognitively impaired cluster (+11.08 years) who also showed widespread elevation in L-brainAGE, with the highest deviance observed in frontal and temporal regions. The cognitively spared cluster showed a moderate increase in G-brainAGE (+8.94 years), and higher L-brainAGE localized in the anterior cingulate cortex. Psychotic symptom severity in both clusters showed a positive but non-significant association with G-brainAGE. Discussion: Accelerated aging in schizophrenia can be detected at the early disease stages and appears more closely associated with cognitive dysfunction rather than clinical symptoms. Future studies replicating our findings in multi-site cohorts with larger numbers of participants are warranted.

Hippocampal volume reduction is associated with direct measure of insulin resistance in adults.

Hippocampal integrity is highly susceptible to metabolic dysfunction, yet its mechanisms are not well defined. We studied 126 healthy individuals aged 23-61 years. Insulin resistance (IR) was quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Body mass index (BMI), adiposity, fasting insulin, glucose, leptin as well as structural neuroimaing with automatic hippocampal subfield segmentation were performed. Data analysis using unsupervised machine learning (k-means clustering) identified two subgroups reflecting a pattern of more pronounced hippocampal volume reduction being concurrently associated with greater adiposity and insulin resistance; the hippocampal volume reductions were uniform across subfields. Individuals in the most deviant subgroup were predominantly women (79 versus 42 %) with higher BMI [27.9 (2.5) versus 30.5 (4.6) kg/m2], IR (SSPG concentration, [156 (61) versus 123 (70) mg/dL] and leptinemia [21.7 (17.0) versus 44.5 (30.4) µg/L]. The use of person-based modeling in healthy individuals suggests that adiposity, insulin resistance and compromised structural hippocampal integrity behave as a composite phenotype; female sex emerged as risk factor for this phenotype.

Construct validity for computational linguistic metrics in individuals at clinical risk for psychosis: Associations with clinical ratings.

Language deficits are prevalent in psychotic illness, including its risk states, and are related to marked impairment in functioning. It is therefore important to characterize language impairment in the psychosis spectrum in order to develop potential preventive interventions. Natural language processing (NLP) metrics of semantic coherence and syntactic complexity have been used to discriminate schizophrenia patients from healthy controls (HC) and predict psychosis onset in individuals at clinical high-risk (CHR) for psychosis. To date, no studies have yet examined the construct validity of key NLP features with respect to clinical ratings of thought disorder in a CHR cohort. Herein we test the association of key NLP metrics of coherence and complexity with ratings of positive and negative thought disorder, respectively, in 60 CHR individuals, using Andreasen's Scale of Assessment of Thought, Language and Communication (TLC) Scale to measure of positive and negative thought disorder. As hypothesized, in CHR individuals, the NLP metric of semantic coherence was significantly correlated with positive thought disorder severity and the NLP metrics of complexity (sentence length and determiner use) were correlated with negative thought disorder severity. The finding of construct validity supports the premise that NLP analytics, at least in respect to core features of reduction of coherence and complexity, are capturing clinically relevant language disturbances in risk states for psychosis. Further psychometric study is required, in respect to reliability and other forms of validity.

A case report and first-person account of an individual at risk for psychosis who improved during the COVID-19 pandemic.

Background: The COVID-19 pandemic is expected to increase stress and mental health symptoms. We present the case of a young man at risk for psychosis who has paradoxically shown symptomatic and functional improvement as a result of circumstances produced by COVID-19. These changes were unexpected given the client's persistent mental health struggles in the year leading up to the COVID-19 outbreak in the United States and the expectation of an exacerbation of psychotic-like symptoms. Methods: This report is based on clinical assessments and the client's first-person account during the height of the pandemic when stay at home orders were in place. Results: During the pandemic, the client demonstrated increased agency by taking on more responsibility at home and obtaining part-time employment. He showed improvement in his mood and relationships with others, had less symptom-related distress, and significantly reduced his cannabis use. The client interpreted these improvements in terms of changing his mindset toward more adaptive thoughts and engaging in healthy coping skills such as praying, reading, and healthy eating. Conclusions: This case highlights the importance of fostering agency in clients during a time of crisis and ensuring that clinicians be aware of potential biases about mental health symptom exacerbation.