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.

Fibre density and fibre-bundle cross-section of the corticospinal tract are distinctly linked to psychosis-specific symptoms in antipsychotic-naïve patients with first-episode schizophrenia.

Multiple lines of research support the dysconnectivity hypothesis of schizophrenia. However, findings on white matter (WM) alterations in patients with schizophrenia are widespread and non-specific. Confounding factors from magnetic resonance image (MRI) processing, clinical diversity, antipsychotic exposure, and substance use may underlie some of the variability. By application of refined methodology and careful sampling, we rectified common confounders investigating WM and symptom correlates in a sample of strictly antipsychotic-naïve first-episode patients with schizophrenia. Eighty-six patients and 112 matched controls underwent diffusion MRI. Using fixel-based analysis (FBA), we extracted fibre-specific measures such as fibre density and fibre-bundle cross-section. Group differences on fixel-wise measures were examined with multivariate general linear modelling. Psychopathology was assessed with the Positive and Negative Syndrome Scale. We separately tested multivariate correlations between fixel-wise measures and predefined psychosis-specific versus anxio-depressive symptoms. Results were corrected for multiple comparisons. Patients displayed reduced fibre density in the body of corpus callosum and in the middle cerebellar peduncle. Fibre density and fibre-bundle cross-section of the corticospinal tract were positively correlated with suspiciousness/persecution, and negatively correlated with delusions. Fibre-bundle cross-section of isthmus of corpus callosum and hallucinatory behaviour were negatively correlated. Fibre density and fibre-bundle cross-section of genu and splenium of corpus callosum were negative correlated with anxio-depressive symptoms. FBA revealed fibre-specific properties of WM abnormalities in patients and differentiated associations between WM and psychosis-specific versus anxio-depressive symptoms. Our findings encourage an itemised approach to investigate the relationship between WM microstructure and clinical symptoms in patients with schizophrenia.

Standing alone: experiences of vaccine-hesitant Danish healthcare professionals during COVID-19.

AIM: The aim of the study was to explore the experiences of Danish healthcare professionals who were hesitant about the COVID-19 vaccine. METHODS: Interviews were conducted over the telephone in January and February 2021. RESULTS: Healthcare professionals experienced the need to avoid impossible conversations about vaccine hesitancy with their colleagues. They felt a lack of knowledge of long-term experience with the vaccine and a need to balance trust in themselves and the authorities. CONCLUSIONS: Healthcare professionals who were hesitant towards the COVID-19 vaccine felt they had to keep their concerns to themselves and felt isolated and pressured by their managers. This study is especially important for managers, who must ensure a trusting working environment in which employees can discuss their concerns without feeling pressured.

Global fractional anisotropy predicts transition to psychosis after 12 months in individuals at ultra-high risk for psychosis.

OBJECTIVE: Psychosis spectrum disorders are associated with cerebral changes, but the prognostic value and clinical utility of these findings are unclear. Here, we applied a multivariate statistical model to examine the predictive accuracy of global white matter fractional anisotropy (FA) for transition to psychosis in individuals at ultra-high risk for psychosis (UHR). METHODS: 110 UHR individuals underwent 3 Tesla diffusion-weighted imaging and clinical assessments at baseline, and after 6 and 12 months. Using logistic regression, we examined the reliability of global FA at baseline as a predictor for psychosis transition after 12 months. We tested the predictive accuracy, sensitivity and specificity of global FA in a multivariate prediction model accounting for potential confounders to FA (head motion in scanner, age, gender, antipsychotic medication, parental socioeconomic status and activity level). In secondary analyses, we tested FA as a predictor of clinical symptoms and functional level using multivariate linear regression. RESULTS: Ten UHR individuals had transitioned to psychosis after 12 months (9%). The model reliably predicted transition at 12 months (χ2  = 17.595, p = 0.040), accounted for 15-33% of the variance in transition outcome with a sensitivity of 0.70, a specificity of 0.88 and AUC of 0.87. Global FA predicted level of UHR symptoms (R2  = 0.055, F = 6.084, p = 0.016) and functional level (R2  = 0.040, F = 4.57, p = 0.036) at 6 months, but not at 12 months. CONCLUSION: Global FA provided prognostic information on clinical outcome and symptom course of UHR individuals. Our findings suggest that the application of prediction models including neuroimaging data can inform clinical management on risk for psychosis transition.

Adenylyl Cyclase 6 Expression Is Essential for Cholera Toxin-Induced Diarrhea.

BACKGROUND: Cholera toxin (CT)-induced diarrhea is mediated by cyclic adenosine monophosphate (cAMP)-mediated active Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). Although the constitutive activation of adenylyl cyclase (AC) in response to CT is due to adenosine diphosphate ribosylation of the small G protein α-subunit activating CFTR with consequent secretory diarrhea, the AC isoform(s) involved remain unknown. METHODS: We generated intestinal epithelial cell-specific adenylyl cyclase 6 (AC6) knockout mice to study its role in CT-induced diarrhea. RESULTS: AC6 messenger RNA levels were the highest of all 9 membrane-bound AC isoforms in mouse intestinal epithelial cells. Intestinal epithelial-specific AC6 knockout mice (AC6loxloxVillinCre) had undetectable AC6 levels in small intestinal and colonic epithelial cells. No significant differences in fluid and food intake, plasma electrolytes, intestinal/colon anatomy and morphology, or fecal water content were observed between genotypes. Nevertheless, CT-induced fluid accumulation in vivo was completely absent in AC6loxloxVillinCre mice, associated with a lack of forskolin- and CT-induced changes in the short-circuit current (ISC) of the intestinal mucosa, impaired cAMP generation in acutely isolated small intestinal epithelial cells, and significantly impaired apical CFTR levels in response to forskolin. CONCLUSIONS: AC6 is a novel target for the treatment of CT-induced diarrhea.

Widespread higher fractional anisotropy associates to better cognitive functions in individuals at ultra-high risk for psychosis.

In schizophrenia patients, cognitive functions appear linked to widespread alterations in cerebral white matter microstructure. Here we examine patterns of associations between regional white matter and cognitive functions in individuals at ultra-high risk for psychosis. One hundred and sixteen individuals at ultra-high risk for psychosis and 49 matched healthy controls underwent 3 T magnetic resonance diffusion-weighted imaging and cognitive assessments. Group differences on fractional anisotropy were tested using tract-based spatial statistics. Group differences in cognitive functions, voxel-wise as well as regional fractional anisotropy were tested using univariate general linear modeling. Multivariate partial least squares correlation analyses tested for associations between patterns of regional fractional anisotropy and cognitive functions. Univariate analyses revealed significant impairments on cognitive functions and lower fractional anisotropy in superior longitudinal fasciculus and cingulate gyrus in individuals at ultra-high risk for psychosis. Partial least squares correlation analysis revealed different associations between patterns of regional fractional anisotropy and cognitive functions in individuals at ultra-high risk for psychosis compared to healthy controls. Widespread higher fractional anisotropy was associated with better cognitive functioning for individuals at ultra-high risk for psychosis, but not for the healthy controls. Furthermore, patterns of cognitive functions were associated with an interaction-effect on regional fractional anisotropy in fornix, medial lemniscus, uncinate fasciculus, and superior cerebellar peduncle. Aberrant associations between patterns of cognitive functions to white matter may be explained by dysmyelination.

Reduced Gene Expression of Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Whole Blood in Euthyroid Patients One Year After Hemithyroidectomy for Benign Euthyroid Goiter.

We have previously reported decreased thyroid function within the laboratory reference range and changes in mitochondrial function after hemithyroidectomy. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and coactivator-1ß (PGC-1ß) are key regulators of mitochondrial biogenesis and function. The aim was to examine the influence of hemithyroidectomy on the longitudinal change in mRNA expression of these genes. In addition, we measured longitudinal changes in mRNA expressions of the mitochoncrial-related genes nuclear factor erythroid-derived 2-like 2 (NFE2L2), mitochondrial transcription factor A (TFAM), and sodium dismutase 2 (SOD2). Twenty-eight patients were examined before and 1, 3, 6, and 12 months after hemithyroidectomy for benign euthyroid goiter. Thyroid stimulating hormone (TSH) and thyroid hormones were measured, and whole blood gene expression of PGC-1α, PGC-1ß, NFE2L2, TFAM, and SOD2 was examined by reverse transcription quantitative Polymerase Chain Reaction. We used mixed effect regression models to investigate changes in gene expression with time. Averaged over all follow-up visits, TSH increased (p=0.001), tT3 declined (p=0.01), and fT4/tT3 ratio increased (p=0.03) over one-year follow-up, but fT4 remained unchanged. Averaged over all follow-up visits, whole blood PGC-1α levels (p<0.001) and SOD2 (p=0.009) levels declined, but PGC-1ß, TFAM, and NFE2L2 did not change over one-year follow-up. The study demonstrates significant downregulation of whole blood PGC-1α and SOD2 gene expressions in hemithyroidectomized patients with a concomitant increase in TSH concentration within the reference range. Thus, hemithyroidectomized patients may likely have impaired mitochondrial function.

Anti-vascular endothelial growth factor therapy in breast cancer.

Neo-angiogenesis is a critical process for tumor growth and invasion and has become a promising target in cancer therapy. This manuscript reviews three currently relevant anti-angiogenic agents targeting the vascular endothelial growth factor system: bevacizumab, ramucirumab and sorafenib. The efficacy of anti-angiogenic drugs in adjuvant therapy or as neo-adjuvant treatment has been estimated in clinical trials of advanced breast cancer. To date, the overall observed clinical improvements are unconvincing, and further research is required to demonstrate the efficacy of anti-angiogenic drugs in breast cancer treatments. The outcomes of anti-angiogenic therapy have been highly variable in terms of tumor response. New methods are needed to identify patients who will benefit from this regimen. The development of biomarkers and molecular profiling are relevant research areas that may strengthen the ability to focus anti-angiogenic therapy towards suitable patients, thereby increase the cost-effectiveness, currently estimated to be inadequate.

Brief rapport: Perceptual aberration in patients at ultra-high risk for psychosis.

BACKGROUND: Ultra-high risk (UHR) is considered a forerunner of psychosis, but most UHR individuals do not later convert, yet remain symptomatic, disabled and help-seeking. Thus, there is an increased recognition of the UHR phenotype as a syndrome in itself, rather than merely a risk syndrome. It is therefore essential to investigate outcomes other than transition to psychosis. For this purpose, perceptual aberration appears to be a distinct, as well as a stable and less state-specific vulnerability indicator. We aimed to investigate perceptual aberration and associations with functional, neuro and social cognitive risk factors in an UHR sample. METHOD: One hundred and twenty UHR and 64 healthy controls were compared on levels of perceptual aberration using the perceptual aberration scale. We further investigated cross-sectional associations between perceptual aberration and CAARMS (as a measure of subthreshold psychotic symptoms) and functional, neuro and social cognitive risk factors within the UHR using Spearmans ρ. RESULTS: Perceptual aberration was significantly higher in UHR than in healthy controls and was associated with social functioning, executive functioning, and emotion recognition. CONCLUSION: Our findings are consistent with a view of perceptual aberration as a stable vulnerability indicator that varies little with clinical state.

Head and neck ultrasound training improves the diagnostic performance of otolaryngology residents.

Objective: Surgeon-performed head and neck ultrasound (US) is increasingly used among otolaryngologists in office-based and surgical settings. However, it is unknown how formal US training affects otolaryngology residents' diagnostic workup of patients with cervical pathology. This study examined how a formal US course for residents affected their outpatient clinic US performance and diagnostic accuracy. Methods: We conducted a randomized cross-over trial, where 13 otolaryngology residents participated in a 6-h formal US course. Participants were randomized to perform head and neck US on four patient cases before and after completing the course. Eight patients with and without neck pathology were invited to participate as test cases. The ultrasound examinations were video recorded and anonymized before two consultants rated the US performance using the Objective Structured Assessment of Ultrasound Skills (OSAUS) scale. Otolaryngology residents wrote an ultrasound report with a diagnosis based on their US examination, which was used to calculate the specificity and sensitivity. Results: We found a statistically significant difference in the OSAUS score before compared to after the hands-on training (p = .035). The diagnostic accuracy also increased from 62% before the course to 75% after the course (p = .02). Specificity increased from 54% prior to the course to 62% following the course, and sensitivity increased from 64% prior to the course to 79% following the course. The intraclass correlation coefficient with "absolute agreement" was 0.63. Conclusion: This study demonstrates that short, formal ultrasound training can improve otolaryngology residents' ultrasound skills and diagnostic accuracy in an outpatient clinic setting. Lay summary: This study looks at the change of otolaryngology residents' diagnostic workup of patients after they take a formal ultrasound course and shows that they get better at using ultrasound and make more accurate diagnoses if they take a formal course. Level of Evidence: Level 2.

Structural and functional connectivity in relation to executive functions in antipsychotic-naïve patients with first episode schizophrenia and levels of glutamatergic metabolites.

Patients with schizophrenia exhibit structural and functional dysconnectivity but the relationship to the well-documented cognitive impairments is less clear. This study investigates associations between structural and functional connectivity and executive functions in antipsychotic-naïve patients experiencing schizophrenia. Sixty-four patients with schizophrenia and 95 matched controls underwent cognitive testing, diffusion weighted imaging and resting state functional magnetic resonance imaging. In the primary analyses, groupwise interactions between structural connectivity as measured by fixel-based analyses and executive functions were investigated using multivariate linear regression analyses. For significant structural connections, secondary analyses examined whether functional connectivity and associations with executive functions also differed for the two groups. In group comparisons, patients exhibited cognitive impairments across all executive functions compared to controls (p < 0.001), but no group difference were observed in the fixel-based measures. Primary analyses revealed a groupwise interaction between planning abilities and fixel-based measures in the left anterior thalamic radiation (p = 0.004), as well as interactions between cognitive flexibility and fixel-based measures in the isthmus of corpus callosum and cingulum (p = 0.049). Secondary analyses revealed increased functional connectivity between grey matter regions connected by the left anterior thalamic radiation (left thalamus with pars opercularis p = 0.018, and pars orbitalis p = 0.003) in patients compared to controls. Moreover, a groupwise interaction was observed between cognitive flexibility and functional connectivity between contralateral regions connected by the isthmus (precuneus p = 0.028, postcentral p = 0.012), all p-values corrected for multiple comparisons. We conclude that structural and functional connectivity appear to associate with executive functions differently in antipsychotic-naïve patients with schizophrenia compared to controls.

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.

Premorbid functioning in adolescence associates with comorbid disorders in individuals at ultra-high risk for psychosis: A brief report.

AIM: This study examines associations between premorbid adjustment and comorbid disorders in individuals at ultra-high risk (UHR) for psychosis. METHODS: Premorbid social and academic adjustment data were collected from 146 UHR individuals using the Premorbid Adjustment Scale. Comorbid disorders were determined by the Structural Clinical Interview for DSM-IV. RESULTS: Logistic regressions showed lower premorbid social adjustment associated with personality disorders. Lower premorbid academic adjustment associated with affective disorders. More specifically, poor premorbid social adjustment in early and late adolescence associated with personality disorders. Lower premorbid social adjustment in late adolescence and lower premorbid academic adjustment in early adolescence associated with affective disorders. CONCLUSION: Partly corroborating evidence from schizophrenia samples, our findings suggest that poor premorbid adjustment relate to distinct comorbid disorders in UHR individuals. If replicated, it indicates that premorbid adjustment deficits may be a key area for targeted interventions improving the clinical prognosis of UHR individuals.

Sleep disturbances and the association with attenuated psychotic symptoms in individuals at ultra high-risk of psychosis.

Sleep disturbances are common in individuals at ultra high-risk (UHR) of psychosis and have proven to play a causal role in the occurrence of psychotic symptoms in healthy individuals. Only a few studies have systematically investigated sleep disturbances in UHR individuals. The help-seeking UHR individuals were 18-40 years old, and we included 72 UHR individuals according to the Comprehensive Assessment of At-Risk Mental State criteria (CAARMS) and 36 healthy controls. Sleep was measured with a modified version of the Karolinska Sleep Questionnaire and actigraphy for one night, and melatonin was measured at awakening and bedtime. We compared subjective rated sleep and actigraphy between healthy and UHR individuals (t-test and chi-square test) and examined the association between a CAARMS-composite score (linear regression). UHR individuals subjectively experienced poor sleep, categorised as disturbed sleep- and awakening index compared with healthy controls. We found no differences in actigraphy variables or morning/evening melatonin between UHR and healthy controls (t-test and chi-square). A high CAARMS-composite score was associated with high morning melatonin (B = 0.15, CI 0.02 to 0.27, p = 0.024) and high awakening index (B = 1.86, CI 0.58 to 3.14, p = 0.004) in UHR individuals. The results suggest that UHR individuals with high CAARMS scores have a delayed sleep phase; they have difficulties waking up and feel exhausted at awakening. It might be necessary to evaluate how UHR individuals sleep, and it would be of great interest to follow these patients over time according to the development of psychosis.

Associations between saliva alpha-amylase, heart rate variability, saliva cortisol and cognitive performance in individuals at ultra high-risk for psychosis.

BACKGROUND: Cognitive impairments are present in individuals at ultra-high risk (UHR) of psychosis and UHR individuals exhibit a hyperactive and dysfunctional HPA-axis. Increasing stress levels could potentially lead to cognitive impairments and no previous studies have examined the association between physiological stress biomarkers and cognition in UHR individuals. This study aims to examine the association between saliva alpha amylase (SAA), heart rate variability (HRV), saliva cortisol, and cognition in UHR individuals. METHOD: We included 72 UHR individuals, aged 18-40, fulfilling criteria of the comprehensive assessment of at-risk mental state (CAARMS). Cognitive tests indexed the 7 core domains as stated by Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). Physiological stress levels were observed for one day: saliva was collected at awakening, 30 min and 60 min after awakening and at bedtime. HRV was measured during sleep and before awakening. We used generalized linear model and controlled for multiple testing using false discovery rate (FDR). RESULTS: Higher levels of SAA were significantly associated with lower cognitive performance in the domains of verbal and visual learning and memory, sustained attention, working memory and global neurocognition looking at unadjusted data. Controlling for FDR visual memory, sustained attention and global neurocognition remained significant associated with SAA. We discovered no associations between cortisol and cognition. CONCLUSION: Visual learning and memory, sustained attention and global neurocognition remained significantly associated with SAA. This finding supports our hypothesis that an association between abnormal stress biomarkers and impaired cognition might be present in UHR individuals.

A longitudinal study on physiological stress in individuals at ultra high-risk of psychosis.

INTRODUCTION: Individuals at ultra high-risk (UHR) of psychosis exhibit significantly higher stress levels than healthy controls (HC). This study investigates how physiological stress measures differ between HC and UHR individuals and how physiological stress is associated with attenuated psychotic symptoms and changes over time in UHR individuals. Additionally, it examines how the use of medication affects physiological levels of stress. METHOD: The study included 72 UHR individuals and 36 HC. UHR were included according to the comprehensive assessment of at-risk mental state (CAARMS); a total-CAARMS score measured the attenuated psychotic symptoms and was calculated from the four psychosis subscales. HC and UHR were examined at baseline, and 47 UHR individuals were followed up after six months. Physiological stress measures were salivary cortisol, alpha-amylase (SAA) and heart-rate variability (HRV). Saliva was collected at four-time points during the day. RESULTS: There was no significant difference regarding cortisol (awakening response) or SAA measures between HC and UHR individuals. The use of antipsychotics and antidepressants was associated with low HRV in UHR individuals. In an exploratory analysis of 19 UHR individuals, we found an association between the change in total-CAARMS (six months total-CAARMS minus baseline total CAARMS) and the change in HRV during sleep (six months HRV minus baseline HRV). CONCLUSION: Our findings indicate that the use of antipsychotics and antidepressants could be associated with lower HRV in UHR individuals. There might be potential to investigate how HRV develops during the course of illness in UHR individuals.

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.

[Cognitive deficits in epilepsy].

Cognitive deficits are common in people with epilepsy and may have impact on education, work, and personal life. Furthermore, cognitive symptoms are often present before seizure onset and often persist upon seizure freedom. As presented in this review, epilepsy is more than just seizures and alike epileptic activity, cognitive dysfunction is a symptom of underlying pathophysiology of the brain and a condition which needs to be addressed when the diagnosis of epilepsy is set. Early identification of cognitive difficulties, relevant rehabilitation plans, and uniform and easily accessible communication across sectors are needed.

Premorbid adjustment associates with cognitive and functional deficits in individuals at ultra-high risk of psychosis.

Premorbid social and academic adjustment are important predictors of cognitive and functional performance in schizophrenia. Whether this relationship is also present in individuals at ultra-high risk (UHR) for psychosis is the focus of the present study. Using baseline data from a randomised clinical trial (N = 146) this study investigated associations between premorbid adjustment and neuro- and social cognition and functioning in UHR individuals aged 18-40 years. Patients were evaluated with the Premorbid Adjustment Scale (PAS) comprising a social and an academic domain. Using validated measures neurocognition was assessed in the domains of processing speed, executive function, attention, verbal learning and memory, visual learning and memory, and working memory along with estimated IQ. Social cognitive domains assessed were theory of mind, emotion recognition, and attributional bias. Functional assessment comprised the domains of social- and role functioning, functional capacity, and quality of life. Linear regression analyses revealed poor premorbid academic adjustment to be associated with poorer performance in processing speed, working memory, attention, full scale IQ, and verbal IQ. Poor premorbid social adjustment was associated with theory of mind deficits. Additionally, both premorbid adjustment domains were associated with social- and role functioning and quality of life. Corroborating evidence from schizophrenia samples, our findings indicate poor premorbid adjustment to correlate with deficits in specific cognitive and functional domains in UHR states. Early premorbid adjustment difficulties may therefore indicate a poor cognitive and functional trajectory associated with significant impairments in early and established psychotic disorders suggesting targets for primary intervention.

Differential Effects of Aripiprazole and Amisulpride on Negative and Cognitive Symptoms in Patients With First-Episode Psychoses.

Introduction: Aripiprazole is hypothesized to have an effect on negative and cognitive symptoms in schizophrenia. Likewise, amisulpride is one of the only second-generation antipsychotics with which an effect on negative symptoms is reported. In the present study, we compare the effect of aripiprazole and amisulpride in initially antipsychotic-naïve patients with first-episode psychoses. Methods: Psychopathology and cognitive measures from two consecutive cohorts of antipsychotic-naïve first episode psychotic patients were obtained before and after 6 weeks of antipsychotic monotherapy with either aripiprazole or amisulpride. Matched healthy controls were included to account for retest effects on the cognitive measures. Analyses of variance (repeated-measures ANOVA) were performed to detect effect of time and possible cohort*time interactions. Results: Longitudinal data was obtained from 47 and 48 patients treated for 6 weeks with amisulpride or aripiprazole, respectively. For the Wallwork negative symptom dimension, there was a cohort*time interaction [F (1, 93) = 4.29, p = 0.041] and a significant effect of time [F (1, 93) = 6.03, p = 0.016], which was driven by an improvement in patients treated with aripiprazole [t (47) = 4.1, p < 0.001] and not observed in patients treated with amisulpride (p > 0.5). For the eight cognitive measures, no cohort*time interaction was found and neither was cognitive improvement in any of the cohorts when accounting for retest effect. Conclusion: Patients treated with aripiprazole improved on negative symptoms, which was not the case for patients treated with amisulpride. This may point to a general effect of a partial D2 receptor agonist on negative symptoms in patients with first-episode psychoses. There was, however, no improvement in cognitive functions.