Human Fronto-Tectal and Fronto-Striatal-Tectal Pathways Activate Differently During Anti-Saccades

Almost all cortical areas in the vertebrate brain take part in recurrent connections through the subcortical basal ganglia (BG) nuclei, through parallel inhibitory and excitatory loops. It has been suggested that these circuits can modulate our reactions to external events such that appropriate reactions are chosen from many available options, thereby imposing volitional control over behavior. The saccade system is an excellent model system to study cortico-BG interactions. In this study two possible pathways were investigated that might regulate automaticity of eye movements in the human brain; the cortico-tectal pathway, running directly between the frontal eye fields (FEF) and superior colliculus (SC) and the cortico-striatal pathway from the FEF to the SC involving the caudate nucleus (CN) in the BG. In an event-related functional magnetic resonance imaging (fMRI) paradigm participants made pro- and anti-saccades. A diffusion tensor imaging (DTI) scan was made for reconstruction of white matter tracts between the FEF, CN and SC. DTI fiber tracts were used to divide both the left and right FEF into two sub-areas, projecting to either ipsilateral SC or CN. For each of these FEF zones an event-related fMRI timecourse was extracted. In general activity in the FEF was larger for anti-saccades. This increase in activity was lateralized with respect to anti-saccade direction in FEF zones connected to the SC but not for zones only connected to the CN. These findings suggest that activity along the contralateral FEF–SC projection is responsible for directly generating anti-saccades, whereas the pathway through the BG might merely have a gating function withholding or allowing a pro-saccade

Non-steroidal anti-inflammatory drugs and the risk of psychosis

The objective of the current research was to examine the relation between nonsteroidal anti-inflammatory drugs (NSAID) use and risk of psychosis. To this end we performed a longitudinal case-control study using prescription data from a Dutch health insurance company. Men aged 25 years or over and women aged 30 years or over were excluded to prevent inclusion of non-incident cases. This resulted in eighty-two cases and 359 randomly selected controls from the same population. The overall relative risk of incident antipsychotic use for NSAID users, adjusted for age and prescription frequency, was 0.80 (95% CI: 0.48-1.33). After stratification for gender the risk of psychosis was significantly lower (59%) in male NSAID users only. The relative risks for male and female subjects were 0.41 (95% CI: 0.17-0.97) and 1.31 (95% CI: 0.65-2.64), respectively. These results suggest that in men NSAIDs may lower the risk of psychosis. (c) 2006 Elsevier B.V. and ECNP. All rights reserved

Impaired Cerebellar Functional Connectivity in Schizophrenia Patients and Their Healthy Siblings

The long-standing notion of schizophrenia as a disorder of connectivity is supported by emerging evidence from recent neuroimaging studies, suggesting impairments of both structural and functional connectivity in schizophrenia. However, investigations are generally restricted to supratentorial brain regions, thereby excluding the cerebellum. As increasing evidence suggests that the cerebellum contributes to cognitive and affective processing, aberrant connectivity in schizophrenia may include cerebellar dysconnectivity. Moreover, as schizophrenia is highly heritable, unaffected family members of schizophrenia patients may exhibit similar connectivity profiles. The present study applies resting-state functional magnetic resonance imaging to determine cerebellar functional connectivity profiles, and the familial component of cerebellar connectivity profiles, in 62 schizophrenia patients and 67 siblings of schizophrenia patients. Compared to healthy control subjects, schizophrenia patients showed impaired functional connectivity between the cerebellum and several left-sided cerebral regions, including the hippocampus, thalamus, middle cingulate gyrus, triangular part of the inferior frontal gyrus, supplementary motor area, and lingual gyrus (all p < 0.0025, whole-brain significant). Importantly, siblings of schizophrenia patients showed several similarities to patients in cerebellar functional connectivity, suggesting that cerebellar dysconnectivity in schizophrenia might be related to familial factors. In conclusion, our findings suggest that dysconnectivity in schizophrenia involves the cerebellum and that this defect may be related to the risk to develop the illness

Social behavior and autism traits in a sex chromosomal disorder:Klinefelter (47XXY) syndrome

Although Klinefelter syndrome (47,XXY) has been associated with psychosocial difficulties, knowledge of the social behavioral phenotype is limited. We examined specific social abilities and autism traits in Klinefelter syndrome. Scores of 31 XXY men on the Scale for Interpersonal Behavior and the Autism Spectrum Questionnaire were compared to 24 and 20 control men respectively. XXY men reported increased distress during social interactions and less engagement in specific social behaviors. In the XXY group, levels of autism traits were significantly higher across all dimensions of the autism phenotype. These findings call for a clinical investigation of vulnerability to autism in Klinefelter syndrome. Klinefelter syndrome might serve as a model for studying a role of the X chromosome in social behavioral dysfunction and autism-like behavior

Disrupted upregulation of salience network connectivity during acute stress in siblings of schizophrenia patients

BACKGROUND: An adaptive neural stress response is essential to adequately cope with a changing environment. It was previously argued that sympathetic/noradrenergic activity during acute stress increases salience network (SN) connectivity and reduces executive control network (ECN) connectivity in healthy controls, with opposing effects in the late aftermath of stress. Altered temporal dynamics of these networks in response to stress are thought to play a role in the development of psychopathology in vulnerable individuals. METHODS: We exposed male healthy controls (n = 40, mean age = 33.9) and unaffected siblings of schizophrenia patients (n = 39, mean age = 33.2) to the stress or control condition of the trier social stress test and subsequently investigated resting state functional connectivity of the SN and ECN directly after and 1.5 h after stress. RESULTS: Acute stress resulted in increased functional connectivity within the SN in healthy controls, but not in siblings (group × stress interaction pfwe < 0.05). In the late aftermath of stress, stress reduced functional connectivity within the SN in both groups. Moreover, we found increased functional connectivity between the ECN and the cerebellum in the aftermath of stress in both healthy controls and siblings of schizophrenia patients. CONCLUSIONS: The results show profound differences between siblings of schizophrenia patients and controls during acute stress. Siblings lacked the upregulation of neural resources necessary to quickly and adequately cope with a stressor. This points to a reduced dynamic range in the sympathetic response, and may constitute a vulnerability factor for the development of psychopathology in this at-risk group

Brain structure, IQ, and psychopathology in young offspring of patients with schizophrenia or bipolar disorder

BACKGROUND.: Studying offspring of schizophrenia (SZo) and bipolar disorder patients (BDo) provides important information on the putative neurodevelopmental trajectories underlying development toward severe mental illnesses. We compared intracranial volume (ICV), as a marker for neurodevelopment, and global and local brain measures between SZo or BDo and control offspring (Co) in relation to IQ and psychopathology. METHODS.: T1-weighted magnetic resonance imaging (MRI) brain scans were obtained from 146 participants (8-19 years; 40 SZo, 66 BDo, 40 Co). Linear mixed models were applied to compare ICV, global, and local brain measures between groups. To investigate the effect of ICV, IQ (four subtests Wechsler Intelligence Scale for Children/Wechsler Adult Intelligence Scale-III) or presence of psychopathology these variables were each added to the model. RESULTS.: SZo and BDo had significantly lower IQ and more often met criteria for a lifetime psychiatric disorder than Co. ICV was significantly smaller in SZo than in BDo (d = -0.56) and Co (d = -0.59), which was largely independent of IQ (respectively, d = -0.54 and d = -0.35). After ICV correction, the cortex was significantly thinner in SZo than in BDo (d = -0.42) and Co (d = -0.75) and lateral ventricles were larger in BDo than in Co (d = 0.55). Correction for IQ or lifetime psychiatric diagnosis did not change these findings. CONCLUSIONS.: Despite sharing a lower IQ and a higher prevalence of psychiatric disorders, brain abnormalities in BDo appear less pronounced (but are not absent) than in SZo. Lower ICV in SZo implies that familial risk for schizophrenia has a stronger association with stunted early brain development than familial risk for bipolar disorder

The role of depression in the prediction of a "late" remission in first-episode psychosis:An analysis of the OPTiMiSE study

Objective: The identification of predictors of psychosis remission could guide early clinical decision-making for treatment of first-episode schizophrenia (FES). Methods: We analyzed two non-independent subsamples of patients with FES ages 18-40 years from the OPTiMiSE study dataset to investigate the demographic and clinical factors that might help to differentiate "late" re-mitters (i.e., not in remission at week 2 or 4, but achieving remission within a 10-week follow-up period) from non-remitters within the same period. Results: Subsample 1 included 216 individuals (55 females, mean age 25.9 years) treated with amisulpride in an open-label design who were not in remission at week 2. Early symptomatic response between baseline and week 2 (odds ratio (OR)- 4.186, 95% confidence interval (CI)- 2.082-8.416, p < 0.001) and older age (OR- 1.081, 95% = CI 1.026-1.138, p- 0.003) were the only variables significantly associated with a higher probability of psychosis remission at week 4. Subsample 2 was composed of the 72 participants (19 females, mean age 25.1 years) who were not in remission at week 4 and completed a 6-week double-blind randomized trial comparing continuation of amisulpride with switch to olanzapine. Depression at baseline (as measured with the Calgary Depression Scale for Schizophrenia) was significantly associated with a nearly 3-fold lower likelihood of psychosis remission during the 10-week follow-up (hazard ratio = 2.865, 95% CI = 1.187-6.916, p = 0.019). Conclusion: Our results reinforce the importance of assessing depressive symptoms in people with FES and support the relevance of an early response (as early as 2 weeks) as a predictor of clinical outcome in this population. (C) 2021 Elsevier B.V. All rights reserved

The Community Assessment of Psychic Experiences:Optimal cut-off scores for detecting individuals with a psychotic disorder

OBJECTIVES: The need for a brief screening tool for psychosis is widely recognized. The Community Assessment of Psychic Experiences (CAPE) is a popular self‐report measure of psychosis, but a cut‐off score that can detect those most likely to fulfill diagnostic criteria for psychotic disorder is not established. METHODS: A case–control sample from the Genetic Risk and Outcome of Psychosis Project study (N = 1375, healthy individuals, n = 507, and individuals with a psychotic disorder, n = 868), was used to examine cut‐off scores of the CAPE with receiver operating curve analyses. We examined 27 possible cut‐off scores computed from a combination of scores from the frequency and distress scales of the various factors of the CAPE. RESULTS: The weighted severity positive symptom dimension was most optimal in detecting individuals with a psychotic disorder (>1.75 cut‐off; area under the curve = 0.88; sensitivity, 75%; specificity, 88%), which correctly identified 80% of the sample as cases or controls with a diagnostic odds ratio of 22.69. CONCLUSIONS: The CAPE can be used as a first screening tool to detect individuals who are likely to fulfill criteria for a psychotic disorder. The >1.75 cut‐off of the weighted severity positive symptom dimension provides a better prediction than all alternatives tested so far

Investigation of the genetic association between quantitative measures of psychosis and schizophrenia:A polygenic risk score analysis

The presence of subclinical levels of psychosis in the general population may imply that schizophrenia is the extreme expression of more or less continuously distributed traits in the population. In a previous study, we identified five quantitative measures of schizophrenia (positive, negative, disorganisation, mania, and depression scores). The aim of this study is to examine the association between a direct measure of genetic risk of schizophrenia and the five quantitative measures of psychosis. Estimates of the log of the odds ratios of case/control allelic association tests were obtained from the Psychiatric GWAS Consortium (PGC) (minus our sample) which included genome-wide genotype data of 8,690 schizophrenia cases and 11,831 controls. These data were used to calculate genetic risk scores in 314 schizophrenia cases and 148 controls from the Netherlands for whom genotype data and quantitative symptom scores were available. The genetic risk score of schizophrenia was significantly associated with case-control status (p<0.0001). In the case-control sample, the five psychosis dimensions were found to be significantly associated with genetic risk scores; the correlations ranged between.15 and.27 (all p<.001). However, these correlations were not significant in schizophrenia cases or controls separately. While this study confirms the presence of a genetic risk for schizophrenia as categorical diagnostic trait, we did not find evidence for the genetic risk underlying quantitative schizophrenia symptom dimensions. This does not necessarily imply that a genetic basis is nonexistent, but does suggest that it is distinct from the polygenic risk score for schizophrenia

Meta-analysis of epigenetic aging in schizophrenia reveals multifaceted relationships with age, sex, illness duration, and polygenic risk

Background: The study of biological age acceleration may help identify at-risk individuals and reduce the rising global burden of age-related diseases. Using DNA methylation (DNAm) clocks, we investigated biological aging in schizophrenia (SCZ), a mental illness that is associated with an increased prevalence of age-related disabilities and morbidities. In a whole blood DNAm sample of 1090 SCZ cases and 1206 controls across four European cohorts, we performed a meta-analysis of differential aging using three DNAm clocks (i.e., Hannum, Horvath, and Levine). To dissect how DNAm aging contributes to SCZ, we integrated information on duration of illness and SCZ polygenic risk, as well as stratified our analyses by chronological age and biological sex. Results: We found that blood-based DNAm aging is significantly altered in SCZ independent from duration of the illness since onset. We observed sex-specific and nonlinear age effects that differed between clocks and point to possible distinct age windows of altered aging in SCZ. Most notably, intrinsic cellular age (Horvath clock) is decelerated in SCZ cases in young adulthood, while phenotypic age (Levine clock) is accelerated in later adulthood compared to controls. Accelerated phenotypic aging was most pronounced in women with SCZ carrying a high polygenic burden with an age acceleration of + 3.82 years (CI 2.02–5.61, P = 1.1E−03). Phenotypic aging and SCZ polygenic risk contributed additively to the illness and together explained up to 14.38% of the variance in disease status. Conclusions: Our study contributes to the growing body of evidence of altered DNAm aging in SCZ and points to intrinsic age deceleration in younger adulthood and phenotypic age acceleration in later adulthood in SCZ. Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings indicate that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. Our study did not find that DNAm aging could be explained by the duration of illness of patients, but we did observe age- and sex-specific effects that warrant further investigation. Finally, our results show that combining genetic and epigenetic predictors can improve predictions of disease outcomes and may help with disease management in schizophrenia.</p