Perceptions of stigma in youth at clinical high risk for psychosis and depressive symptomatology.

It is unclear what types of stigma youth at clinical high risk for psychosis (CHR) experience, and the relationship between them and symptomatology. 94 CHR youth, and a control group of 45 youth with no psychosis spectrum symptoms (NP) were rated for perceived devaluation (i.e. negative views from others) and internalized mental health stigma (i.e. the extent to which they would agree with said views) as well as positive and mood symptomatology. CHR youth reported stigma more frequently than the NP group (χ2(1) = 53.55, p < .001) and at higher levels (perceived devaluation: t (137) = 8.54, p < .001; internalized stigma: t (137) = 7.48, p < .001). Surprisingly, in the CHR group, positive symptoms held no significant relationship to stigma measures. However, ratings of perceived devaluation stigma were associated with depressive symptomatology (ß = 0.27, t = 2.68, p = .0087) and depression scores were conversely associated with perceived devaluation stigma (ß = 0.30, t = 2.05, p = .043). These findings speak to the relationship between depressive symptomatology and perceived devaluation stigma in CHR youth. Perceived devaluation stigma showed greater clinical significance and could have different mechanisms than internalized stigma in CHR youth. It is also noteworthy that while positive symptoms play a central role in defining the CHR syndrome, they seem less relevant to the experience of stigma than mood symptoms. These findings highlight the importance of interventions aimed at ameliorating youth's exposure to negative views about mental health as those managing depressive symptomatology.

Country-level gender inequality is associated with structural differences in the brains of women and men.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

Quantitative Susceptibility Mapping MRI in Deep-Brain Nuclei in First-Episode Psychosis.

BACKGROUND: Psychosis is related to neurochemical changes in deep-brain nuclei, particularly suggesting dopamine dysfunctions. We used an magnetic resonance imaging-based technique called quantitative susceptibility mapping (QSM) to study these regions in psychosis. QSM quantifies magnetic susceptibility in the brain, which is associated with iron concentrations. Since iron is a cofactor in dopamine pathways and co-localizes with inhibitory neurons, differences in QSM could reflect changes in these processes. METHODS: We scanned 83 patients with first-episode psychosis and 64 healthy subjects. We reassessed 22 patients and 21 control subjects after 3 months. Mean susceptibility was measured in 6 deep-brain nuclei. Using linear mixed models, we analyzed the effect of case-control differences, region, age, gender, volume, framewise displacement (FD), treatment duration, dose, laterality, session, and psychotic symptoms on QSM. RESULTS: Patients showed a significant susceptibility reduction in the putamen and globus pallidus externa (GPe). Patients also showed a significant R2* reduction in GPe. Age, gender, FD, session, group, and region are significant predictor variables for QSM. Dose, treatment duration, and volume were not predictor variables of QSM. CONCLUSIONS: Reduction in QSM and R2* suggests a decreased iron concentration in the GPe of patients. Susceptibility reduction in putamen cannot be associated with iron changes. Since changes observed in putamen and GPe were not associated with symptoms, dose, and treatment duration, we hypothesize that susceptibility may be a trait marker rather than a state marker, but this must be verified with long-term studies.

Dysconnectivity in Schizophrenia Revisited: Abnormal Temporal Organization of Dynamic Functional Connectivity in Patients With a First Episode of Psychosis.

BACKGROUND AND HYPOTHESIS: Abnormal functional connectivity between brain regions is a consistent finding in schizophrenia, including functional magnetic resonance imaging (fMRI) studies. Recent studies have highlighted that connectivity changes in time in healthy subjects. We here examined the temporal changes in functional connectivity in patients with a first episode of psychosis (FEP). Specifically, we analyzed the temporal order in which whole-brain organization states were visited. STUDY DESIGN: Two case-control studies, including in each sample a subgroup scanned a second time after treatment. Chilean sample included 79 patients with a FEP and 83 healthy controls. Mexican sample included 21 antipsychotic-naïve FEP patients and 15 healthy controls. Characteristics of the temporal trajectories between whole-brain functional connectivity meta-states were examined via resting-state functional MRI using elements of network science. We compared the cohorts of cases and controls and explored their differences as well as potential associations with symptoms, cognition, and antipsychotic medication doses. STUDY RESULTS: We found that the temporal sequence in which patients' brain dynamics visited the different states was more redundant and segregated. Patients were less flexible than controls in changing their network in time from different configurations, and explored the whole landscape of possible states in a less efficient way. These changes were related to the dose of antipsychotics the patients were receiving. We replicated the relationship with antipsychotic medication in the antipsychotic-naïve FEP sample scanned before and after treatment. CONCLUSIONS: We conclude that psychosis is related to a temporal disorganization of the brain's dynamic functional connectivity, and this is associated with antipsychotic medication use.

Is Cortical Theta-Gamma Phase-Amplitude Coupling Memory-Specific?

One of the proposed neural mechanisms involved in working memory is coupling between the theta phase and gamma amplitude. For example, evidence from intracranial recordings shows that coupling between hippocampal theta and cortical gamma oscillations increases selectively during working memory tasks. Theta-gamma phase-amplitude coupling can also be measured non-invasively through scalp EEG; however, EEG can only assess coupling within cortical areas, and it is not yet clear if this cortical-only coupling is truly memory-specific, or a more general phenomenon. We tested this directly by measuring cortical coupling during three different conditions: a working memory task, an attention task, and a passive perception condition. We find similar levels of theta-gamma coupling in all three conditions, suggesting that cortical theta-gamma phase-amplitude coupling is not a memory-specific signal, but instead reflects some other attentional or perceptual processes. Implications for understanding the brain dynamics of visual working memory are discussed.

The enduring gap in educational attainment in schizophrenia according to the past 50 years of published research: a systematic review and meta-analysis.

BACKGROUND: Educational attainment is associated with wellbeing and health, but patients with schizophrenia achieve lower levels of education than people without. Several effective interventions can ameliorate this situation. However, the magnitude of the education gap in schizophrenia and its change over time are unclear. We aimed to reconstruct the trajectories of educational attainment in patients with schizophrenia and, if reported, their healthy comparator controls. METHODS: We did a systematic review and meta-analysis including all studies reporting on patients with schizophrenia (of mean age ≥18 years) and describing the number of years of education of the participants, with or without healthy controls. There were no other design constraints on studies. We excluded studies that included only patients with other schizophrenia spectrum disorders and studies that did not specify the number of years of education of the participants. 22 reviewers participated in retrieving data from a search in PubMed and PsycINFO (Jan 1, 1970, to Nov 24, 2020). We estimated the birth date of participants from their mean age and publication date, and meta-analysed these data using random-effects models, focusing on educational attainment, the education gap, and changes over time. The primary outcome was years of education. The protocol was registered on PROSPERO (CRD42020220546). FINDINGS: From 32 593 initial references, we included 3321 studies reporting on 318 632 patients alongside 138 675 healthy controls (170 941 women and 275 821 men from studies describing sex or gender; data on ethnicity were not collected). Patients' educational attainment increased over time, mirroring that of controls. However, patients with schizophrenia in high-income countries had 19 months less education than controls (-1·59 years, 95% CI -1·66 to -1·53; p<0·0001), which is equivalent to a Cohen's d of -0·56 (95% CI -0·58 to -0·54) and implies an odds ratio of 2·58 for not completing 12 years of education (ie, not completing secondary education) for patients compared with controls. This gap remained stable throughout the decades; the rate of change in number of total years of education in time was not significant (annual change: 0·0047 years, 95% CI -0·0005 to 0·0099; p=0·078). For patients in low-income and middle-income countries, the education gap was significantly smaller than in high-income countries (smaller by 0·72 years, 0·85 to 0·59; p<0·0001), yet there was evidence that this gap was widening over the years, approaching that of high-income countries (annual change: -0·024 years, -0·037 to -0·011; p=0·0002). INTERPRETATION: Patients with schizophrenia have faced persistent inequality in educational attainment in the last century, despite advances in psychosocial and pharmacological treatment. Reducing this gap should become a priority to improve their functional outcomes. FUNDING: Ciencia y Tecnología para el Desarrollo (CYTED) to the Latin American Network for the Study of Early Psychosis (ANDES).

Effects of socioeconomic status in cognition of people with schizophrenia: results from a Latin American collaboration network with 1175 subjects.

BACKGROUND: Cognition heavily relies on social determinants and genetic background. Latin America comprises approximately 8% of the global population and faces unique challenges, many derived from specific demographic and socioeconomic variables, such as violence and inequality. While such factors have been described to influence mental health outcomes, no large-scale studies with Latin American population have been carried out. Therefore, we aim to describe the cognitive performance of a representative sample of Latin American individuals with schizophrenia and its relationship to clinical factors. Additionally, we aim to investigate how socioeconomic status (SES) relates to cognitive performance in patients and controls. METHODS: We included 1175 participants from five Latin American countries (Argentina, Brazil, Chile, Colombia, and Mexico): 864 individuals with schizophrenia and 311 unaffected subjects. All participants were part of projects that included cognitive evaluation with MATRICS Consensus Cognitive Battery and clinical assessments. RESULTS: Patients showed worse cognitive performance than controls across all domains. Age and diagnosis were independent predictors, indicating similar trajectories of cognitive aging for both patients and controls. The SES factors of education, parental education, and income were more related to cognition in patients than in controls. Cognition was also influenced by symptomatology. CONCLUSIONS: Patients did not show evidence of accelerated cognitive aging; however, they were most impacted by a lower SES suggestive of deprived environment than controls. These findings highlight the vulnerability of cognitive capacity in individuals with psychosis in face of demographic and socioeconomic factors in low- and middle-income countries.

Functional Dysconnectivity in Ventral Striatocortical Systems in 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is a genetic neurodevelopmental disorder that represents one of the greatest known risk factors for psychosis. Previous studies in psychotic subjects without the deletion have identified a dopaminergic dysfunction in striatal regions, and dysconnectivity of striatocortical systems, as an important mechanism in the emergence of psychosis. Here, we used resting-state functional MRI to examine striatocortical functional connectivity in 22q11.2DS patients. We used a 2 × 2 factorial design including 125 subjects (55 healthy controls, 28 22q11.2DS patients without a history of psychosis, 10 22q11.2DS patients with a history of psychosis, and 32 subjects with a history of psychosis without the deletion), allowing us to identify network effects related to the deletion and to the presence of psychosis. In line with previous results from psychotic patients without 22q11.2DS, we found that there was a dorsal to ventral gradient of hypo- to hyperstriatocortical connectivity related to psychosis across both patient groups. The 22q11.2DS was additionally associated with abnormal functional connectivity in ventral striatocortical networks, with no significant differences identified in the dorsal system. Abnormalities in the ventral striatocortical system observed in these individuals with high genetic risk to psychosis may thus reflect a marker of illness risk.

Gender, age and geographical representation over the past 50 years of schizophrenia research.

Previous studies have suggested that subjects participating in schizophrenia research are not representative of the demographics of the global population of people with schizophrenia, particularly in terms of gender and geographical location. We here explored if this has evolved throughout the decades, examining changes in geographical location, gender and age of participants in studies of schizophrenia published in the last 50 years. We examined this using a meta-analytical approach on an existing database including over 3,000 studies collated for another project. We found that the proportion of studies and participants from low-and-middle income countries has significantly increased over time, with considerable input from studies from China. However, it is still low when compared to the global population they represent. Women have been historically under-represented in studies, and still are in high-income countries. However, a significantly higher proportion of female participants have been included in studies over time. The age of participants included has not changed significantly over time. Overall, there have been improvements in the geographical and gender representation of people with schizophrenia. However, there is still a long way to go so research can be representative of the global population of people with schizophrenia, particularly in geographical terms.

Abnormal nodal and global network organization in resting state functional MRI from subjects with the 22q11 deletion syndrome.

The 22q11 deletion syndrome is a genetic disorder associated with a high risk of developing psychosis, and is therefore considered a neurodevelopmental model for studying the pathogenesis of schizophrenia. Studies have shown that localized abnormal functional brain connectivity is present in 22q11 deletion syndrome like in schizophrenia. However, it is less clear whether these abnormal cortical interactions lead to global or regional network disorganization as seen in schizophrenia. We analyzed from a graph-theory perspective fMRI data from 40 22q11 deletion syndrome patients and 67 healthy controls, and reconstructed functional networks from 105 brain regions. Between-group differences were examined by evaluating edge-wise strength and graph theoretical metrics of local (weighted degree, nodal efficiency, nodal local efficiency) and global topological properties (modularity, local and global efficiency). Connectivity strength was globally reduced in patients, driven by a large network comprising 147 reduced connections. The 22q11 deletion syndrome network presented with abnormal local topological properties, with decreased local efficiency and reductions in weighted degree particularly in hub nodes. We found evidence for abnormal integration but intact segregation of the 22q11 deletion syndrome network. Results suggest that 22q11 deletion syndrome patients present with similar aberrant local network organization as seen in schizophrenia, and this network configuration might represent a vulnerability factor to psychosis.

Neural basis of the visual working memory deficit in schizophrenia: Merging evidence from fMRI and EEG.

Although people with schizophrenia (PSZ) exhibit robust and reliable deficits in working memory (WM) capacity, the neural processes that give rise to this impairment remain poorly understood. One reason for this lack of clarity is that most studies employ a single neural recording modality-each with strengths and weaknesses-with few examples of integrating results across modalities. To address this gap, we conducted a secondary analysis that combined data from an overlapping set of subjects in previously published electroencephalographic and functional magnetic resonance imaging studies that used nearly identical working memory tasks (visual change detection). The prior studies found similar patterns of results for both posterior parietal BOLD activation and suppression of the alpha frequency band within the EEG. Specifically, both signals exhibited abnormally shallow modulation as a function of the amount of information being stored in WM in PSZ. In the present study, both alpha suppression and posterior parietal BOLD activity increased as the number of items stored in WM increased. The magnitude of alpha suppression modulation was correlated with the magnitude of BOLD signal modulation in PSZ, but not in HCS. This finding suggests that the same illness-related biological processes constrain both alpha suppression and BOLD signal modulation as a function of WM storage in PSZ. The complementary strengths of these two techniques may thus combine to advance the identification of the processes underlying WM deficits in PSZ.

Uso de cannabis en jóvenes hospitalizados por un primer episodio de psicosis: un estudio caso-control

Background: Cannabis use among young people in Chile has increased significantly in the last years. There is a consistent link between cannabis and psychosis. Aim: To compare cannabis use in patients with a first episode of psychosis and healthy controls. Material and Methods: We included 74 patients aged 20 ± 3 years (78% males) admitted to hospital with a first episode of psychosis and a group of 60 healthy controls aged 23 ± 4 years (63% males). Cannabis consumption was assessed, including age of first time use and length of regular use. Results: Patients with psychosis reported a non-significantly higher frequency of life-time cannabis use. Patients had longer periods of regular cannabis use compared with healthy subjects (Odds ratio [OR] 2.4; 95% confi-dence intervals [CI] 1.14-5.05). Patients also used cannabis for the first time at an earlier age (16 compared with 17 years, p < 0.0). The population attributable fraction for regular cannabis use associated with hospital admissions due to psychosis was 17.7% (95% CI 1.2-45.5%). Conclusions: Cannabis use is related to psychosis in this Chilean group of patients. This relationship is stronger in patients with early exposure to the drug and longer the regular use. One of every five admissions due to psychosis is associated with cannabis consumption. These data should influence cannabis legisla-tion and the public policies currently being discussed in Chile.

Transitions between human functional brain networks reveal complex, cost-efficient and behaviorally-relevant temporal paths.

Resting-state functional MRI activity is organized as a complex network. However, this coordinated brain activity changes with time, raising questions about its evolving temporal arrangement. Does the brain visit different configurations through time in a random or ordered way? Advances in this area depend on developing novel paradigms that would allow us to shed light on these issues. We here propose to study the temporal changes in the functional connectome by looking at transition graphs of network activity. Nodes of these graphs correspond to brief whole-brain connectivity patterns (or meta-states), and directed links to the temporal transition between consecutive meta-states. We applied this method to two datasets of healthy subjects (160 subjects and a replication sample of 54), and found that transition networks had several non-trivial properties, such as a heavy-tailed degree distribution, high clustering, and a modular organization. This organization was implemented at a low biological cost with a high cost-efficiency of the dynamics. Furthermore, characteristics of the subjects' transition graphs, including global efficiency, local efficiency and their transition cost, were correlated with cognition and motor functioning. All these results were replicated in both datasets. We conclude that time-varying functional connectivity patterns of the brain in health progress in time in a highly organized and complex order, which is related to behavior.

[Cannabis use among hospitalized young people experiencing a first episode of psychosis: a case control study]. / Uso de cannabis en jóvenes hospitalizados por un primer episodio de psicosis: un estudio caso-control.

BACKGROUND: Cannabis use among young people in Chile has increased significantly in the last years. There is a consistent link between cannabis and psychosis. AIM: To compare cannabis use in patients with a first episode of psychosis and healthy controls. MATERIAL AND METHODS: We included 74 patients aged 20 ± 3 years (78% males) admitted to hospital with a first episode of psychosis and a group of 60 healthy controls aged 23 ± 4 years (63% males). Cannabis consumption was assessed, including age of first time use and length of regular use. RESULTS: Patients with psychosis reported a non-significantly higher frequency of life-time cannabis use. Patients had longer periods of regular cannabis use compared with healthy subjects (Odds ratio [OR] 2.4; 95% confi-dence intervals [CI] 1.14-5.05). Patients also used cannabis for the first time at an earlier age (16 compared with 17 years, p < 0.0). The population attributable fraction for regular cannabis use associated with hospital admissions due to psychosis was 17.7% (95% CI 1.2-45.5%). CONCLUSIONS: Cannabis use is related to psychosis in this Chilean group of patients. This relationship is stronger in patients with early exposure to the drug and longer the regular use. One of every five admissions due to psychosis is associated with cannabis consumption. These data should influence cannabis legisla-tion and the public policies currently being discussed in Chile.

Imaging Social and Environmental Factors as Modulators of Brain Dysfunction: Time to Focus on Developing Non-Western Societies.

Social and environmental factors are known risk factors and modulators of mental health disorders. We here conducted a nonsystematic review of the neuroimaging literature studying the effects of poverty, urbanicity, and community violence, highlighting the opportunities of studying non-Western developing societies such as those in Latin America. Social and environmental factors in these communities are widespread and have a large magnitude, as well as an unequal distribution, providing a good opportunity for their characterization. Studying the effect of poverty in these settings could help to explore the brain effect of economic improvements, disentangle the effect of absolute and relative poverty, and characterize the modulating impact of poverty on the underlying biology of mental health disorders. Exploring urbanicity effects in highly unequal cities could help identify the specific factors that modulate this effect as well as examine a possible dose-response effect by studying megacities. Studying brain changes in those living among violence, which is particularly high in places such as Latin America, could help to characterize the interplay between brain predisposition and exposure to violence. Furthermore, exploring the brain in an adverse environment should shed light on the mechanisms underlying resilience. We finally provide examples of two methodological approaches that could contribute to this field, namely a big cohort study in the developing world and a consortium-based meta-analytic approach, and argue about the potential translational value of this research on the development of effective social policies and successful personalized medicine in disadvantaged societies.