Cortical Volume Differences in Subjects at Risk for Psychosis Are Driven by Surface Area.

In subjects at risk for psychosis, the studies on gray matter volume (GMV) predominantly reported volume loss compared with healthy controls (CON). However, other important morphological measurements such as cortical surface area (CSA) and cortical thickness (CT) were not systematically compared. So far, samples mostly comprised subjects at genetic risk or at clinical risk fulfilling an ultra-high risk (UHR) criterion. No studies comparing UHR subjects with at-risk subjects showing only basic symptoms (BS) investigated the differences in CSA or CT. Therefore, we aimed to unravel the contribution of the 2 morphometrical measures constituting the cortical volume (CV) and to test whether these groups inhere different morphometric features. We conducted a surface-based morphometric analysis in 34 CON, 46 BS, and 39 UHR to examine between-group differences in CV, CSA, and CT vertex-wise across the whole cortex. Compared with BS and CON, UHR individuals presented increased CV in frontal and parietal regions, which was driven by larger CSA. These groups did not differ in CT. Yet, at-risk subjects who later developed schizophrenia showed thinning in the occipital cortex. Furthermore, BS presented increased CSA compared with CON. Our results suggest that volumetric differences in UHR subjects are driven by CSA while CV loss in converters seems to be based on cortical thinning. We attribute the larger CSA in UHR to aberrant pruning representing a vulnerability to develop psychotic symptoms reflected in different levels of vulnerability for BS and UHR, and cortical thinning to a presumably stress-related cortical decomposition.

Evaluation of the Combined Treatment Approach "Robin" (Standardized Manual and Smartphone App) for Adolescents at Clinical High Risk for Psychosis.

Introduction: The prevention of schizophrenia and other psychotic disorders has led researchers to focus on early identification of individuals at clinical high risk (CHR) for psychosis and to treat the at-risk symptoms in the pre-psychotic period. Although at-risk symptoms such as attenuated hallucinations or delusions are common in adolescents and associated with a marked reduction in global functioning, the evidence base of effective interventions for adolescents at CHR state and even first-episode psychosis is limited. Thus, the present protocol describes a study design that combines therapy modules for CHR adolescents with a smartphone application supporting the young individuals between the therapy sessions. The treatment approach "Robin" is based on existing therapy strategies for adolescents with first episode of psychosis and the available recommendations for adults with at-risk symptoms. Methods: The evaluation aims firstly to compare the efficacy of Robin in 30 CHR adolescents aged 14-18 to an active control group (treatment as usual) from a previous study. Primary outcome measures will be at-risk symptomatology, comorbid diagnosis, functioning, self-efficacy, and quality of life. For the prospective intervention condition (16 weekly individual sessions + a minimum 4 family sessions), help-seeking adolescents with CHR for psychosis, aged 14-18, will be recruited over 3 years. At-risk and comorbid symptoms, functioning, self-efficacy, and quality of life are monitored at six time points (baseline, during the treatment period; immediately after intervention; and 6, 12, and 24 months later) and compared with the respective measures of the active control group. Discussion: To the best of our knowledge, this is the first controlled trial to test the efficacy of a specific early psychosis treatment in combination with a smartphone application for adolescents at CHR for developing psychosis. The results of the study are expected to add information that may substantially decrease the burden of CHR adolescents and increase their resilience. It may offer age-adapted and targeted strategies to guide clinicians in the treatment of these vulnerable individuals. Furthermore, research in the field of early intervention will be enriched by our findings. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03829527.

Neurocognition in help-seeking individuals at risk for psychosis: Prediction of outcome after 24 months.

An important aim in schizophrenia research is to optimize the prediction of psychosis and to improve strategies for early intervention. The objectives of this study were to explore neurocognitive performance in individuals at risk for psychosis and to optimize predictions through a combination of neurocognitive and psychopathological variables. Information on clinical outcomes after 24 months was available from 118 subjects who had completed an extensive assessment at baseline. Subjects who had converted to psychosis were compared with subjects who had not. Multivariate Cox regression analyses were used to determine which baseline measure best predicted a conversion to psychosis. The premorbid IQ and the neurocognitive domains of processing speed, learning/memory, working memory and verbal fluency significantly discriminated between converters and non-converters. When entered into multivariate regression analyses, the combination of PANSS positive/negative symptom severity and IQ best predicted the clinical outcomes. Our results confirm previous evidence suggesting moderate premorbid cognitive deficits in individuals developing full-blown psychosis. Overall, clinical symptoms appeared to be a more sensitive predictor than cognitive performance. Nevertheless, the two might serve as complementary predictors when assessing the risk for psychosis.

Stigma and suicidal ideation among young people at risk of psychosis after one year.

Suicidality is common among individuals at risk of psychosis. Emerging findings suggest that mental illness stigma contributes to suicidality. However, it is unclear whether stigma variables are associated with suicidality among young people at risk of psychosis. This longitudinal study assessed perceived public stigma and the cognitive appraisal of stigma as a stressor (stigma stress) as predictors of suicidal ideation among individuals at risk of psychosis over the period of one year. One hundred and seventy-two participants between 13 and 35 years of age were included who were at high or ultra-high risk of psychosis or at risk of bipolar disorder. At one-year follow-up, data were available from 73 completers. In multiple logistic regressions an increase of stigma stress (but not of perceived stigma) over one year was significantly associated with suicidal ideation at one-year follow-up, controlling for age, gender, symptoms, comorbid depression and suicidal ideation at baseline. Interventions to reduce public stigma and stigma stress could therefore improve suicide prevention among young people at risk of psychosis.

Pathways between stigma and suicidal ideation among people at risk of psychosis.

Mental illness stigma may contribute to suicidality and is associated with social isolation and low self-esteem among young people at risk of psychosis. However, it is unclear whether mental illness stigma contributes to suicidality in this population. We therefore examined the associations of self-labeling and stigma stress with suicidality among young people at risk. Self-labeling as "mentally ill", stigma stress, social isolation, self-esteem, symptoms and suicidal ideation were assessed in 172 individuals at risk of psychosis. Self-labeling and stigma stress were examined as predictors of suicidality by path analysis. Increased self-labeling as "mentally ill" was associated with suicidality, directly as well as indirectly mediated by social isolation. More stigma stress was related to social isolation which in turn was associated with low self-esteem, depression and suicidal ideation. Social isolation fully mediated the link between stigma stress and suicidal ideation. Interventions to reduce the public stigma associated with risk of psychosis as well as programs to facilitate non-stigmatizing awareness of at-risk mental state and to reduce stigma stress among young people at risk of psychosis might strengthen suicide prevention in this population.

Heterogeneity of Psychosis Risk Within Individuals at Clinical High Risk: A Meta-analytical Stratification.

IMPORTANCE: Individuals can be classified as being at clinical high risk (CHR) for psychosis if they meet at least one of the ultra-high-risk (UHR) inclusion criteria (brief limited intermittent psychotic symptoms [BLIPS] and/or attenuated psychotic symptoms [APS] and/or genetic risk and deterioration syndrome [GRD]) and/or basic symptoms [BS]. The meta-analytical risk of psychosis of these different subgroups is still unknown. OBJECTIVE: To compare the risk of psychosis in CHR individuals who met at least one of the major inclusion criteria and in individuals not at CHR for psychosis (CHR-). DATA SOURCES: Electronic databases (Web of Science, MEDLINE, Scopus) were searched until June 18, 2015, along with investigation of citations of previous publications and a manual search of the reference lists of retrieved articles. STUDY SELECTION: We included original follow-up studies of CHR individuals who reported the risk of psychosis classified according to the presence of any BLIPS, APS and GRD, APS alone, GRD alone, BS, and CHR-. DATA EXTRACTION AND SYNTHESIS: Independent extraction by multiple observers and random-effects meta-analysis of proportions. Moderators were tested with meta-regression analyses (Bonferroni corrected). Heterogeneity was assessed with the I2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and the Egger test. MAIN OUTCOMES AND MEASURES: The proportion of each subgroup with any psychotic disorder at 6, 12, 24, 36, and 48 or more months of follow-up. RESULTS: Thirty-three independent studies comprising up to 4227 individuals were included. The meta-analytical proportion of individuals meeting each UHR subgroup at intake was: 0.85 APS (95%CI, 0.79-0.90), 0.1 BLIPS (95%CI, 0.06-0.14), and 0.05 GRD (95%CI, 0.03-0.07). There were no significant differences in psychosis risk at any time point between the APS and GRD and the APS-alone subgroups. There was a higher risk of psychosis in the any BLIPS greater than APS greater than GRD-alone subgroups at 24, 36, and 48 or more months of follow-up. There was no evidence that the GRD subgroup has a higher risk of psychosis than the CHR- subgroup. There were too few BS or BS and UHR studies to allow robust conclusions. CONCLUSIONS AND RELEVANCE: There is meta-analytical evidence that BLIPS represents separate risk subgroup compared with the APS. The GRD subgroup is infrequent and not associated with an increased risk of psychosis. Future studies are advised to stratify their findings across these different subgroups. The CHR guidelines should be updated to reflect these differences.

Self-labelling and stigma as predictors of attitudes towards help-seeking among people at risk of psychosis: 1-year follow-up.

Mental health service use is helpful but rare among young people at risk of psychosis. The label and stigma associated with mental illness may affect attitudes towards help-seeking. We examined 67 individuals at risk of psychosis over the course of 1 year. An increase of self-labelling as "mentally ill" predicted more positive attitudes towards psychiatric medication, while increased perceived stigma and the cognitive appraisal of stigma as a stressor predicted poorer attitudes towards psychotherapy after 1 year. Early intervention could improve non-stigmatizing awareness of at-risk mental state and reduce the public stigma associated with at-risk status to facilitate help-seeking.

Stigma as a stressor and transition to schizophrenia after one year among young people at risk of psychosis.

According to stress-vulnerability models, social stressors contribute to the onset of schizophrenia. Stigma and discrimination associated with mental illness may be a stressor for young people at risk of psychosis even prior to illness onset, but quantitative longitudinal data on this issue are lacking. We examined the cognitive appraisal of stigma-related stress as predictor of transition to schizophrenia among young people at risk of psychosis. In Zürich, Switzerland, 172 participants between 13 and 35years old and with either high or ultra-high risk of psychosis or risk of bipolar disorder were included. With 71 dropouts, transition was assessed during 12months among 101 participants of whom 13 converted to schizophrenia. At baseline, the cognitive appraisal of stigma as a stressor was measured by self-report, based on the primary appraisal of stigma as harmful and the secondary appraisal of resources to cope with stigma. Positive and negative symptoms were examined using the Positive and Negative Syndrome Scale. Compared with participants who did not convert to schizophrenia, converters had significantly more positive (p<.001) and negative (p<.001) symptoms and reported higher levels of stigma-related harm (p=.003) and stress (p=.009) at baseline. More perceived harm due to stigma at baseline predicted transition to schizophrenia (odds ratio 2.34, 95%-CI 1.19-4.60) after adjusting for age, gender, symptoms and functioning. Stigma stress may increase the risk of transition to schizophrenia. Research is needed on interventions that reduce public negative attitudes towards young people at risk and that support individuals at risk to cope with stigma-related stress.

Early Recognition of High Risk of Bipolar Disorder and Psychosis: An Overview of the ZInEP "Early Recognition" Study.

Early detection of persons with first signs of emerging psychosis is regarded as a promising strategy to reduce the burden of the disease. In recent years, there has been increasing interest in early detection of psychosis and bipolar disorders, with a clear need for sufficient sample sizes in prospective research. The underlying brain network disturbances in individuals at risk or with a prodrome are complex and yet not well known. This paper provides the rationale and design of a prospective longitudinal study focused on at-risk states of psychosis and bipolar disorder. The study is carried out within the context of the Zurich Program for Sustainable Development of Mental Health services (Zürcher Impulsprogramm zur Nachhaltigen Entwicklung der Psychiatrie). Persons at risk for psychosis or bipolar disorder between 13 and 35 years of age are examined by using a multi-level-approach (psychopathology, neuropsychology, genetics, electrophysiology, sociophysiology, magnetic resonance imaging, near-infrared spectroscopy). The included adolescents and young adults have four follow-ups at 6, 12, 24, and 36 months. This approach provides data for a better understanding of the relevant mechanisms involved in the onset of psychosis and bipolar disorder, which can serve as targets for future interventions. But for daily clinical practice a practicable "early recognition" approach is required. The results of this study will be useful to identify the strongest predictors and to delineate a prediction model.

Longitudinal course of self-labeling, stigma stress and well-being among young people at risk of psychosis.

Stigma may undermine the well-being of young people at risk of psychosis. We therefore measured self-labeling, stigma variables and well-being at baseline and again one year later among 77 at-risk participants. An increase in self-labeling during this period predicted heightened stigma stress after one year and a decrease in stigma stress predicted better well-being at follow-up, controlling for symptoms, psychiatric comorbidity and sociodemographic variables. Besides early intervention programmes, strategies are needed to reduce the public stigma associated with at-risk status and to support young people at risk to better cope with self-labeling and stigma stress.

Well-being among persons at risk of psychosis: the role of self-labeling, shame, and stigma stress.

OBJECTIVE: When young people at risk of psychosis experience early signs of the disorder or early intervention, they may label themselves as "mentally ill." However, empirical data related to the potentially harmful effects of self-labeling and stigma among young people at risk of psychosis are lacking. This study used a stress-coping model to examine mechanisms by which stigma may exert an impact on young people at risk of psychosis. METHODS: The authors assessed self-reports of perceived public stigma, shame about having a mental illness, self-labeling, and the cognitive appraisal of stigma as a stressor (stigma stress) as predictors of well-being among 172 residents of Zürich, Switzerland, who were between 13 and 35 years old. All participants were at high risk or ultra-high risk of psychosis or at risk of bipolar disorder. Psychiatric symptoms were assessed by the Positive and Negative Syndrome Scale, and well-being was measured by instruments that assessed quality of life, self-esteem, and self-efficacy. RESULTS: Perceived public stigma, shame, and self-labeling were independently associated with increased stigma stress. More stigma stress, in turn, predicted reduced well-being, independent of age, gender, symptoms, and psychiatric comorbidity. Stigma stress partly mediated the effects of perceived public stigma, shame, and self-labeling on well-being. CONCLUSIONS: Perceived public stigma, shame, and self-labeling appear to be associated with stigma stress and reduced well-being among young people at risk of psychosis. With early intervention programs gaining traction worldwide, effective strategies to address the shame and stigma associated with at-risk states and early psychosis are needed.

Evaluation of trait adjectives and ego pathology in schizophrenia: an N400 study.

The N400, an event-related brain potential (ERP), can be triggered by semantic or arithmetic violations in visual or auditory stimulus material. Schizophrenia patients exhibit an altered N400 presumably resulting from impaired semantic memory associative networks. The present study investigates, whether an altered N400 can also be found in semantic violations of the own self-concept. We use simple descriptive sentences to combine semantics with the self-concept in order to explore differences and possible deficits in schizophrenia patients. Schizophrenia patients and controls were shown trait adjectives in reference to themselves. Participants had to decide if the presented trait adjective was congruent or incongruent with their own self-concept. Only in controls, the N400 was significantly more negative in the incongruent compared to the congruent condition. Controls seemed to profit from a stable self-concept as they were faster in judging if a given trait was descriptive for the self than for someone else, which might result from processes related to the self-reference effect. Interestingly, in schizophrenia patients, the higher the scores for ego pathology were, the smaller the N400 effect turned out to be. The diminished N400 effect is probably associated with a disturbed self-concept in schizophrenia.

Aberrant coupling within and across the default mode, task-positive, and salience network in subjects at risk for psychosis.

The task-positive network (TPN) is anticorrelated with activity in the default mode network (DMN), and possibly reflects competition between the processing of external and internal information, while the salience network (SN) is pivotal in regulating TPN and DMN activity. Because abnormal functional connectivity in these networks has been related to schizophrenia, we tested whether alterations are also evident in subjects at risk for psychosis. Resting-state functional magnetic resonance imaging was tested in 28 subjects with basic symptoms reporting subjective cognitive-perceptive symptoms; 19 with attenuated or brief, limited psychotic symptoms; and 29 matched healthy controls. We characterized spatial differences in connectivity patterns, as well as internetwork connectivity. Right anterior insula (rAI) was selected as seed region for identifying the SN; medioprefrontal cortex (MPFC) for the DMN and TPN. The 3 groups differed in connectivity patterns between the MPFC and right dorsolateral prefrontal cortex (rDLPFC), and between the rAI and posterior cingulate cortex (PCC). In particular, the typically observed antagonistic relationship in MPFC-rDLPFC, rAI-PCC, and internetwork connectivity of DMN-TPN was absent in both at-risk groups. Notably, those connectivity patterns were associated with symptoms related to reality distortions, whereas enhanced connectivity strengths of MPFC-rDLPFC and TPN-DMN were related to poor performance in cognitive functions. We propose that the loss of a TPN-DMN anticorrelation, accompanied by an aberrant spatial extent in the DMN, TPN, and SN in the psychosis risk state, reflects the confusion of internally and externally focused states and disturbance of cognition, as seen in psychotic disorders.

Temporal variability and spatial diffusion of the N2 event-related potential in high-functioning patients with schizophrenia.

Recent theories of schizophrenia have proposed a fundamental instability of information processing on a neurophysiological level, which can be measured as an increase in latency variability of event-related potentials (ERPs). If this reflects a fundamental deficit of the schizophrenic illness, it should also occur in high-functioning patients. These patients have also been observed to show a more diffuse activation pattern in neuroimaging studies, which is thought to reflect compensatory processes to maintain task performance. In the present study we investigated temporal variability and spatial diffusion of the visual N2 component in a group of high-functioning patients with preserved cognitive performance. 28 patients with schizophrenia and 28 control participants matched for gender, age and education participated in the study. Subjects performed a visual Go/Nogo task, while event-related potentials were obtained. Trial-to-trial latency variability was calculated with a Wavelet-based method. Patients with schizophrenia showed a robust increase in N2 latency variability at electrodes Fz and Cz in all task conditions. Regarding spatial distribution healthy participants showed a focused fronto-central N2 peak. In contrast, patients with schizophrenia showed a more diffuse pattern and additional negative peaks over lateral electrodes in the Nogo condition. These results clearly show that even in high-functioning patients with schizophrenia a higher temporal variability of ERPs can be observed. This provides support for temporal instability of information processing as a fundamental deficit associated with schizophrenia. The more diffuse scalp distribution might reflect processes that compensate for this instability when cognitive control is required.

Pre-reflective and reflective self-reference: a spatiotemporal EEG analysis.

Functional imaging studies consistently support the role of the medial prefrontal cortex to be a part of a functional network of reflective self-awareness. The current study introduces a new linguistic task which (1) directly compares self-reference and other-reference, and (2) separates pre-reflective from reflective aspects of self-awareness. Twenty-six healthy volunteers evaluated trait adjectives in reference to the self or a close friend while a continuous 30-channel EEG was recorded. Low-resolution brain electromagnetic tomography (LORETA) was used for statistical brain imaging. As expected, the direct comparison of self-reference to other-reference revealed the MPFC to be significant and strongly more active during the self-reference condition. Pre-reflective aspects of self seem to be implemented to a greater degree in the ventral, reflective aspects of the self in dorsal parts of the MPFC. In the pre-reflective self condition, brain areas that receive homeostatic afferents from somatic and visceral sensation of the body such as the insula and the somatosensory cortex were strongly activated as early as 134 ms after stimulus onset. The right inferior parietal lobe seems to be involved in self-referential processing in general.

Mental own-body and body-part transformations in microgravity.

The aim of this experiment was to investigate the influence of gravity on the cognitive ability to mentally transform images of bodies or body parts. A total of eight participants were tested in two separate parabolic flight missions. In the main experiment, participants had to make a discrimination judgement (left or right) about pictures of a human figure with one arm outstretched, and pictures of a body part (hand). The stimuli appeared in varying views and orientations. Response times and error rates were measured. In microgravity, the participants showed increased response times overall as well as increased error rates when compared to 1 g for both types of stimuli. Thus, a task that requires the mental transformation of one's own body or body parts becomes more difficult during microgravity. This is in contrast to previous studies showing no effect of microgravity on the mental rotation of abstract 3D objects and to our follow-up case study in which participants applied an object-based mental rotation strategy. Moreover, the analysis of response times suggests that in microgravity body-part stimuli are affected more strongly than body figures.