Neurobiologically Based Stratification of Recent-Onset Depression and Psychosis: Identification of Two Distinct Transdiagnostic Phenotypes.

BACKGROUND: Identifying neurobiologically based transdiagnostic categories of depression and psychosis may elucidate heterogeneity and provide better candidates for predictive modeling. We aimed to identify clusters across patients with recent-onset depression (ROD) and recent-onset psychosis (ROP) based on structural neuroimaging data. We hypothesized that these transdiagnostic clusters would identify patients with poor outcome and allow more accurate prediction of symptomatic remission than traditional diagnostic structures. METHODS: HYDRA (Heterogeneity through Discriminant Analysis) was trained on whole-brain volumetric measures from 577 participants from the discovery sample of the multisite PRONIA study to identify neurobiologically driven clusters, which were then externally validated in the PRONIA replication sample (n = 404) and three datasets of chronic samples (Centre for Biomedical Research Excellence, n = 146; Mind Clinical Imaging Consortium, n = 202; Munich, n = 470). RESULTS: The optimal clustering solution was two transdiagnostic clusters (cluster 1: n = 153, 67 ROP, 86 ROD; cluster 2: n = 149, 88 ROP, 61 ROD; adjusted Rand index = 0.618). The two clusters contained both patients with ROP and patients with ROD. One cluster had widespread gray matter volume deficits and more positive, negative, and functional deficits (impaired cluster), and one cluster revealed a more preserved neuroanatomical signature and more core depressive symptomatology (preserved cluster). The clustering solution was internally and externally validated and assessed for clinical utility in predicting 9-month symptomatic remission, outperforming traditional diagnostic structures. CONCLUSIONS: We identified two transdiagnostic neuroanatomically informed clusters that are clinically and biologically distinct, challenging current diagnostic boundaries in recent-onset mental health disorders. These results may aid understanding of the etiology of poor outcome patients transdiagnostically and improve development of stratified treatments.

Heterogeneity and Classification of Recent Onset Psychosis and Depression: A Multimodal Machine Learning Approach.

Diagnostic heterogeneity within and across psychotic and affective disorders challenges accurate treatment selection, particularly in the early stages. Delineation of shared and distinct illness features at the phenotypic and brain levels may inform the development of more precise differential diagnostic tools. We aimed to identify prototypes of depression and psychosis to investigate their heterogeneity, with common, comorbid transdiagnostic symptoms. Analyzing clinical/neurocognitive and grey matter volume (GMV) data from the PRONIA database, we generated prototypic models of recent-onset depression (ROD) vs. recent-onset psychosis (ROP) by training support-vector machines to separate patients with ROD from patients with ROP, who were selected for absent comorbid features (pure groups). Then, models were applied to patients with comorbidity, ie, ROP with depressive symptoms (ROP+D) and ROD participants with sub-threshold psychosis-like features (ROD+P), to measure their positions within the affective-psychotic continuum. All models were independently validated in a replication sample. Comorbid patients were positioned between pure groups, with ROP+D patients being more frequently classified as ROD compared to pure ROP patients (clinical/neurocognitive model: χ2 = 14.874; P < .001; GMV model: χ2 = 4.933; P = .026). ROD+P patient classification did not differ from ROD (clinical/neurocognitive model: χ2 = 1.956; P = 0.162; GMV model: χ2 = 0.005; P = .943). Clinical/neurocognitive and neuroanatomical models demonstrated separability of prototypic depression from psychosis. The shift of comorbid patients toward the depression prototype, observed at the clinical and biological levels, suggests that psychosis with affective comorbidity aligns more strongly to depressive rather than psychotic disease processes. Future studies should assess how these quantitative measures of comorbidity predict outcomes and individual responses to stratified therapeutic interventions.

Gender differences in the experience of psychotic-like experiences and their associated factors: A study of adolescents from the general population.

"Psychotic-Like Experiences" (PLEs) are common in the general population. While they are usually transient and resolve spontaneously, they can be distressing and signify increased risk for later psychosis or other psychopathology. It is important to investigate factors associated with PLEs which could be targeted to reduce their prevalence and impact. Males and females are known to experience PLEs differently, but any gender differences in the relationships between PLEs and other, potentially targetable, factors are currently unknown. 302 adolescents (175 females, mean age = 16.03, SD = 0.75; 127 males, mean age = 16.09, SD = 0.74) from secondary schools in the West Midlands region of the UK completed baseline self-report measures of positive PLEs, measured by the Community Assessment of Psychic Experiences (CAPE-P), and several potentially related factors including: cannabis use, perceived stress, anxiety, depression, and daily hassles. PLEs were common in this sample, with 67.5% of individuals experiencing at least one CAPE-P item 'often' or 'almost always'. Females reported significantly higher levels of PLEs, and associated distress, than males. Anxiety, depressive, and stress symptoms were similarly associated with PLEs in both genders. However, there was a significant interaction of gender and daily hassles in the association with PLEs. In summary, there were significant gender differences in the experience of PLEs in this sample. Although daily hassles were more common in females, they had a significantly stronger association with PLEs in males. Thus, addressing "daily life stress" in adolescents may require tailoring towards the more emotional perception of stress in females, and towards everyday life hassles in males.

An Investigation of Behavioural and Self-Reported Cognitive Empathy Deficits in Adolescents With Autism Spectrum Disorders and Adolescents With Behavioural Difficulties.

Deficits in empathy have been considered hallmarks in individuals with autism spectrum disorders (ASD) but are also considered to underlie antisocial behaviour associated with individuals with callous unemotional traits (CU). Research has suggested that individuals with autism spectrum disorders show more difficulties with cognitive empathy, and that individuals diagnosed with behaviours difficulties, characterised by CU traits and antisocial behaviour, demonstrate low affective empathy. In the current manuscript we present findings of two studies. The first study describes the validation of a new stimulus set developed for the empathic accuracy task, focused on its cognitive component. The second study compares the performance of 27 adolescents with ASD, 27 age matched typically developing adolescents and 17 adolescents with behavioural difficulties on the empathic accuracy task and a self-report measure of empathy. While, no differences were observed between the three groups across the empathy accuracy task, the adolescents with ASD and CD showed deficits in their cognitive empathy across the self-report measure. Adolescents with ASD showed lower scores in particularly their perspective taking abilities, whereas the adolescences with behavioural difficulties showed more difficulties with their online simulation. No differences in self-reported affective empathy across the three groups were observed. Clinical implications of the findings are discussed.

Does cortical brain morphology act as a mediator between childhood trauma and transition to psychosis in young individuals at ultra-high risk?

BACKGROUND: Childhood trauma, particularly sexual abuse, has been associated with transition to psychosis in individuals at "ultra-high risk" (UHR). This study investigated whether the effects of various forms of childhood trauma on transition to psychosis are mediated by cortical thickness and surface area abnormalities. METHODS: This prospective study used data from 62 UHR individuals from a previous (PACE 400) cohort study. At follow-up, 24 individuals had transitioned to psychosis (UHR-T) and 38 individuals had not transitioned (UHR-NT). Student-t/Mann-Whitney-U tests were performed to assess morphological differences in childhood trauma (low/high) and transition. Mediation analyses were conducted using regression and bootstrapping techniques. RESULTS: UHR individuals with high sexual trauma histories presented with decreased cortical thickness in bilateral middle temporal gyri and the left superior frontal gyrus compared to those with low sexual trauma. Participants with high physical abuse had increased cortical thickness in the right middle frontal gyrus compared to those with low physical abuse. No differences were found for emotional abuse or physical/emotional neglect. Reduced cortical thickness in the right middle temporal gyrus and increased surface area in the right cingulate were found in UHR-T compared to UHR-NT individuals. Sexual abuse had an indirect effect on transition to psychosis, where decreased cortical thickness in the right middle temporal gyrus was a mediator. CONCLUSIONS: Results suggest that childhood sexual abuse negatively impacted on cortical development of the right temporal gyrus, and this heightened the risk of transition to psychosis in our sample. Further longitudinal studies are needed to precisely understand this link.

Adding a Dimension to the Dichotomy: Affective Processes Are Implicated in the Relationship Between Autistic and Schizotypal Traits.

INTRODUCTION: There is a recognized increase in vulnerability to psychosis in autistic people (AP). However, the construct of psychosis (particularly schizophrenia) contains several distinct factors, making understanding the relationship between autism and psychosis complex. Previous research has suggested that affective lability may be particularly related to psychotic experiences for AP who have experienced psychosis (AP-P). There is also a suggestion that psychosis might be a state of extreme (over)empathizing, perhaps related to emotional processes. METHOD: We recruited three groups: AP-P (N = 23), a group of AP who had not experienced psychosis (AP-NP; N = 59) and a neurotypical control group (NC, N = 41). Participants completed measures of autistic traits, schizotypal traits (as a proxy for psychosis-proneness), emotional processes, and perspective taking (as a proxy for the type of empathizing most theoretically likely to be linked to psychosis). As well as comparisons between groups, regression analyses were used to understand the influence of dependent variables on schizotypal traits. RESULTS: We found that AP-P had significantly higher rates of schizotypy (positive and disorganized), as well as higher rates of emotional difficulties. Across all groups, affective lability had a positive and significant association with positive and disorganized schizotypal traits. Differences in perspective taking between groups were small and generally non-significant, particularly in adjusted comparisons; additionally, its impact on schizotypy was small and non-significant. DISCUSSION: Our findings suggest that positive and disorganized schizotypy, in particular, have a relationship with affective lability. This, in turn, supports the idea of emotional processes as related to the development of schizotypal traits and psychosis across all individuals, regardless of autism diagnostic status. We found no evidence of empathy relating to any subscale of schizotypy, or the total schizotypy score. We contend that emotional processes should be considered in exploration of the relationship between autism and schizotypy in future. This may help to explain some of the findings of overlap between these constructs in previous research. Factors known to affect neurodevelopment of emotion systems such as history of early trauma, challenges during pregnancy and birth, and early childhood experiences of adversity during critical windows of development need further consideration in future research.

Neural correlates of top-down guidance of attention to food: An fMRI study.

We investigated the neural correlates of working memory guided attentional selection of food versus non-food stimuli in young women. Participants were thirty-two women, aged 20.6y (± 0.5) who were presented with a cue (food or non-food item) to hold in working memory. Subsequently, they had to search for a target in a 2-item display where target and distractor stimuli were each flanked by a picture of a food or a non-food item. The behavioural data showed that attention is particularly efficiently drawn to food stimuli when thinking about food. Using fMRI, we found that holding a non-food versus food stimulus in working memory was associated with increased activity in occipital gyrus, fusiform, inferior and superior frontal gyrus. In the posterior cingulum, retrosplenial cortex, a food item that re-appeared in the search array when it was held in memory led to a reduced response, compared to when it did not re-appear. The reverse effect was found for non-food stimuli. The extent of the reappearance effect correlated with the attentional capture of food as measured behaviourally. In conclusion, these results suggest that holding food in mind may bias attention because thinking of food facilitated neuronal responses to sensory input related to food stimuli and because holding food-related information in mind is less taxing on memory.

Depressive and socially anxious symptoms, psychosocial maturity, and risk perception: Associations with risk-taking behaviour.

Risk-taking behaviour and onset of mental illness peak in adolescence and young adulthood. This study evaluated the interconnectedness of the domains of risk-taking behaviour, mental health (symptoms of depression and social anxiety), psychosocial maturity, risk perception, age, and gender in a sample of 306 adolescents and young adults. Participants between the ages of 16 and 35 completed online self-report measures assessing risk-taking behaviour, depressive symptoms, socially anxious symptoms, psychosocial maturity and risk perception. Socially anxious symptoms, psychosocial maturity, and risk perception were directly associated with risk-taking behaviour. Correlations between depressive symptoms, socially anxious symptoms, and psychosocial maturity were found. Psychosocial maturity proved a better predictor of risk-taking behaviour than age in this cohort. The findings indicate that mental health impacts upon risk-taking behaviour and that consideration should be given to psychosocial maturity in attempts to reduce adolescent and young adult risk-taking behaviour.

The impact of psychotic experiences in the early stages of mental health problems in young people.

BACKGROUND: Anxiety and depressive symptoms and psychotic experiences constitute common features of emerging mental disorders in young people. Psychotic experiences and the ultra-high risk (UHR) state for psychosis appear to have a particular importance for clinical presentation, progression of symptomatology, quality of life and functioning, but the impact of psychotic experiences in individuals seeking help at non-UHR services, compared to UHR services, is under-researched. METHODS: Sixty-nine young people (Mage ± SD at baseline = 20.8 ± 2.6, range 16-26 years, 48 females) presenting to mental health services were grouped according to UHR and non-UHR status. They were assessed at baseline for anxiety and depressive symptoms, psychological distress, psychosocial functioning and quality of life. They were followed up at three, six, and 12 months. Data were analysed using mixed linear modelling. RESULTS: UHR individuals reported higher levels of depressive symptoms and psychological distress, and lower levels of role functioning and quality of life compared to non-UHR individuals. No differences were reported for anxiety symptoms or social functioning. Decline in psychosocial functioning was not associated with clinical deterioration or reduction of quality of life. CONCLUSIONS: Psychotic experiences appear to be particularly associated with depressive symptoms and psychological distress, impaired role functioning and quality of life in help-seeking young people in the medium-term. It is therefore important to pay special attention to psychotic experiences in the early stages of mental health problems even if psychotic symptoms are not the main motivation for help-seeking.

The role of coping in the association between subclinical psychotic experiences and functioning: A within study replication in two independent adolescent samples.

An inverse association between psychosocial functioning and psychotic experiences is now established in both clinical and non-clinical populations, however the mechanisms which drive this are unclear. Adolescents with subclinical psychotic experiences (SPE) are more likely to use maladaptive coping strategies and less likely to use adaptive ones, and maladaptive coping has also been associated with poor functioning. A within study replication in two adolescent samples from the general populations of Melbourne, Australia (n = 723) and Birmingham, United Kingdom (n = 239), was conducted to determine whether the association between SPE and psychosocial functioning is mediated by coping style. SPE were associated with reduced general and family functioning and to a lesser extent with reduced peer functioning. Task-oriented (focusing on solving the problem) and emotion-oriented (negative emotional responses) coping were found to mediate the relationship between SPE and three types of functioning in both the Melbourne and the Birmingham samples. The within study replication consistently found that coping style mediates SPE and psychosocial functioning, despite significant differences in age, gender, functioning, use of coping styles, and level of SPE between the two samples. Longitudinal research is needed to fully understand any causal role coping may play in the relationship between SPE and poor functioning. The results have important public health and clinical implications, and suggest that techniques which increase levels of adaptive coping and reduce levels of maladaptive coping (in particular emotion-oriented styles) may help to break the cycle between SPE, functional decline, and eventual need for care.

Stress hormones and verbal memory in young people over the first 12 weeks of treatment for psychosis.

AIMS: Memory impairment in psychosis may be mediated through detrimental effects of hypothalamic-pituitary-adrenal (HPA) axis function. This study prospectively investigated the relationship between cortisol, sulphate dehydroepiandrosterone (DHEA(S) and cortisol: DHEA(S) ratio and memory in 35 first-episode psychosis (FEP) patients during the first 12 weeks of treatment and 23 healthy controls (HC). METHODS: Morning blood sampling and tests of attention, working memory and verbal memory occurred at baseline and 12-week follow-up. RESULTS: FEP and HC groups did not significantly differ in levels of cortisol, DHEA(S) or their ratio at baseline or over 12-weeks. The FEP group performed significantly below HC on all cognitive measures at baseline and over 12-weeks. Cortisol levels were unrelated to cognition in both groups. At baseline, DHEA(S) was positively associated with attention in HCs, but negatively associated with attention in FEP participants. Change in DHEA(S) was negatively associated with change in memory over 12-weeks in both groups. At 12-weeks, there was a negative correlation between the cortisol: DHEA(S) ratio and attention in both groups. CONCLUSIONS: These findings are mostly in contrast to findings in chronic schizophrenia. Investigation at different illness phases and over longer-follow-up periods is required to determine the complex relationship between HPA-axis and memory functioning in psychosis.

A pilot study to assess the effect of acute exercise on brain glutathione.

The brain is highly susceptible to oxidative stress due to its high metabolic demand. Increased oxidative stress and depletion of glutathione (GSH) are observed with aging and many neurological diseases. Exercise training has the potential to reduce oxidative stress in the brain. In this study, nine healthy sedentary males (aged 25 ± 4 years) undertook a bout of continuous moderate intensity exercise and a high-intensity interval (HII) exercise bout on separate days. GSH concentration in the anterior cingulate was assessed by magnetic resonance spectroscopy (MRS) in four participants, before and after exercise. This was a pilot study to evaluate the ability of the MRS method to detect exercise-induced changes in brain GSH in humans for the first time. MRS is a non-invasive method based on nuclear magnetic resonance, which enables the quantification of metabolites, such as GSH, in the human brain in vivo. To add context to brain GSH data, other markers of oxidative stress were also assessed in the periphery (in blood) at three time points [pre-, immediately post-, and post (∼1 hour)-exercise]. Moderate exercise caused a significant decrease in brain GSH from 2.12 ± 0.64 mM/kg to 1.26 ± 0.36 mM/kg (p = .04). Blood GSH levels increased immediately post-HII exercise, 580 ± 101 µM to 692 ± 102 µM (n = 9, p = .006). The findings from this study show that brain GSH is altered in response to acute moderate exercise, suggesting that exercise may stimulate an adaptive response in the brain. Due to the challenges in MRS methodology, this pilot study should be followed up with a larger exercise intervention trial.

Is it all in the reward? Peers influence risk-taking behaviour in young adulthood.

The presence of peers is suggested to increase risk-taking behaviour by heightening response to reward. The current study investigated this using a computerized financial risk-taking task which was performed twice by a group of young adults (n = 201, median age 19.8 years): once alone and once while in the presence of two peers. An overall increase in risk-taking was observed when with peers compared to when alone (CHANGE). CHANGE was positively associated with self-reported levels of reward responsiveness and fun seeking while older age and lack of perseverance were associated with reduced CHANGE. The association between risk-taking when with peers and both resistance to the influence of peers and age was indirect through reward responsiveness. Reward responsiveness was positively associated with impulsiveness. Only in those who showed a peer-related decrease in risk-taking (1/3 of participants), risk-taking in the presence of peers was associated with increased impulsiveness. The current findings suggest an important role for reward responsiveness in risk-taking behaviour and demonstrate the influence of peers. Increased understanding of these processes has direct implications for prevention and intervention efforts. Placing risk-taking behaviour within varying (social) contexts with an eye for differences in personality, development, and emotions provides ample scope for future research.

Neuroanatomical Predictors of Functional Outcome in Individuals at Ultra-High Risk for Psychosis.

Most individuals at ultra-high risk (UHR) for psychosis do not transition to frank illness. Nevertheless, many have poor clinical outcomes and impaired psychosocial functioning. This study used voxel-based morphometry to investigate if baseline grey and white matter brain densities at identification as UHR were associated with functional outcome at medium- to long-term follow-up. Participants were help-seeking UHR individuals (n = 109, 54M:55F) who underwent magnetic resonance imaging at baseline; functional outcome was assessed an average of 9.2 years later. Primary analysis showed that lower baseline grey matter density, but not white matter density, in bilateral frontal and limbic areas, and left cerebellar declive were associated with poorer functional outcome (Social and Occupational Functioning Assessment Scale [SOFAS]). These findings were independent of transition to psychosis or persistence of the at-risk mental state. Similar regions were significantly associated with lower self-reported levels of social functioning and increased negative symptoms at follow-up. Exploratory analyses showed that lower baseline grey matter densities in middle and inferior frontal gyri were significantly associated with decline in Global Assessment of Functioning (GAF) score over follow-up. There was no association between baseline grey matter density and IQ or positive symptoms at follow-up. The current findings provide novel evidence that those with the poorest functional outcomes have the lowest grey matter densities at identification as UHR, regardless of transition status or persistence of the at-risk mental state. Replication and validation of these findings may allow for early identification of poor functional outcome and targeted interventions.

Risk Perception and Risk-Taking Behaviour during Adolescence: The Influence of Personality and Gender.

This study investigated the influence of personality characteristics and gender on adolescents' perception of risk and their risk-taking behaviour. Male and female participants (157 females: 116 males, aged 13-20) completed self-report measures on risk perception, risk-taking and personality. Male participants perceived behaviours as less risky, reportedly took more risks, were less sensitive to negative outcomes and less socially anxious than female participants. Path analysis identified a model in which age, behavioural inhibition and impulsiveness directly influenced risk perception, while age, social anxiety, impulsiveness, sensitivity to reward, behavioural inhibition and risk perception itself were directly or indirectly associated with risk-taking behaviour. Age and behavioural inhibition had direct relationships with social anxiety, and reward sensitivity was associated with impulsiveness. The model was representative for the whole sample and male and female groups separately. The observed relationship between age and social anxiety and the influence this may have on risk-taking behaviour could be key for reducing adolescent risk-taking behaviour. Even though adolescents may understand the riskiness of their behaviour and estimate their vulnerability to risk at a similar level to adults, factors such as anxiety regarding social situations, sensitivity to reward and impulsiveness may exert their influence and make these individuals prone to taking risks. If these associations are proven causal, these factors are, and will continue to be, important targets in prevention and intervention efforts.

Longer-term increased cortisol levels in young people with mental health problems.

Disturbance of hypothalamus-pituitary-adrenal axis activity is commonly reported in a range of mental disorders in blood, saliva and urine samples. This study aimed to look at longer-term cortisol levels and their association with clinical symptoms. Hair strands of 30 young people (16-25 years) presenting with mental health problems (Mage±SD=21±2.4, 26 females) and 28 healthy controls (HC, Mage±SD=20±2.9, 26 females) were analyzed for cortisol concentrations, representing the past 6 months prior to hair sampling. Clinical participants completed an assessment on psychiatric symptoms, functioning and lifestyle factors. All participants completed the Perceived Stress Scale. Hair cortisol concentrations representing the past 3 (but not 3-6) months were significantly increased in clinical participants compared to HC. Perceived stress in the past month was significantly higher in clinical participants compared to HC, but not significantly correlated with hair cortisol. Hair cortisol levels were not significantly associated with any other measures. Hair segment analyses revealed longer-term increased levels of cortisol in the past 3 months in early mental health problems. Further insight into the role of cortisol on the pathogenesis of mental illnesses requires longitudinal studies relating cortisol to psychopathology and progression of illness.

Baseline grey matter volume of non-transitioned "ultra high risk" for psychosis individuals with and without attenuated psychotic symptoms at long-term follow-up.

INTRODUCTION: Two thirds of individuals identified as ultra-high risk (UHR) for psychosis do not transition to psychosis over the medium to long-term (non-transition; UHR-NT). Nevertheless, many of these individuals have persistent attenuated psychotic symptoms (APS). The current study examined whether there were differences in baseline grey matter volume (i.e. at initial identification as UHR) in UHR-NT individuals whom had APS compared to those without APS (No-APS) at medium to long-term follow-up. METHODS: Participants were help-seeking individuals who were identified as being at UHR for psychosis between 2 and 12years previously (mean=7.5). The sample consisted of 109 participants who underwent a Magnetic Resonance Imaging scan at baseline and who had not been observed to develop a psychotic disorder over the follow-up period (UHR-NT). Using voxel-based morphometry, baseline grey matter volume (GMV) was compared between participants with (N=30) and without (N=79) APS at follow-up. RESULTS: At baseline, the APS and No-APS groups were clinically indistinguishable. At follow-up, the APS group had significantly worse symptoms and impaired functioning. Individuals with APS had reduced baseline GMV in frontal, temporal, posterior and cingulate regions compared to those without APS at follow-up. Reduced GMV was associated with more severe positive, negative and depressive symptoms and lower global functioning in the combined UHR-NT cohort. These associations were independent of later APS outcome. DISCUSSION: This study found that differences in regional GMV are discernible at an early stage of UHR and may be specific to individuals who have APS and psychopathology at follow-up. Our findings suggest that lower GMV at baseline may confer neurobiological risk for later APS and/or increased psychopathology while the absence of these structural abnormalities might be protective.

The relationship between stress, HPA axis functioning and brain structure in first episode psychosis over the first 12 weeks of treatment.

Stress and abnormal hypothalamic-pituitary-adrenal axis functioning have been implicated in the early phase of psychosis and may partly explain reported changes in brain structure. This study used magnetic resonance imaging to investigate whether biological measures of stress were related to brain structure at baseline and to structural changes over the first 12 weeks of treatment in first episode patients (n=22) compared with matched healthy controls (n=22). At baseline, no significant group differences in biological measures of stress, cortical thickness or hippocampal volume were observed, but a significantly stronger relationship between baseline levels of cortisol and smaller white matter volumes of the cuneus and anterior cingulate was found in patients compared with controls. Over the first 12 weeks of treatment, patients showed a significant reduction in thickness of the posterior cingulate compared with controls. Patients also showed a significant positive relationship between baseline cortisol and increases in hippocampal volume over time, suggestive of brain swelling in association with psychotic exacerbation, while no such relationship was observed in controls. The current findings provide some support for the involvement of stress mechanisms in the pathophysiology of early psychosis, but the changes are subtle and warrant further investigation.

Discrete alterations of brain network structural covariance in individuals at ultra-high risk for psychosis.

BACKGROUND: Investigation of aberrant large-scale brain networks offers novel insight into the role these networks play in diverse psychiatric disorders such as schizophrenia. Although studies report altered functional brain connectivity in participants at ultra-high risk (UHR) for psychosis, it is unclear whether these alterations extend to structural brain networks. METHODS: Whole-brain structural covariance patterns of 133 participants at UHR for psychosis (51 of whom subsequently developed psychosis) and 65 healthy control (HC) subjects were studied. Following data preprocessing (using VBM8 toolbox), the mean signal in seed regions relating to specific networks (visual, auditory, motor, speech, semantic, executive control, salience, and default-mode) were extracted, and voxel-wise analyses of covariance were conducted to compare the association between whole-brain signal and each seed region for UHR and HC individuals. The UHR participants who transitioned to psychosis were compared with the UHR participants who did not. RESULTS: Significantly reduced structural covariance was observed in the UHR sample compared with the HC sample for the default-mode network, and increased covariance was observed for the motor and executive control networks. When the UHR participants who transitioned to psychosis were compared with the UHR participants who did not, aberrant structural covariance was observed in the salience, executive control, auditory, and motor networks. CONCLUSIONS: Whole-brain structural covariance analyses revealed subtle changes of connectivity of the default-mode, executive control, salience, motor, and auditory networks in UHR individuals for psychosis. Although we found significant differences, these are small changes and tend to reflect largely intact structural networks.