Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium.

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Connectome architecture shapes large-scale cortical alterations in schizophrenia: a worldwide ENIGMA study.

Schizophrenia is a prototypical network disorder with widespread brain-morphological alterations, yet it remains unclear whether these distributed alterations robustly reflect the underlying network layout. We tested whether large-scale structural alterations in schizophrenia relate to normative structural and functional connectome architecture, and systematically evaluated robustness and generalizability of these network-level alterations. Leveraging anatomical MRI scans from 2439 adults with schizophrenia and 2867 healthy controls from 26 ENIGMA sites and normative data from the Human Connectome Project (n = 207), we evaluated structural alterations of schizophrenia against two network susceptibility models: (i) hub vulnerability, which examines associations between regional network centrality and magnitude of disease-related alterations; (ii) epicenter mapping, which identifies regions whose typical connectivity profile most closely resembles the disease-related morphological alterations. To assess generalizability and specificity, we contextualized the influence of site, disease stages, and individual clinical factors and compared network associations of schizophrenia with that found in affective disorders. Our findings show schizophrenia-related cortical thinning is spatially associated with functional and structural hubs, suggesting that highly interconnected regions are more vulnerable to morphological alterations. Predominantly temporo-paralimbic and frontal regions emerged as epicenters with connectivity profiles linked to schizophrenia's alteration patterns. Findings were robust across sites, disease stages, and related to individual symptoms. Moreover, transdiagnostic comparisons revealed overlapping epicenters in schizophrenia and bipolar, but not major depressive disorder, suggestive of a pathophysiological continuity within the schizophrenia-bipolar-spectrum. In sum, cortical alterations over the course of schizophrenia robustly follow brain network architecture, emphasizing marked hub susceptibility and temporo-frontal epicenters at both the level of the group and the individual. Subtle variations of epicenters across disease stages suggest interacting pathological processes, while associations with patient-specific symptoms support additional inter-individual variability of hub vulnerability and epicenters in schizophrenia. Our work outlines potential pathways to better understand macroscale structural alterations, and inter- individual variability in schizophrenia.

Fronto-temporal cortical grey matter thickness and surface area in the at-risk mental state and recent-onset schizophrenia: a magnetic resonance imaging study.

BACKGROUND: Studies to date examining cortical thickness and surface area in young individuals At Risk Mental State (ARMS) of developing psychosis have revealed inconsistent findings, either reporting increased, decreased or no differences compared to mentally healthy individuals. The inconsistencies may be attributed to small sample sizes, varying age ranges, different ARMS identification criteria, lack of control for recreational substance use and antipsychotic pharmacotherapy, as well as different methods for deriving morphological brain measures. METHODS: A surfaced-based approach was employed to calculate fronto-temporal cortical grey matter thickness and surface area derived from magnetic resonance imaging (MRI) data collected from 44 young antipsychotic-naïve ARMS individuals, 19 young people with recent onset schizophrenia, and 36 age-matched healthy volunteers. We conducted group comparisons of the morphological measures and explored their association with symptom severity, global and socio-occupational function levels, and the degree of alcohol and cannabis use in the ARMS group. RESULTS: Grey matter thickness and surface areas in ARMS individuals did not significantly differ from their age-matched healthy counterparts. However, reduced left-frontal grey matter thickness was correlated with greater symptom severity and lower function levels; the latter being also correlated with smaller left-frontal surface areas. ARMS individuals with more severe symptoms showed greater similarities to the recent onset schizophrenia group. The morphological measures in ARMS did not correlate with the lifetime level of alcohol or cannabis use. CONCLUSIONS: Our findings suggest that a decline in function levels and worsening mental state are associated with morphological changes in the left frontal cortex in ARMS but to a lesser extent than those seen in recent onset schizophrenia. Alcohol and cannabis use did not confound these findings. However, the cross-sectional nature of our study limits our ability to draw conclusions about the potential progressive nature of these morphological changes in ARMS.

Youth mental health competencies in regional general practice.

OBJECTIVE: General practitioners (GPs) are key health professionals for referrals to mental health specialists. Youth mental health issues are particularly challenging, requiring a competent assessment and understanding of appropriate referral pathways. We surveyed local GPs about their understanding of youth mental health problems and needs to competently look after young patients. METHODS: GPs working in the Hunter region were contacted via email, fax and post over a 6-month period in 2019. RESULTS: Seventy-five GPs participated. They reported 577 of 1698 (34%) of young people seen 2 weeks prior to being surveyed presented with a mental health problem. Predominantly, referrals were to private practice psychologists and Headspace. Almost a third (31%) reported having limited understanding of 'at-risk mental state' and are 'not always comfortable' when facing a young person with a mental health problem. Nearly all (95%) expressed interest in attending specialised training. GPs identified treatment costs, scarce access to psychiatrists and limited patient engagement as the main obstacles to help young people. CONCLUSIONS: Effective treatment of a mental health problem relies on early identification. GPs are seeing young people on a regular basis but don't feel well equipped for this task and are keen to up-skill, which needs to be addressed by targeted training.

Increased power by harmonizing structural MRI site differences with the ComBat batch adjustment method in ENIGMA.

A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort.

OBJECTIVES: Large-scale genetic analysis of common variation in schizophrenia has been a powerful approach to understanding this complex but highly heritable psychotic disorder. To further investigate loci, genes and pathways associated more specifically in the well-characterized Australian Schizophrenia Research Bank cohort, we applied genome-wide single-nucleotide polymorphism analysis in these three annotation categories. METHODS: We performed a case-control genome-wide association study in 429 schizophrenia samples and 255 controls. Post-genome-wide association study analyses were then integrated with genomic annotations to explore the enrichment of variation at the gene and pathway level. We also examine candidate single-nucleotide polymorphisms with potential function within expression quantitative trait loci and investigate overall enrichment of variation within tissue-specific functional regulatory domains of the genome. RESULTS: The strongest finding (p = 2.01 × 10-6, odds ratio = 1.82, 95% confidence interval = [1.42, 2.33]) in genome-wide association study was with rs10252923 at 7q21.13, downstream of FZD1 (frizzled class receptor 1). While this did not stand alone after correction, the involvement of FZD1 was supported by gene-based analysis, which exceeded the threshold for genome-wide significance (p = 2.78 × 10-6). CONCLUSION: The identification of FZD1, as an independent association signal at the gene level, supports the hypothesis that the Wnt signalling pathway is altered in the pathogenesis of schizophrenia and may be an important target for therapeutic development.

Effects of immune activation during early or late gestation on schizophrenia-related behaviour in adult rat offspring.

Maternal exposure to infectious agents during gestation has been identified as a significant risk factor for schizophrenia. Using a mouse model, past work has demonstrated that the gestational timing of the immune-activating event can impact the behavioural phenotype and expression of dopaminergic and glutamatergic neurotransmission markers in the offspring. In order to determine the inter-species generality of this effect to rats, another commonly used model species, the current study investigated the impact of a viral mimetic Poly (I:C) at either an early (gestational day 10) or late (gestational day 19) time-point on schizophrenia-related behaviour and neurotransmitter receptor expression in rat offspring. Exposure to Poly (I:C) in late, but not early, gestation resulted in transient impairments in working memory. In addition, male rats exposed to maternal immune activation (MIA) in either early or late gestation exhibited sensorimotor gating deficits. Conversely, neither early nor late MIA exposure altered locomotor responses to MK-801 or amphetamine. In addition, increased dopamine 1 receptor mRNA levels were found in the nucleus accumbens of male rats exposed to early gestational MIA. The findings from this study diverge somewhat from previous findings in mice with MIA exposure, which were often found to exhibit a more comprehensive spectrum of schizophrenia-like phenotypes in both males and females, indicating potential differences in the neurodevelopmental vulnerability to MIA exposure in the rat with regards to schizophrenia related changes.

Ten-year audit of clients presenting to a specialised service for young people experiencing or at increased risk for psychosis.

BACKGROUND: Despite strong research interest in psychosis risk identification and the potential for early intervention, few papers have sought to document the implementation and evaluation of specialised psychosis related services. Assessment of Ultra High Risk (UHR) has been given priority, but it is equally as important to identify appropriate comparison groups and other baseline differences. This largely descriptive service evaluation paper focuses on the 'baseline characteristics' of referred clients (i.e., previously assessed characteristics or those identified within the first two months following service presentation). METHODS: Data are reported from a 10-year layered service audit of all presentations to a 'Psychological Assistance Service' for young people (PAS, Newcastle, Australia). Baseline socio-demographic and clinical characteristics (N =1,997) are described (including clients' psychosis and UHR status, previous service contacts, hospitalisation rates, and diagnostic and comorbidity profiles). Key groups are identified and comparisons made between clients who received ongoing treatment and those who were primarily assessed and referred elsewhere. RESULTS: Clients averaged 19.2 (SD =4.5) years of age and 59% were male. One-tenth of clients (9.6%) were categorised as UHR, among whom there were relatively high rates of attenuated psychotic symptoms (69.1%), comorbid depression (62.3%), anxiety (42.9%), and attentional and related problems (67.5%). Overall, one-fifth (19.8%) experienced a recent psychotic episode, while a further 14.5% were categorised as having an existing psychosis (46.7% with a schizophrenia diagnosis), amongst whom there were relatively high rates of comorbid substance misuse (52.9%), psychosocial (70.2%) and physical health (37.7%) problems. The largest group presenting to PAS were those with non-psychotic disorders (43.7%), who provide a valuable comparison group against which to contrast the health trajectories of those with UHR and recent psychosis. Ongoing treatment by PAS was preferentially given to those experiencing or at risk for psychosis and those reporting greater current distress or dysfunction. CONCLUSIONS: Whether or not UHR clients transition to psychosis, they displayed high rates of comorbid depression and anxiety at service presentation, with half receiving ongoing treatment from PAS. Although international comparisons with similar services are difficult, the socio-demographic and comorbidity patterns observed here were viewed as largely consistent with those reported elsewhere.

Pre-attentive and Attentive Auditory Event-related Potentials in Children With Attention-Deficit Hyperactivity Disorder and Autism.

Abnormalities in auditory processing are believed to play a major role in autism and attention-deficit hyperactivity disorder (ADHD). Both conditions often co-occur in children, causing difficulties in deciding the most promising intervention. Event-related potentials (ERPs) have been investigated and are showing promise to act as potential biomarkers for both conditions. This study investigated mismatch negativity (MMN) using a passive listening task and P3b in an active auditory go/no-go discrimination task. Recordings were available from 103 children (24 females): 35 with ADHD, 27 autistic, 15 autistic children with co-occurring ADHD, and 26 neurotypical (NT) children. The age range considered was between 4 and 17 years, but varied between groups. The results revealed increases in the MMN and P3b amplitudes with age. Older children with ADHD exhibited smaller P3b amplitudes, while younger autistic children showed reduced MMN amplitudes in response to phoneme changes compared to their NT counterparts. Notably, children diagnosed with autism and ADHD did not follow this pattern; instead, they exhibited more similarities to NT children. The reduced amplitudes of phonetically elicited MMN in children with autism and reduced P3b in children with ADHD suggest that the two respective ERPs can act as potential biomarkers for each condition. However, optimisation and standardisation of the testing protocol, as well as longitudinal studies are required in order to translate these findings into clinical practice.

Gene expression profiling in treatment-naive schizophrenia patients identifies abnormalities in biological pathways involving AKT1 that are corrected by antipsychotic medication.

Distinct gene expression profiles can be detected in peripheral blood mononuclear cells (PBMCs) in patients with schizophrenia; however, little is known about the effects of antipsychotic medication. This study compared gene expression profiles in PMBCs from treatment-naive patients with schizophrenia before and after antipsychotic drug treatment. PBMCs were obtained from 10 treatment-naive schizophrenia patients before and 6 wk after initiating antipsychotic drug treatment and compared to PMBCs collected from 11 healthy community volunteers. Genome-wide expression profiling was conducted using Illumina HumanHT-12 expression bead arrays and analysed using significance analysis of microarrays. This analysis identified 624 genes with altered expression (208 up-regulated, 416 down-regulated) prior to antipsychotic treatment (p < 0.05) including schizophrenia-associated genes AKT1, DISC1 and DGCR6. After 6-8 wk treatment of patients with risperidone or risperidone in combination with haloperidol, only 106 genes were altered, suggesting that the treatment corrected the expression of a large proportion of genes back to control levels. However, 67 genes continued to show the same directional change in expression after treatment. Ingenuity® pathway analysis and gene set enrichment analysis implicated dysregulation of biological functions and pathways related to inflammation and immunity in patients with schizophrenia. A number of the top canonical pathways dysregulated in treatment-naive patients signal through AKT1 that was up-regulated. After treatment, AKT1 returned to control levels and less dysregulation of these canonical pathways was observed. This study supports immune dysfunction and pathways involving AKT1 in the aetiopathophysiology of schizophrenia and their response to antipsychotic medication.

Generalization of cognitive training in an Australian sample of schizophrenia patients.

OBJECTIVE: The present study was undertaken to evaluate the effect of cognitive training in improving trained and untrained cognitive processes in schizophrenia. METHODS: A simple pre- and post experimental study with a three month follow-up was conducted to determine the efficacy of cognitive training in speed of processing and executive functions improving cognition in 22 schizophrenia patients. RESULTS: Significant improvement was found in those cognitive domains specifically targeted in the training protocol, but also to a limited extent on verbal memory and social cognition. There was also evidence of improvements in symptoms and social functioning. The training effects failed to transfer to community functioning skills however. Except for social cognition, these improvements were maintained at 3month follow-up. CONCLUSION: The study highlights the importance of understanding the mechanisms that contribute to the transfer of skills as well as the maintenance of cognitive changes in individuals with schizophrenia.

Cerebellar grey-matter deficits, cannabis use and first-episode schizophrenia in adolescents and young adults.

Epidemiological data link adolescent cannabis use to psychosis and schizophrenia, but its contribution to schizophrenia neuropathology remains controversial. First-episode schizophrenia (FES) patients show regional cerebral grey- and white-matter changes as well as a distinct pattern of regional grey-matter loss in the vermis of the cerebellum. The cerebellum possesses a high density of cannabinoid type 1 receptors involved in the neuronal diversification of the developing brain. Cannabis abuse may interfere with this process during adolescent brain maturation leading to 'schizophrenia-like' cerebellar pathology. Magnetic resonance imaging and cortical pattern matching techniques were used to investigate cerebellar grey and white matter in FES patients with and without a history of cannabis use and non-psychiatric cannabis users. In the latter group we found lifetime dose-dependent regional reduction of grey matter in the right cerebellar lobules and a tendency for more profound grey-matter reduction in lobule III with younger age at onset of cannabis use. The overall regional grey-matter differences in cannabis users were within the normal variability of grey-matter distribution. By contrast, FES subjects had lower total cerebellar grey-matter:total cerebellar volume ratio and marked grey-matter loss in the vermis, pedunculi, flocculi and lobules compared to pair-wise matched healthy control subjects. This pattern and degree of grey-matter loss did not differ from age-matched FES subjects with comorbid cannabis use. Our findings indicate small dose-dependent effects of juvenile cannabis use on cerebellar neuropathology but no evidence of an additional effect of cannabis use on FES cerebellar grey-matter pathology.

Finding the needle in the haystack: a review of microarray gene expression research into schizophrenia.

BACKGROUND: With an estimated 80% heritability, molecular genetic research into schizophrenia has remained inconclusive. Recent large-scale, genome-wide association studies only identified a small number of susceptibility genes with individually very small effect sizes. However, the variable expression of the phenotype is not well captured in diagnosis-based research as well as when assuming a 'heterogenic risk model' (as apposed to a monogenic or polygenic model). Hence, the expression of susceptibility genes in response to environmental factors in concert with other disease-promoting or protecting genes has increasingly attracted attention. METHOD: The current review summarises findings of microarray gene expression research with relevance to schizophrenia as they emerged over the past decade. RESULTS: Most findings from post mortem, peripheral tissues and animal models to date have linked altered gene expression in schizophrenia to presynaptic function, signalling, myelination, neural migration, cellular immune mechanisms, and response to oxidative stress consistent with multiple small effects of many individual genes. However, the majority of results are difficult to interpret due to small sample sizes (i.e. potential type-2 errors), confounding factors (i.e. medication effects) or lack of plausible neurobiological theory. CONCLUSION: Nevertheless, microarray gene expression research is likely to play an important role in the future when investigating gene/gene and gene/environment interactions by adopting a neurobiologically sound theoretical framework.

Visual scanpath abnormalities in 22q11.2 deletion syndrome: is this a face specific deficit?

People with 22q11.2 deletion syndrome (22q11DS) have deficits in face emotion recognition. However, it is not known whether this is a deficit specific to faces, or represents maladaptive information processing strategies to complex stimuli in general. This study examined the specificity of face emotion processing deficits in 22q11DS by exploring recognition accuracy and visual scanpath performance to a Faces task compared to a Weather Scene task. Seventeen adolescents with 22q11DS (11=females, age=17.4) and 18 healthy controls (11=females, age=17.7) participated in the study. People with 22q11DS displayed an overall impoverished scanning strategy to face and weather stimuli alike, resulting in poorer accuracy across all stimuli for the 22q11DS participants compared to controls. While the control subjects altered their information processing in response to faces, a similar change was not present in the 22q11DS group indicating different visual scanpath strategies to identify category within each of the tasks, of which faces appear to represent a particularly difficult subcategory. To conclude, while this study indicates that people with 22q11DS have a general visual processing deficit, the lack of strategic change between tasks suggest that the 22q11DS group did not adapt to the change in stimuli content as well as the controls, indicative of cognitive inflexibility rather than a face specific deficit.

E-technology social support programs for autistic children: Can they work?

Autism is a neurodevelopmental condition with associated difficulties that present differently across individuals. One such difficulty is recognizing basic and complex facial expressions. Research has previously found that there are many evidence-based support programs available for building non-verbal communication skills. These programs are frequently administered with a therapist or in a group setting, making them inflexible in nature. Programs hosted on e-technology are becoming increasingly popular, with many parents supportive of them. Applications (apps) that are hosted on technology such as iPads or mobile phones allow users to engage in building skills in real-time social settings and own what they are learning. These technologies are frequently used by autistic children, with apps typically focusing on identifying facial features. Yet at this current time, there are mixed reviews of how to design such programs and what their theoretical backing is, with many studies using a mix of observation and psychological assessments as outcome measures. Eye-tracking and electroencephalography are established methodologies that measure neural processing and gaze behaviors while viewing faces. To better support the field moving forward, objective measures such as these are a way to measure outcomes of apps that are designed for helping children on the spectrum build skills in understanding facial expressions.

Cerebellar grey matter deficits in first-episode schizophrenia mapped using cortical pattern matching.

Cerebellar dysfunction has been proposed to lead to "cognitive dysmetria" in schizophrenia via the cortico-cerebellar-thalamic-cortical circuit, contributing to a range of cognitive and clinical symptoms of the disorder. Here we investigated total cerebellar grey and white matter volumes and cerebellar regional grey matter abnormalities in 13 remitted first-episode schizophrenia patients with less than 2 years' duration of illness. Patient data were compared to 13 pair-wise age, gender, and handedness-matched healthy volunteers using cortical pattern averaging on high-resolution magnetic resonance images. Total cerebellar volume and total grey matter volumes in first-episode schizophrenia patients did not differ from healthy control subjects, but total cerebellar white matter was increased and total grey to white matter ratios were reduced in patients. Four clusters of cerebellar grey matter reduction were identified: (i) in superior vermis; (ii) in the left lobuli VI; (iii) in right-inferior lobule IX, extending into left lobule IX; and (iv) bilaterally in the areas of lobuli III, peduncle and left flocculus. Grey matter deficits were particularly prominent in right lobuli III and IX, left flocculus and bilateral pedunculi. These cerebellar areas have been implicated in attention control, emotional regulation, social functioning, initiation of smooth pursuit eye movements, eye-blink conditioning, language processing, verbal memory, executive function and the processing of spatial and emotional information. Consistent with common clinical, cognitive, and pathophysiological signs of established illness, our findings demonstrate cerebellar pathology as early as in first-episode schizophrenia.

Visual scanning of faces in 22q11.2 deletion syndrome: Attention to the mouth or the eyes?

Previous research demonstrates that people with 22q11.2 deletion syndrome (22q11DS) have social and interpersonal skill deficits. However, the basis of this deficit is unknown. This study examined, for the first time, how people with 22q11DS process emotional face stimuli using visual scanpath technology. The visual scanpaths of 17 adolescents and age/gender matched healthy controls were recorded while they viewed face images depicting one of seven basic emotions (happy, sad, surprised, angry, fear, disgust and neutral). Recognition accuracy was measured concurrently. People with 22q11DS differed significantly from controls, displaying visual scanpath patterns that were characterised by fewer fixations and a shorter scanpath length. The 22q11DS group also spent significantly more time gazing at the mouth region and significantly less time looking at eye regions of the faces. Recognition accuracy was correspondingly impaired, with 22q11DS subjects displaying particular deficits for fear and disgust. These findings suggest that 22q11DS is associated with a maladaptive visual information processing strategy that may underlie affect recognition accuracy and social functioning deficits in this group.

Young rural people at risk for schizophrenia: time for mental health services to translate research evidence into best practice of care.

Early intervention into prodromal schizophrenia has shown promise, but controversy continues regarding the ethical acceptability of identifying a group of 'ultra high risk' individuals of whom only 30 to 50% will develop a psychotic disorder. With well developed early intervention services this group faces the possibility of being labelled as 'pre-psychotic', a condition for which the well known stigma associated with the diagnosis of schizophrenia or bipolar disorder is likely to be associated. In addition, the use of potent antipsychotic and other medications (albeit usually at lower doses than those used for those with manifest psychosis) mandates consideration of the risks associated with their use and neurological and metabolic side effects. The potential for iatrogenic morbidity in the 'false positive' group must be weighed against the need of the 'true positives' identified through screening and assessment. Current evidence for the concept of 'at-risk mental state' was reviewed within a neurodevelopmental framework, including emerging data on the effectiveness of early intervention for the purpose of providing recommendations for community mental health services. The review suggests that different treatment strategies may be appropriate depending on the clinical stage of the condition as long as the benefits of intervention outweigh its risk burden. It further suggests that the severity of psychoses and the evidence of its early onset in utero and its acceleration in adolescence positions 'ultra high risk' intervention as a core model for early intervention for young people by teasing apart the symptomatic components of the 'prepsychotic state' and ensuring the population is reaching targeted mental health services for screening. The model is not restricted to the delivery of intervention for 'pre-psychotic' young people but is applicable for targeted programmes for a number of clinical groups considered at 'ultra high risk'. However, only further research in naturalistic populations embedded in clinical practice and ideally conducted in partnership of mental health services with academic research institutions will help clarify potential risks of early identification and intervention and assist in updating and making more explicit the clinical guidelines services will use in approaching those in the 'ultra high risk' group.

Australian Schizophrenia Research Bank: a database of comprehensive clinical, endophenotypic and genetic data for aetiological studies of schizophrenia.

OBJECTIVE: This article describes the establishment of the Australian Schizophrenia Research Bank (ASRB), which operates to collect, store and distribute linked clinical, cognitive, neuroimaging and genetic data from a large sample of people with schizophrenia and healthy controls. METHOD: Recruitment sources for the schizophrenia sample include a multi-media national advertising campaign, inpatient and community treatment services and non-government support agencies. Healthy controls have been recruited primarily through multi-media advertisements. All participants undergo an extensive diagnostic and family history assessment, neuropsychological evaluation, and blood sample donation for genetic studies. Selected individuals also complete structural MRI scans. RESULTS: Preliminary analyses of 493 schizophrenia cases and 293 healthy controls are reported. Mean age was 39.54 years (SD = 11.1) for the schizophrenia participants and 37.38 years (SD = 13.12) for healthy controls. Compared to the controls, features of the schizophrenia sample included a higher proportion of males (cases 65.9%; controls 46.8%), fewer living in married or de facto relationships (cases 16.1%; controls 53.6%) and fewer years of education (cases 13.05, SD = 2.84; controls 15.14, SD = 3.13), as well as lower current IQ (cases 102.68, SD = 15.51; controls 118.28, SD = 10.18). These and other sample characteristics are compared to those reported in another large Australian sample (i.e. the Low Prevalence Disorders Study), revealing some differences that reflect the different sampling methods of these two studies. CONCLUSION: The ASRB is a valuable and accessible schizophrenia research facility for use by approved scientific investigators. As recruitment continues, the approach to sampling for both cases and controls will need to be modified to ensure that the ASRB samples are as broadly representative as possible of all cases of schizophrenia and healthy controls.

Effect of Immune Activation during Early Gestation or Late Gestation on Inhibitory Markers in Adult Male Rats.

People with schizophrenia exhibit deficits in inhibitory neurons and cognition. The timing of maternal immune activation (MIA) may present distinct schizophrenia-like phenotypes in progeny. We investigated whether early gestation [gestational day (GD) 10] or late gestation (GD19) MIA, via viral mimetic polyI:C, produces deficits in inhibitory neuron indices (GAD1, PVALB, SST, SSTR2 mRNAs) within cortical, striatal, and hippocampal subregions of male adult rat offspring. In situ hybridisation revealed that polyI:C offspring had: (1) SST mRNA reductions in the cingulate cortex and nucleus accumbens shell, regardless of MIA timing; (2) SSTR2 mRNA reductions in the cortex and striatum of GD19, but not GD10, MIA; (3) no alterations in cortical or striatal GAD1 mRNA of polyI:C offspring, but an expected reduction of PVALB mRNA in the infralimbic cortex, and; (4) no alterations in inhibitory markers in hippocampus. Maternal IL-6 response negatively correlated with adult offspring SST mRNA in cortex and striatum, but not hippocampus. These results show lasting inhibitory-related deficits in cortex and striatum in adult offspring from MIA. SST downregulation in specific cortical and striatal subregions, with additional deficits in somatostatin-related signalling through SSTR2, may contribute to some of the adult behavioural changes resulting from MIA and its timing.