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BACKGROUND: In schizophrenia, relative stability in the magnitude of fluid cognitive deficits across age and illness duration is inconsistent with evidence of accelerated deterioration in brain regions known to support these functions. These discrepant brain-cognition outcomes may be explained by variability in cognitive reserve (CR), which in neurological disorders has been shown to enable resilience against brain pathology and minimize its impact on cognitive or clinical indicators of illness. METHODS: Age-related changes in fluid reasoning, working memory and frontal brain volume, area and thickness were mapped using regression analysis in 214 individuals with schizophrenia or schizoaffective disorder and 168 healthy controls. In patients, these changes were modelled as a function of CR. RESULTS: Patients showed exaggerated age-related decline in brain structure, but not fluid cognition compared to controls. In the patient group, no moderation of age-related brain structural change by CR was evident. However, age-related cognitive change was moderated by CR, such that only patients with low CR showed evidence of exaggerated fluid reasoning decline that paralleled the exaggerated age-related deterioration of underpinning brain structures seen in all patients. CONCLUSIONS: In schizophrenia-spectrum illness, CR may negate ageing effects on fluid cognition by conferring resilience against pathologically exaggerated structural brain deterioration through some form of compensation. CR may represent an important modifier that could explain inconsistencies in brain structure - cognition outcomes evident in the extant literature.

The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Growing evidence suggests that testosterone may play a role in the pathophysiology of schizophrenia given that testosterone has been linked to cognition and negative symptoms in schizophrenia. Here, we determine the extent to which serum testosterone levels are related to neural activity in affective processing circuitry in men with schizophrenia. Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as 32 healthy controls and 26 people with schizophrenia performed a facial emotion identification task. Whole brain analyses were performed to determine regions of differential activity between groups during processing of angry versus non-threatening faces. A follow-up ROI analysis using a regression model in a subset of 16 healthy men and 16 men with schizophrenia was used to determine the extent to which serum testosterone levels were related to neural activity. Healthy controls displayed significantly greater activation than people with schizophrenia in the left inferior frontal gyrus (IFG). There was no significant difference in circulating testosterone levels between healthy men and men with schizophrenia. Regression analyses between activation in the IFG and circulating testosterone levels revealed a significant positive correlation in men with schizophrenia (r=.63, p=.01) and no significant relationship in healthy men. This study provides the first evidence that circulating serum testosterone levels are related to IFG activation during emotion face processing in men with schizophrenia but not in healthy men, which suggests that testosterone levels modulate neural processes relevant to facial emotion processing that may interfere with social functioning in men with schizophrenia.

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia.

Bipolar disorder is a complex neuropsychiatric disorder presenting with episodic mood disturbances. In this study we use a transcriptomic imputation approach to identify novel genes and pathways associated with bipolar disorder, as well as three diagnostically and genetically distinct subtypes. Transcriptomic imputation approaches leverage well-curated and publicly available eQTL reference panels to create gene-expression prediction models, which may then be applied to “impute” genetically regulated gene expression (GREX) in large GWAS datasets. By testing for association between phenotype and GREX, rather than genotype, we hope to identify more biologically interpretable associations, and thus elucidate more of the genetic architecture of bipolar disorder.We applied GREX prediction models for 13 brain regions (derived from CommonMind Consortium and GTEx eQTL reference panels) to 21,488 bipolar cases and 54,303 matched controls, constituting the largest transcriptomic imputation study of bipolar disorder (BPD) to date. Additionally, we analyzed three specific BPD subtypes, including 14,938 individuals with subtype 1 (BD-I), 3,543 individuals with subtype 2 (BD-II), and 1,500 individuals with schizoaffective subtype (SAB).We identified 125 gene-tissue associations with BPD, of which 53 represent independent associations after FINEMAP analysis. 29/53 associations were novel; i.e., did not lie within 1Mb of a locus identified in the recent PGC-BD GWAS. We identified 37 independent BD-I gene-tissue associations (10 novel), 2 BD-II associations, and 2 SAB associations. Our BPD, BD-I and BD-II associations were significantly more likely to be differentially expressed in post-mortem brain tissue of BPD, BD-I and BD-II cases than we might expect by chance. Together with our pathway analysis, our results support long-standing hypotheses about bipolar disorder risk, including a role for oxidative stress and mitochondrial dysfunction, the post-synaptic density, and an enrichment of circadian rhythm and clock genes within our results.

Background Increases in pro-inflammatory cytokines are found in the brain and blood of people with schizophrenia. However, increased cytokines are not evident in all people with schizophrenia, but are found in a subset. The cytokine changes that best define this subset, termed the “elevated inflammatory biotype”, are still being identified. Methods Using quantitative RT-PCR, we measured five cytokine mRNAs (IL-1β, IL-2 IL-6, IL-8 and IL-18) from peripheral blood of healthy controls and of people with schizophrenia or schizoaffective disorder (n = 165). We used a cluster analysis of the transcript levels to define those with low and those with elevated levels of cytokine expression. From the same cohort, eight cytokine proteins (IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12, IFNγ and TNFα) were measured in serum and plasma using a Luminex Magpix-based assay. We compared peripheral mRNA and protein levels across diagnostic groups and between those with low and elevated levels of cytokine expression according to our transcription-based cluster analysis. Results We found an overall decrease in the anti-inflammatory IL-2 mRNA (p = 0.006) and an increase in three serum cytokines, IL-6 (p = 0.010), IL-8 (p = 0.024) and TNFα (p

BackgroundTwo single-nucleotide polymorphisms (SNPs) (rs4281084 and rs12155594) within the neuregulin-1 (NRG1) gene have been associated with psychosis transition. However, the neurobiological changes associated with these SNPs remain unclear. We aimed to determine what relationship these two SNPs have on lateral ventricular volume and white matter integrity, as abnormalities in these brain structures are some of the most consistent in schizophrenia.MethodsStructural (n = 370) and diffusion (n = 465) magnetic resonance imaging data were obtained from affected and unaffected individuals predominantly of European descent. The SNPs rs4281084, rs12155594, and their combined allelic load were examined for their effects on lateral ventricular volume, fractional anisotropy (FA) as well as axial (AD) and radial (RD) diffusivity. Additional exploratory analyses assessed NRG1 effects on gray matter volume, cortical thickness, and surface area throughout the brain.ResultsIndividuals with a schizophrenia age of onset ⩽25 and a combined allelic load ⩾3 NRG1 risk alleles had significantly larger right (up to 50%, padj = 0.01) and left (up to 45%, padj = 0.05) lateral ventricle volumes compared with those with allelic loads of less than three. Furthermore, carriers of three or more risk alleles, regardless of age of onset and case status, had significantly reduced FA and elevated RD but stable AD in the frontal cortex compared with those carrying fewer than three risk alleles.ConclusionsOur findings build on a growing body of research supporting the functional importance of genetic variation within the NRG1 gene and complement previous findings implicating the rs4281084 and rs12155594 SNPs as markers for psychosis transition.

Bipolar disorder is a highly heritable psychiatric disorder that features episodes of mania and depression. We performed the largest genome-wide association study to date, including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 sentinel variants at loci with P-4 in an independent sample of 9,412 cases and 137,760 controls. In the combined analysis, 30 loci reached genome-wide significant evidence for association, of which 20 were novel. These significant loci contain genes encoding ion channels and neurotransmitter transporters (CACNA1C, GRIN2A, SCN2A, SLC4A1), synaptic components (RIMS1, ANK3), immune and energy metabolism components. Bipolar disorder type I (depressive and manic episodes; ~73% of our cases) is strongly genetically correlated with schizophrenia whereas bipolar disorder type II (depressive and hypomanic episodes; ~17% of our cases) is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for bipolar disorder.

Background: Cytokine messenger RNA (mRNA) transcripts derived from peripheral blood can be used to identify individuals with putative inflammation, and patients with schizophrenia increased proportions of those with elevated cytokines. However, the reliability of the TwoStep clustering algorithm, used to identify elevated cytokine subsets, has not been systematically examined. Here we use bootstrapping procedures to assess the reliability of this method.

Background: The kynurenine pathway (KP) of tryptophan (TRP) catabolism is considered to link the immune and neurotransmitter systems. The KP metabolite kynurenic acid (KYNA) shows increases in the brain of patients with schizophrenia. Here, we tested whether changes in brain KP enzyme mRNAs and plasma KP metabolites are related to cytokine levels in schizophrenia. We expected Kynurenine Aminotransferase II (KATII) mRNA to be increased in brains of people with schizophrenia, particularly in patients displaying elevated cytokines. Furthermore, we expected that the kynurenine (KYN)–TRP ratio in the plasma of chronically ill patients to be associated with cognitive and brain volume abnormalities in schizophrenia with high inflammation.

Contains fulltext : 193179.pdf (Publisher’s version ) (Open Access) The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Schizophrenia is a severe mental disorder characterized by a diverse set of symptoms, including positive (hallucinations, delusions) and negative (lack of motivation, social withdrawal, blunted affect) symptoms and cognitive impairment. Cognitive deficits are recognized as forming part of the core psychopathology of schizophrenia, with impairments in learning, memory and attention being common (Weickert et al. 2000; Palmer et al. 2009). Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that potentiates synaptic strength and plasticity underlying learning and memory (Lu & Chow, 1999; Poo, 2001; Egan et al. 2003; Hariri et al. 2003; Lu, 2003; Dempster et al. 2005). A single nucleotide polymorphism in the human BDNF gene produces a valine to methionine substitution in the protein prodomain that influences intracellular trafficking, activity-dependent release of BDNF, learning and brain activity (Egan et al. 2003; Hariri et al. 2003). Lower levels of both brain and blood BDNF have also been implicated in the majority of studies of the pathophysiology of schizophrenia (Weickert et al. 2003; Xiu et al. 2009; Rizos et al. 2010; Green et al. 2011). Peripheral blood can provide an important reservoir of BDNF, reflecting BDNF secreted from the brain and BDNF that may be available to influence brain function (Schmidt & Duman, 2010). However, the extent to which circulating BDNF correlates with human brain activity during learning has not been demonstrated and the extent to which lower circulating BDNF may be indicative of the neural correlates of cognitive impairment in schizophrenia has not been shown. Low peripheral BDNF is reported in first-episode psychosis (Buckley et al. 2007) and is associated with cognitive impairment in chronically ill people with schizophrenia (Zhang et al. 2012b). Peripheral BDNF levels are also significantly decreased in people with mild cognitive impairment (Yu et al. 2008). Thus, peripheral BDNF levels may be useful as a biomarker in health and disease. However, to more fully interpret what any change in a potential biomarker may mean for brain function, a relationship between peripheral BDNF and brain activity should be established in the healthy and diseased states. One reason that general predictions about blood–brain relationships in schizophrenia are difficult to make is that studies of peripheral BDNF levels in schizophrenia have reported inconsistent results. Although the majority of studies report decreased circulating BDNF levels (Pirildar et al. 2004; Tan et al. 2005; Grillo et al. 2007; Rizos et al. 2008), some find increased levels (Gama et al. 2007; Reis et al. 2008), and one study reports no significant difference in plasma BDNF levels in people with schizophrenia compared to healthy controls (Lee & Kim, 2009). A recent meta-analysis supports an overall reduction in peripheral BDNF levels in schizophrenia (Green et al. 2011). However, the extent to which alterations in blood BDNF levels relate to abnormal learning-related brain activity in schizophrenia, as compared to healthy individuals, remains to be demonstrated. Healthy cortical neurons innervate and supply BDNF to several brain regions, including the striatum (Alexander et al. 1986; Altar & DiStefano, 1998). As striatal neurons are trophically dependent on BDNF supplied through anterograde transport from the frontal cortex (Hofer et al. 1990; Altar et al. 1997; Rauskolb et al. 2010; Dieni et al. 2012), higher levels of BDNF would be expected to relate to stronger frontal–striatal activity in a healthy brain, and a reduction of prefrontal cortical BDNF, as found in schizophrenia (Weickert et al. 2003; Hashimoto et al. 2005), would be expected to negatively impact striatal function in schizophrenia. There is abundant evidence from neuropsychological and neuroimaging studies demonstrating significant learning impairments and frontal–striatal dysfunction in schizophrenia (Pantelis et al. 1997; Meyer-Lindenberg et al. 2002; Murray et al. 2008; Howes et al. 2009; Weickert et al. 2010; Morris et al. 2012). Probabilistic association learning (requiring gradual learning of probabilistic-based cue–outcome associations) elicits frontal–parietal–striatal activity in healthy people (Poldrack et al. 1999; Fera et al. 2005) and is related to reduced activity in a neural network that includes the dorsolateral prefrontal cortex (DLPFC), parietal cortex and caudate nucleus in schizophrenia (Weickert et al. 2009). Probabilistic association learning is impaired in people with schizophrenia (Weickert et al. 2002; Foerde et al. 2008; Horan et al. 2008), the offspring of people with schizophrenia who are at high risk of developing schizophrenia (Wagshal et al. 2012, 2013) and in unaffected siblings of people with schizophrenia (Weickert et al. 2010; Wagshal et al. 2014), with deficits in overall performance and learning rate. In the present study, we sought to define the relationship between peripheral BDNF levels and the neural processes underlying probabilistic association learning in healthy people and people with schizophrenia. First, we confirmed the reduced brain activation in people with schizophrenia versus healthy controls during a probabilistic association learning test using functional magnetic resonance imaging (fMRI). Second, we tested the extent to which plasma BDNF levels are related to brain activity in healthy people during probabilistic association learning. Third, we determined whether a similar relationship was also present in schizophrenia. We predicted a positive relationship between plasma BDNF levels and brain activity in a neural network consisting of prefrontal–parietal cortices and striatum, which has previously been shown to be relevant for probabilistic association learning in healthy adults. Based on the majority of work showing dysregulation of either BDNF levels or prefrontal cortex activity along with an increase in the truncated BDNF receptor (Weickert et al. 2003; Hashimoto et al. 2005; Wong et al. 2010, 2013; Ray et al. 2014), which is thought to block trophic effects in schizophrenia, we further predicted an abnormal relationship between plasma BDNF levels and brain activity in schizophrenia.

Background Schizophrenia is a disabling and often unremitting mental illness with an unknown cause that is characterized by heterogeneity in psychotic symptom presentation, cognitive deficits and treatment response. There is accumulating evidence for the role of inflammation in the etiology of schizophrenia. Inflammatory markers have been identified in the brains and peripheral blood of chronically ill patients with schizophrenia and in first episode patients and these markers have been associated with structural and functional brain abnormalities and cognitive deficits. Intercellular adhesion molecule 1 (ICAM-1) is a transmembrane protein expressed on endothelial cells which binds to leukocyte receptors that promotes transmigration of white blood cells into tissue. While peripheral inflammatory markers are altered in people with schizophrenia relative to controls, the extent to which ICAM-1 is elevated in the brains of people with schizophrenia and peripheral levels of soluble ICAM-1 (sICAM-1) is increased in relation to cognitive impairment in schizophrenia is unknown. Methods In a post-mortem cohort, 8 mRNAs relating to BBB function and 3 immune cell markers were measured by qPCR in the prefrontal cortex of 37 people with schizophrenia and 37 matched controls. In an independent living cohort, sICAM-1 was measured with a Luminex immunoassay from the plasma of 78 chronically ill patients with schizophrenia (all receiving antipsychotic medication) and 73 healthy controls. All participants from the living cohort received the following cognitive assessments: Wechsler Adult Intelligence Scale – 3rd edition to assess current IQ, Controlled Oral Word Association Test verbal fluency and Wechsler Memory Scale-Revised to assess verbal memory. Pearson’s or Spearman’s correlations were performed between cognitive measures and sICAM1 levels as appropriate in schizophrenia patients and healthy controls. Results ICAM-1 was elevated in the brains of people with schizophrenia relative to controls and CD163+ perivascular macrophages were found in the parenchyma. Peripheral sICAM1 was elevated by 29.2% in people with schizophrenia compared to healthy controls, t(140) = -3.988, p < 0.01. In people with schizophrenia, sICAM1 was inversely correlated with immediate verbal memory (r=-0.30, p=0.01), delayed verbal memory (rho=-0.29, p=0.01), verbal abstract reasoning (r=-0.23, p=0.05), and processing speed (rho=-0.28, p=0.02). In healthy controls, sICAM1 levels were inversely correlated with verbal fluency (r=-0.27, p=0.03) and processing speed (rho=-0.26, p=0.03). Discussion The brain endothelium of people with schizophrenia can attract more immune cells via increased ICAM-1. sICAM-1, a cleavage product of ICAM which enables white blood cell migration into tissue (including brain) is significantly elevated in peripheral blood of patients with schizophrenia. sICAM-1 is associated with poor verbal memory, reasoning and processing speed in people with schizophrenia and accounts for variation in cognition of healthy controls. This suggests that increased inflammatory processes, measured in blood, may reflect brain related cognitive deficits that are the hallmark of schizophrenia. Anti-inflammatory treatments may reverse cognitive impairment in schizophrenia.

Most transcranial Direct Current Stimulation (tDCS) trials of schizophrenia administer few sessions and do not assess transfer effects to other cognitive domains. In a randomized, double-blind, sham-controlled, parallel groups trial, we determined the extent to which 4-weeks of 2 mA tDCS at 20 min/day totalling 20 tDCS sessions administered during a spatial working memory test, with anodal right dorsolateral prefrontal cortex (DLPFC) and cathodal left tempo-parietal junction (TPJ) placement, as an adjunct to antipsychotics reduced auditory hallucinations and improved cognition in 12 outpatients with schizophrenia. Anodal tDCS significantly improved language-based working memory after 2 weeks and verbal fluency after 2 and 4 weeks. Thus, four weeks of tDCS appears to be safe and elicits transfer benefits to other prefrontal-dependent cognitive abilities in schizophrenia.

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu)., Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P, This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch.

Studies of patients with Parkinson’s disease receiving dopamimetics report conflicting evidence for early learning of probabilistic cue–outcome associations that elicits frontal–striatal activity. Previous studies of probabilistic association learning in patients with schizophrenia administered antipsychotics have displayed conflicting evidence for normal and abnormal learning. The role of dopaminergic treatment (dopamimetic versus dopamine antagonistic) effects on probabilistic association learning in these diseases that directly impact the dopamine system is not fully understood. The current study examined the effects of dopaminergic therapies on probabilistic association learning in 13 patients with schizophrenia and 8 patients with Parkinson’s disease under two conditions: after withdrawal from dopaminergic treatment and following administration of appropriate dopaminergic treatment. Medication order was counterbalanced in both groups. Patients with Parkinson’s disease failed to demonstrate any significant improvement over 150 trials, under both conditions (receiving or withdrawn from dopamimetics). Patients with schizophrenia withdrawn from antipsychotics displayed significant improvement during later trials only. These results demonstrate an effect of dopamine (DA) signaling on probabilistic association learning in that: (1) dopamine replacement therapy in Parkinson’s disease is insufficient to significantly improve probabilistic association learning and (2) DA receptor blockade impairs and removal of DA receptor blockade significantly improves frontal–striatal-dependent probabilistic association learning in schizophrenia, which is a novel finding and is opposite to the effects shown following removal of DA receptor blockade on other cognitive domains reported previously.

Introduction Recent neuropsychological studies show substantial cognitive deficits in patients with frontotemporal dementia (FTD). Schizophrenia (SC) overlaps in terms of neurobehavioural symptoms with FTD. Probabilistic association learning, which is thought to assay fronto-striatal function, is well documented to elicit impairment in SC and has not been investigated in FTD to date; this study compared FTD, SC and a healthy comparison group on probabilistic association learning to determine the extent to which FTD patients were similar in performance to SC patients. Methods Twenty FTD patients, 24 SC patients and 26 healthy controls were assessed using the probabilistic association learning weather prediction test. FTD patients were also divided into behavioural and language variants for comparison to the healthy group. Results FTD patients were impaired during probabilistic association learning in comparison to healthy controls. There was no difference in performance between the FTD and SC groups. FTD behavioural variants performed significantly worse than the healthy comparison group, while FTD language variants did not differ from the healthy comparison group. Conclusions This study provides the first evidence for impaired probabilistic association learning in FTD which is of an equivalent degree to that seen in SC. These results support recent structural neuroimaging studies showing fronto-striatal abnormalities in FTD and suggest that fronto-striatal dysfunction may contribute to cognitive deficits in a significant proportion of people with FTD.

Biomarkers have been sought after in the field of schizophrenia research for decades. In this paper, we discuss some of the concepts around developing biomarkers in an effort to understand why the use of biomarkers for schizophrenia has not been realized. In particular, we address the following 4 questions. Why would we need a diagnostic biomarker for schizophrenia? How is a biomarker typically defined and how does that influence the discovery of biomarkers in schizophrenia? What is the best use of biomarkers in schizophrenia? Do any biomarkers for schizophrenia currently exist? Thus, while we suggest that no biomarker currently exists for schizophrenia, the heterogeneity associated with schizophrenia will most likely need to be taken into account which will result in multiple biomarkers that identify the multiple underlying pathophysiological processes involved in schizophrenia. Therefore, much additional work will be required prior to obtaining any well-established biomarkers for schizophrenia.

Schizophrenia is a heterogeneous psychiatric illness for which the cause or causes are presently unknown. There is increasing evidence from multiple levels of research suggesting that inflammation may play an important role in the development and persistence of psychosis and cognitive impairment in a proportion of people with schizophrenia. This overview of recent literature focuses on studies of neuroinflammation that are considered to be of increasing interest in schizophrenia research and are poised to have an impact on the cause, diagnosis, and potential treatment of at least some forms or subtypes of schizophrenia.

Schizophrenia is a complex disorder with relatively stable prevalence rates estimated at about 0.5–1% (Saha et al., 2005). Schizophrenia is characterized by the occurrence of various psychopathological symptoms that have been described as positive symptoms (delusions and hallucinations), negative symptoms (apathy, lack of motivation, flat affect, poverty of speech, and social withdrawal), disorganized symptoms (disorganized speech and behavior), and cognitive impairment (Moustafa et al., 2016). Traditionally, cognitive impairment was thought to be evident only in elderly deteriorated patients with schizophrenia; however, over the past 25 years, a body of evidence challenged this view and showed that cognitive dysfunction is a core feature of schizophrenia (O'Carroll, 2000; Weickert et al., 2000; Bora et al., 2010). Cognitive deficits can be moderate to severe across several domains, including attention, working memory, verbal learning and memory, and executive functions (Weickert et al., 2000; Bowie and Harvey, 2006). These deficits pre-date the onset of psychosis and further decline in cognitive functioning is observed in the course of illness in most patients (Trotta et al., 2015). Numerous rehabilitation programs have been developed in order to alleviate the burden associated with cognitive impairment in schizophrenia since cognitive deficits respond poorly to antipsychotic treatment (Tao et al., 2015). Below we describe articles in this research topic (mostly focusing on cognitive studies in schizophrenia), dividing them into human vs. animal studies.

Blockade of N-methyl-D-aspartate receptors (NMDARs) produces behavior in healthy people that is similar to the psychotic symptoms and cognitive deficits of schizophrenia and can exacerbate symptoms in people with schizophrenia. However, an endogenous brain disruption of NMDARs has not been clearly established in schizophrenia. We measured mRNA transcripts for five NMDAR subunit mRNAs and protein for the NR1 subunit in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia and control (n=74) brains. Five NMDAR single-nucleotide polymorphisms (SNPs) previously associated with schizophrenia were tested for association with NMDAR mRNAs in postmortem brain and for association with cognitive ability in an antemortem cohort of 101 healthy controls and 48 people with schizophrenia. The NR1 subunit (mRNA and protein) and NR2C mRNA were decreased in postmortem brain from people with schizophrenia (P=0.004, P=0.01 and P=0.01, respectively). In the antemortem cohort, the minor allele of NR2B rs1805502 (T5988C) was associated with significantly lower reasoning ability in schizophrenia. In the postmortem brain, the NR2B rs1805502 (T5988C) C allele was associated with reduced expression of NR1 mRNA and protein in schizophrenia. Reduction in NR1 and NR2C in the DLPFC of people with schizophrenia may lead to altered NMDAR stoichiometry and provides compelling evidence for an endogenous NMDAR deficit in schizophrenia. Genetic variation in the NR2B gene predicts reduced levels of the obligatory NR1 subunit, suggesting a novel mechanism by which the NR2B SNP may negatively influence other NMDAR subunit expression and reasoning ability in schizophrenia.

Many modern learning theories assume that the amount of attention to a cue depends on how well that cue predicted important events in the past. Schizophrenia is associated with deficits in attention and recent theories of psychosis have argued that positive symptoms such as delusions and hallucinations are related to a failure of selective attention. However, evidence demonstrating that attention to irrelevant cues is related to positive symptoms in schizophrenia is lacking. We used a novel method of measuring attention to nonpredictive (and thus irrelevant) cues in a causal learning test (Le Pelley ME, McLaren IP. Learned associability and associative change in human causal learning. Q J Exp Psychol B. 2003;56:68–79) to assess whether healthy adults and people with schizophrenia discriminate previously predictive and nonpredictive cues. In a series of experiments with independent samples, we demonstrated: (1) when people with schizophrenia who had severe positive symptoms successfully distinguished between predictive and nonpredictive cues during training, they failed to discriminate between predictive and nonpredictive cues relative to healthy adults during subsequent testing and (2) learning about nonpredictive cues was correlated with more severe positive symptoms scores in schizophrenia. These results suggest that positive symptoms of schizophrenia are related to increased attention to nonpredictive cues during causal learning. This deficit in selective attention results in learning irrelevant causal associations and may be the basis of positive symptoms in schizophrenia.

Sex and stress hormones are reciprocally regulated and have opposing neurobiological effects (Sinclair et al, 2014). Molecular changes in brain sex and stress hormone receptors indicate that these systems are out of balance in people with schizophrenia. Furthermore, increased stress can precipitate the onset or trigger the relapse of psychosis, while low levels of estrogen can exacerbate symptoms in females with schizophrenia (Heringa et al, 2015). Also, the sex and stress hormone signaling systems are both activated at a time of increased risk for first developing schizophrenia, during human adolescence, when the prefrontal cortex appears primed to respond to cortisol (Sinclair et al, 2011) and when sex steroids are flooding the brain. While we often study these major hormonal systems individually, there is greater awareness that they work in concert and should be considered together.

Thomas Weickert, Isabella Jacomb, Clive Stanton, Rhini Vasudevan, Hugh Powell, Dennis Liu, Cherrie Galletly, Rhoshel Lenroot, Maryanne O'Donnell, and Cynthia Shannon Weickert

Reward detection, surprise detection and prediction-error signaling have all been proposed as roles for the ventral striatum (vStr). Previous neuroimaging studies of striatal function in schizophrenia have found attenuated neural responses to reward-related prediction errors; however, as prediction errors represent a discrepancy in mesolimbic neural activity between expected and actual events, it is critical to examine responses to both expected and unexpected rewards (URs) in conjunction with expected and UR omissions in order to clarify the nature of ventral striatal dysfunction in schizophrenia. In the present study, healthy adults and people with schizophrenia were tested with a reward-related prediction-error task during functional magnetic resonance imaging to determine whether schizophrenia is associated with altered neural responses in the vStr to rewards, surprise prediction errors or all three factors. In healthy adults, we found neural responses in the vStr were correlated more specifically with prediction errors than to surprising events or reward stimuli alone. People with schizophrenia did not display the normal differential activation between expected and URs, which was partially due to exaggerated ventral striatal responses to expected rewards (right vStr) but also included blunted responses to unexpected outcomes (left vStr). This finding shows that neural responses, which typically are elicited by surprise, can also occur to well-predicted events in schizophrenia and identifies aberrant activity in the vStr as a key node of dysfunction in the neural circuitry used to differentiate expected and unexpected feedback in schizophrenia.

Neuroimaging studies have shown both dorsolateral prefrontal (DLPFC) and inferior parietal cortex (iPARC) activation during probabilistic association learning. Whether these cortical brain regions are necessary for probabilistic association learning is presently unknown. Participants' ability to acquire probabilistic associations was assessed during disruptive 1 Hz repetitive transcranial magnetic stimulation (rTMS) of the left DLPFC, left iPARC, and sham using a crossover single-blind design. On subsequent sessions, performance improved relative to baseline except during DLPFC rTMS that disrupted the early acquisition beneficial effect of prior exposure. A second experiment examining rTMS effects on task-naive participants showed that neither DLPFC rTMS nor sham influenced naive acquisition of probabilistic associations. A third experiment examining consecutive administration of the probabilistic association learning test revealed early trial interference from previous exposure to different probability schedules. These experiments, showing disrupted acquisition of probabilistic associations by rTMS only during subsequent sessions with an intervening night's sleep, suggest that the DLPFC may facilitate early access to learned strategies or prior task-related memories via consolidation. Although neuroimaging studies implicate DLPFC and iPARC in probabilistic association learning, the present findings suggest that early acquisition of the probabilistic cue-outcome associations in task-naive participants is not dependent on either region.

Schizophrenia is a disabling illness that is typically first diagnosed during late adolescence to early adulthood. It has an unremitting course and is often treatment-resistant. Many clinical aspects of the illness suggest that sex steroid-nervous system interactions may contribute to the onset, course of symptoms and the cognitive impairment displayed by men and women with schizophrenia. Here, we discuss the actions of oestrogen and testosterone on the brain during adolescent development and in schizophrenia from the perspective of experimental studies in animals, human post-mortem studies, magnetic resonance imaging studies in living humans and clinical trials of sex steroid-based treatments. We present evidence of potential beneficial, as well as detrimental, effects of both testosterone and oestrogen. We provide a rationale for the necessity to further elucidate sex steroid mechanisms of action at different ages, sexes and brain regions to more fully understand the role of testosterone and oestrogen in the pathophysiology of schizophrenia. The weight of the evidence suggests that sex steroid hormones influence mammalian brain function, including both cognition and emotion, and that pharmaceutical agents aimed at sex steroid receptors appear to provide a novel treatment avenue to reduce symptoms and improve cognition in men and women with schizophrenia.

Patients with psychiatric disorders such as schizophrenia commonly present with impaired language. Here we investigate language in schizophrenia with a focus on inflectional morphology, using an intensively studied and relatively well-understood linguistic paradigm. Patients with schizophrenia (n=43) and age-matched healthy control subjects (n=42) were asked to produce past tenses of regular (slip), irregular (swim), and novel (plag) English verbs. Patients were impaired at regulars and novels (slipped, plagged), with relative sparing of irregulars (swam), controlling for numerous subject- and item-specific factors (e.g., IQ, phonological complexity). Additionally, patients' thought-disorder scores significantly predicted their performance at regular and novel (but not irregular) past-tense production. The results support grammatical deficits in schizophrenia, with a relative sparing of lexical memory, and suggest that thought disorder may be linked with grammatical impairments in the disorder.

Cognitive heterogeneity among people with schizophrenia has been defined on the basis of premorbid and current intelligence quotient (IQ) estimates. In a relatively large, community cohort, we aimed to independently replicate and extend cognitive subtyping work by determining the extent of symptom severity and functional deficits in each group. A total of 635 healthy controls and 534 patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited through the Australian Schizophrenia Research Bank. Patients were classified into cognitive subgroups on the basis of the Wechsler Test of Adult Reading (a premorbid IQ estimate) and current overall cognitive abilities into preserved, deteriorated, and compromised groups using both clinical and empirical (k-means clustering) methods. Additional cognitive, functional, and symptom outcomes were compared among the resulting groups. A total of 157 patients (29%) classified as ‘preserved’ performed within one s.d. of control means in all cognitive domains. Patients classified as ‘deteriorated’ (n=239, 44%) performed more than one s.d. below control means in all cognitive domains except estimated premorbid IQ and current visuospatial abilities. A separate 138 patients (26%), classified as ‘compromised,’ performed more than one s.d. below control means in all cognitive domains and displayed greater impairment than other groups on symptom and functional measures. In the present study, we independently replicated our previous cognitive classifications of people with schizophrenia. In addition, we extended previous work by demonstrating worse functional outcomes and symptom severity in the compromised group. Patients with schizophrenia can be categorized into distinct groups according to their cognitive functioning abilities, say scientists. Cognitive impairment and intellect changes following the onset of schizophrenia are well documented, but recent research suggests that patients are affected in many different ways. Thomas Weickert at the University of New South Wales, Sydney, and co-workers across Australia conducted a large-scale study involving 635 healthy controls and 534 patients with schizophrenic symptoms to verify the presence of three distinct cognitive phenotypes in schizophrenia. Utilizing a test to determine pre-illness intelligence, the team classified patients into three categories: 29% were deemed to have 'preserved' relatively high levels of cognitive function, 44% had 'deteriorated' cognition, and 26% displayed 'compromised' cognitive abilities prior to illness onset which persisted and were related to disability. Such classification could help doctors provide tailored treatments and inform understanding of disease progression.

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

Sex hormones impact reward processing, which is dysfunctional in schizophrenia; however, the degree to which testosterone levels relate to reward-related brain activity in healthy men and the extent to which this relationship may be altered in men with schizophrenia has not been determined. We used functional magnetic resonance imaging (fMRI) to measure neural responses in the striatum during reward prediction-errors and hormone assays to measure testosterone and prolactin in serum. To determine if testosterone can have a direct effect on dopamine neurons, we also localized and measured androgen receptors in human midbrain with immunohistochemistry and quantitative PCR. We found correlations between testosterone and prediction-error related activity in the ventral striatum of healthy men, but not in men with schizophrenia, such that testosterone increased the size of positive and negative prediction-error related activity in a valence-specific manner. We also identified midbrain dopamine neurons that were androgen receptor immunoreactive, and found that androgen receptor (AR) mRNA was positively correlated with tyrosine hydroxylase (TH) mRNA in human male substantia nigra. The results suggest that sex steroid receptors can potentially influence midbrain dopamine biosynthesis, and higher levels of serum testosterone are linked to better discrimination of motivationally-relevant signals in the ventral striatum, putatively by modulation of the dopamine biosynthesis pathway via AR ligand binding. However, the normal relationship between serum testosterone and ventral striatum activity during reward learning appears to be disrupted in schizophrenia.

Background: A common functional polymorphism of the brain-derived neurotrophic factor gene ( BDNF Val66Met) was previously associated with diminished episodic memory performance in healthy people. As cognitive function is commonly impaired in patients with systemic lupus erythematosus (SLE), the association of the BDNF Val66Met with neurocognitive function was studied. Objective: To study the association of the BDNF Val66Met with neurocognitive function in a cohort of patients with SLE. Methods: Cognitive function was assessed in 59 patients with SLE with no previous or current central nervous system involvement. Cognitive tests were grouped into five domains (memory, attention/executive function, visuospatial skills, motor function and psychomotor speed) and used to obtain domain Z scores, reflecting the difference between averaged scores of performance on individual tests and published norms in each domain. Genotyping was carried out using a 5′-nuclease assay with 99.9% accuracy. Unpaired t test was used to assess the relationship between genotypes and cognitive function, whereas the effect of possible confounders was assessed in a multivariate analysis. Results: Patients carrying the Met66 allele scored significantly higher on psychomotor, attention/executive and motor function tests, resulting in significantly higher domain Z scores for the psychomotor (p = 0.005) and motor (p = 0.002) domains. Conclusions: The BDNF Met66 allele was associated with better cognitive functioning in the psychomotor and motor domains, even after controlling for differences in ethnicity, sex, depression status and prednisone treatment. These data suggest that the BDNF Met66 allele confers protection against the decline of motor and psychomotor cognitive functions in patients with longstanding SLE.

Response inhibition and interference monitoring and suppression are two important aspects of cognitive control. Previous functional imaging studies have suggested a common network of brain regions underlying these cognitive processes; the dorsolateral prefrontal cortex (DLPFC), the ventrolateral prefrontal cortex (VLPFC), the dorsal cingulate (dACC), and the parietal cortex (PC). The relative contribution of these regions to these cognitive subprocesses, however, has not been determined. Based on previous findings supporting a role for dACC in the monitoring of conflicting information within a stimulus, we hypothesized greater activity in this cortical region during interference monitoring and suppression relative to response inhibition. On the other hand, as response inhibition is characterized by differential cognitive processes such as control implementation, top down modulation of the response, expectancy, and inhibition of behavioural response, we hypothesized increased activity in the other cortical nodes of the cognitive control network relative to interference monitoring and suppression. To this end, we conducted an event-related functional magnetic resonance imaging (fMRI) study in 57 healthy volunteers using a task preferentially involving either interference monitoring and suppression or response inhibition. Accuracy for response inhibition was lower than for interference monitoring and suppression. Imaging data showed activation in DLPFC, dACC, VLPFC, PC for both conditions. Comparisons between the two conditions indicated greater activation bilaterally in DLPFC, VLPFC and PC during response inhibition, and greater activation in the dACC during interference monitoring and suppression. These results extend previous findings by suggesting regional functional specialization within a cortical network supporting cognitive control.

Objective To assess the association of cognitive dysfunction and depression with serum antibodies to N-methyl-D-aspartate (NMDA) receptor (anti-NR2) and analyze clinical and neuroimaging correlates in patients with systemic lupus erythematosus (SLE). Methods Sixty patients underwent neurocognitive assessment, evaluation for depression with the Beck Depression Inventory II (BDI-II) and psychiatric interview (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), brain magnetic resonance imaging, and proton magnetic resonance spectroscopy imaging (1H-MRSI). Cognition was assessed in 5 domains: memory, attention/executive, visuospatial, motor, and psychomotor, and adjusted to each individual's best level of prior cognitive functioning estimated from the reading subtest of the Wide Range Achievement Test–3 (WRAT-3). Serum anti-NR2 antibodies were measured by enzyme-linked immunosorbent assay using a pentapeptide from the human NMDA receptor. Results Cognitive dysfunction was found in 28 of 60 patients (mild in 8, moderate in 20) before adjustment for WRAT-3 and in 35 of 60 patients (mild in 15, moderate in 11, and severe in 9) after adjustment for WRAT-3. The changes were most pronounced in the memory and visuospatial domains. There was no significant association between anti-NR2 antibody levels and cognition. On 1H-MRSI, patients with moderate or severe cognitive dysfunction had significantly higher choline:creatine ratios in the dorsolateral prefrontal cortex and the white matter, compared with patients with mild or absent cognitive dysfunction. Anti-NR2 antibodies were significantly correlated with BDI scores; patients with BDI-II scores of ≥14 had higher serum levels of anti-NR2 antibodies (P = 0.005, 95% confidence interval 0.83, 4.31), and there was a trend toward higher anti-NR2 antibody levels among patients who fulfilled the DSM-IV criteria for major depression. Conclusion Serum anti-NR2 antibodies are associated with depressive mood but not with cognitive dysfunction in SLE at a given time point. Larger longitudinal studies are needed to address the possible association between anti-NR2 antibodies and depression in SLE.

Schizophrenia has been consistently characterized by deficits in the cognitive domains of executive function, working memory, attention, and episodic memory. Although some cognitive abnormalities, such as motor slowing, may be associated with antipsychotic medication administration, generally the cognitive deficits shown by patients with schizophrenia can be attributed at least in part to the disease process. Modulation of the dopamine neurotransmitter system, notably through D2 receptor blockade, has been associated with psychotic symptom reduction and cognitive performance improvements in patients with schizophrenia. Although first-generation antipsychotic medication treatment initially was thought not to result in cognitive improvement, recent studies comparing second-generation antipsychotics to low doses of first-generation antipsychotic medication showed cognitive benefits for first-generation drugs, although perhaps not as great as that found after treatment with second-generation medication. Cognitive improvement associated with administration of antipsychotic medication may be a manifestation of improvement in general cortical information processing. Recent work has shown that specific genetic polymorphisms may interact with antipsychotic medication treatment to influence the degree to which cognitive abilities display improvement after treatment. In particular, the catechol-O-methyltransferase val108/158met polymorphism has been shown to predict working memory improvement after administration of antipsychotic medication to patients with schizophrenia.

Probabilistic category learning engages neural circuitry that includes the prefrontal cortex and caudate nucleus, two regions that show prominent changes with normal aging. However, the specific contributions of these brain regions are uncertain, and the effects of normal aging have not been examined previously in probabilistic category learning. In the present study, using a blood oxygenation level-dependent functional magnetic resonance imaging block design, 18 healthy young adults (mean age, 25.5 ± 2.6 years) and 15 older adults (mean age, 67.1 ± 5.3 years) were assessed on the probabilistic category learning "weather prediction" test. Whole-brain functional images acquired using a 1.5T scanner (General Electric, Milwaukee, WI) with gradient echo, echo planar imaging (3/1 mm; repetition time, 3000 ms; echo time, 50 ms) were analyzed using second-level random-effects procedures [SPM99 (Statistical Parametric Mapping)]. Young and older adults displayed equivalent probabilistic category learning curves, used similar strategies, and activated analogous neural networks, including the prefrontal and parietal cortices and the caudate nucleus. However, the extent of caudate and prefrontal activation was less and parietal activation was greater in older participants. The percentage correct and reaction time were mainly positively correlated with caudate and prefrontal activation in young individuals but positively correlated with prefrontal and parietal cortices in older individuals. Differential activation within a circumscribed neural network in the context of equivalent learning suggests that some brain regions, such as the parietal cortices, may provide a compensatory mechanism for healthy older adults in the context of deficient prefrontal cortex and caudate nuclei responses. Copyright © 2005 Society for Neuroscience.

Background The gene encoding catechol-O-methyltransferase (COMT), an enzyme that regulates prefrontal cortex dopamine, contains a common functional polymorphism ( val 108/158 met ) that influences prefrontal cortex function in an allelic dose-dependent manner. A recent study reported that the COMT val 108/158 met polymorphism influences cognitive- and physiologic-related prefrontal cortex responses to antipsychotic treatment. The present study tested the effects of several COMT polymorphisms on the cognitive response to antipsychotic medication in patients with schizophrenia. Methods Twenty inpatients with schizophrenia or schizoaffective disorder (5 with the val-val genotype, 11 with val-met, and 4 with met-met) were administered cognitive tests at two time points: once after 4 weeks of treatment with antipsychotic medication and once after 4 weeks of placebo administration, according to a counterbalanced, double-blind, within-subject study design. Results Patients homozygous for the COMT met allele displayed significant improvement on the working memory task after treatment. Patients homozygous for the COMT val allele did not show working memory improvement with treatment. Other COMT polymorphisms were not associated with significant differences between treatment and placebo conditions. Conclusions These results support other data suggesting that the COMT val 108/158 met polymorphism might be an important factor in the cognitive response to antipsychotic medication.

Different forms of nondeclarative learning involve regionally specific striatal circuits. The motor circuit (involving the putamen) has been associated with motor–skill learning and the dorsolateral prefrontal cortex (DLPFC) circuit (involving the caudate) has been associated with cognitive–habit learning. Efforts to differentiate functional striatal circuits within patient samples have been limited. Previous studies have provided mixed results regarding striatal-dependent nondeclarative learning deficits in patients with schizophrenia. In this study, a cognitive–habit learning task (probabilistic weather prediction) was used to assess the DLPFC circuit and a motor–skill learning task (pursuit rotor) was used to assess the motor circuit in 35 patients with schizophrenia and 35 normal controls. Patients with schizophrenia displayed significant performance differences from controls on both nondeclarative tasks; however, cognitive–habit learning rate in patients did not differ from controls. There were performance and learning-rate differences on the motor–skill learning task between the whole sample of patients and controls, however, analysis of a subset of patients and controls matched on general intellectual level eliminated learning rate differences between groups. The abnormal performance offset between patients with schizophrenia and controls in the absence of learning rate differences suggests that abnormal cortical processing provides altered input to normal striatal circuitry.

Organizing information and knowledge, and hence categorization, requires specifying boundaries between items, concepts and words. Over-inclusiveness in categorization may be seen as looseness of association; over-inclusive thinking was an early description of schizophrenic thinking. Recent studies suggest semantic memory problems in schizophrenia, and that thought disorder is associated with a disorganized semantic network. One such study [Psychol. Med. 24 (1994) 193], using a word categorization task, found patients slowest to respond to items semantically related to, but outside the category, whereas controls were slower responding to items sharing less features of the category (i.e. borderline). The authors suggested that there is an outward shift of semantic category boundaries in schizophrenia. In Experiment 1, we replicated Chen et al.'s (1994) methods, but did not find this qualitative difference in patients (28 patients, 26 controls). We extended this question in Experiment 2 to a more visual domain using pictures that ‘morphed’ from one entity into another and asked participants to decide when they no longer considered an item to be that item (20 patients, 25 controls). We did not find a difference between patients and controls in their sensitivity to detect boundaries of representations. These two experiments do not support the notion that thought disorder with postulated looseness of association or over-inclusive thinking is related to reduced awareness of boundaries of semantic category membership or entities, and inferentially their featural network. Despite anomalies in the semantic system in schizophrenia, we found aspects to be intact. This specificity of semantic processing is promising, suggesting that research will be informative as to how semantic memory is constructed, and thus how it can selectively break down. Moreover, this study indicates that patients do not ‘fail’ semantic tasks (e.g. priming) because of globally disorganized decision-making: here their capability to make precise distinctions between representations was intact.

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in ‘high’ and ‘low’ proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.

Previous studies on schizophrenia have detected elevated cytokines in both brain and blood, suggesting neuroinflammation may contribute to the pathophysiology in some cases. We aimed to determine the extent to which elevated peripheral cytokine messenger RNA (mRNA) expression: (1) characterizes a subgroup of people with schizophrenia and (2) shows a relationship to cognition, brain volume and/or symptoms. Forty-three outpatients with schizophrenia or schizoaffective disorder and matched healthy controls were assessed for peripheral cytokine mRNAs (interleukin (IL)-1β, IL-2, IL-6, IL-8 and IL-18), intelligence quotient, memory and verbal fluency, symptom severity and cortical brain volumes integral to language (that is, Broca’s and Wernicke’s areas). IL-1β mRNA levels were 28% increased in schizophrenia compared with controls (t(82)=2.64, P

The brain derived neurotrophic factor (BDNF) val66met polymorphism rs6265 influences learning and may represent a risk factor for schizophrenia. Healthy people with high schizotypal personality traits display cognitive deficits that are similar to but not as severe as those observed in schizophrenia and they can be studied without confounds of antipsychotics or chronic illness. How genetic variation in BDNF may impact learning in individuals falling along the schizophrenia spectrum is unknown. We predicted that schizotypal personality traits would influence learning and that schizotypal personality-based differences in learning would vary depending on the BDNF val66met genotype. Eighty-nine healthy adults completed the Schizotypal Personality Questionnaire (SPQ) and a probabilistic association learning test. Blood samples were genotyped for the BDNF val66met polymorphism. An ANOVA was performed with BDNF genotype (val homozygotes and met-carriers) and SPQ score (high/low) as grouping variables and probabilistic association learning as the dependent variable. Participants with low SPQ scores (fewer schizotypal personality traits) showed significantly better learning than those with high SPQ scores. BDNF met-carriers displaying few schizotypal personality traits performed best, whereas BDNF met-carriers displaying high schizotypal personality traits performed worst. Thus, the BDNF val66met polymorphism appears to influence probabilistic association learning differently depending on the extent of schizotypal personality traits displayed.

Summary Background Sex steroids such as oestrogen and testosterone are potent neurodevelopmental hormones that also play a role in neuromodulation and neuroprotection of the mature brain. Sex steroid hormones may also be involved in the pathophysiology of schizophrenia as reduced circulating sex steroid levels and changes in brain sex steroid receptors are found in people with schizophrenia compared to controls. In men with schizophrenia, recent studies have documented an inverse correlation between serum testosterone and negative symptoms. Our study sought to confirm whether men with schizophrenia had lower levels of testosterone relative to controls and to determine whether lower testosterone levels were related to higher symptom severity and impaired cognition. Method Circulating serum hormone levels (testosterone, oestrogen, and prolactin), cognitive function and symptoms were assessed in 29 chronically ill men with schizophrenia or schizoaffective disorder. Twenty healthy men were recruited as a comparison group. A series of regression analyses were performed to determine the extent to which circulating sex steroid hormone levels predict cognition and symptoms in men with schizophrenia. Results We did not find a significant difference in serum testosterone levels between groups. However, circulating testosterone levels significantly predicted performance on verbal memory, processing speed, and working memory in men with schizophrenia. With the exception of an effect of oestrogen on verbal memory, circulating sex steroid levels did not predict cognitive function in healthy men. Testosterone levels were not related to positive or negative symptom severity, but testosterone influenced excitement/hostility levels in our schizophrenia sample. Conclusions The results suggest that circulating sex steroids may modulate cognitive deficits associated with schizophrenia.

Estrogen has been implicated in the development and course of schizophrenia with most evidence suggesting a neuroprotective effect. Treatment with raloxifene, a selective estrogen receptor modulator, can reduce symptom severity, improve cognition and normalize brain activity during learning in schizophrenia. People with schizophrenia are especially impaired in the identification of negative facial emotions. The present study was designed to determine the extent to which adjunctive raloxifene treatment would alter abnormal neural activity during angry facial emotion recognition in schizophrenia. Twenty people with schizophrenia (12 men, 8 women) participated in a 13-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment (120 mg per day orally) and performed a facial emotion recognition task during functional magnetic resonance imaging after each treatment phase. Two-sample t-tests in regions of interest selected a priori were performed to assess activation differences between raloxifene and placebo conditions during the recognition of angry faces. Adjunctive raloxifene significantly increased activation in the right hippocampus and left inferior frontal gyrus compared with the placebo condition (family-wise error, P<0.05). There was no significant difference in performance accuracy or reaction time between active and placebo conditions. To the best of our knowledge, this study provides the first evidence suggesting that adjunctive raloxifene treatment changes neural activity in brain regions associated with facial emotion recognition in schizophrenia. These findings support the hypothesis that estrogen plays a modifying role in schizophrenia and shows that adjunctive raloxifene treatment may reverse abnormal neural activity during facial emotion recognition, which is relevant to impaired social functioning in men and women with schizophrenia.

Background: Schizophrenia is characterized by deficits in executive control and impairments in emotion processing. This study as sessed the nature and extent of potential alterations in the neural substrates supporting the interaction between cognitive control mech an isms and emotion attribution processes in people with schizophrenia. Methods: Functional magnetic resonance imaging was per formed during a verbal emotional go/no-go task. People with schizophrenia and healthy controls responded to word stimuli of a prespecified emotional valence (positive, negative or neutral) while inhibiting responses to stimuli of a different valence. Results: We en rolled 20 people with schizophrenia and 23 controls in the study. Healthy controls activated an extensive dorsal prefrontal‐parietal network while inhibiting responses to negative words compared to neutral words, but showed deactivation of the midcingulate cortex while inhibiting responses to positive words compared to neutral words. People with schizophrenia failed to activate this network during re sponse inhibition to negative words, whereas during response inhibition to positive words they did not deactivate the cingulate, but showed increased responsivity in the frontal cortex. Limitations: Sample heterogeneity is characteristic of studies of schizophrenia and may have contributed to more variable neural responses in the patient sample despite the care taken to control for potentially confound ing variables. Conclusion: Our results showed that schizophrenia is associated with aberrant modulation of neural responses during the interaction between cognitive control and emotion processing. Failure of the frontal circuitry to regulate goal-directed behaviour based on emotion attributions may contribute to deficits in psychosocial functioning in daily life.

Schizophrenia is associated with heterogeneity in symptoms, cognition and treatment response. Probabilistic association learning, involving a gradual learning of cue–outcome associations, activates a frontal-striatal network in healthy adults. Studies of probabilistic association learning in schizophrenia have shown frontal-striatal dysfunction although considerable heterogeneity in performance has also been reported. Anodal transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex has been shown to improve probabilistic association learning in healthy adults. The aim of the current study was to determine the extent to which anodal tDCS to the left dorsolateral prefrontal cortex would reverse probabilistic association learning deficits in schizophrenia. Prior to tDCS, 20 people with schizophrenia performed an initial baseline assessment without stimulation. Anodal tDCS was administered continuously for 20 min at an intensity of 2.0 mA to the left dorsolateral prefrontal cortex in a single-blind, counterbalanced, sham-controlled, cross-over design while participants performed 150 trials of a probabilistic association learning test. Although anodal tDCS failed to improve probabilistic association learning based on the whole sample performance, greater variance in the active relative to the sham conditions suggested a subset of people may respond to treatment. Further correlation, regression and cluster analyses revealed differential effects of baseline performance on active tDCS and sham treatment and that there was a subset of people with schizophrenia who displayed improvement with tDCS suggesting that anodal tDCS to the dorsolateral prefrontal cortex may facilitate access to existing prefrontal cortex neural reserves in people with schizophrenia who show adequate capacity to learn at baseline.