The European Portuguese Version of the Brief Negative Symptom Scale.

Negative symptoms reflect a currently much-untreated loss of normal functioning and are frequently found in psychotic disorders. We present the first translation of the Brief Negative Symptom Scale (BNSS) to European Portuguese and evaluate its validity in a sample of Portuguese male patients with a psychotic spectrum disorder. The Portuguese BNSS showed excellent internal consistency, high convergent validity (i.e., strong correlation with the PANSS negative factor), and high discriminant validity (i.e., a lack of association with the PANSS positive factor). In sum, the present European Portuguese BNSS has shown to be reliable, thus extending this instrument's clinical availability worldwide.

Computer anthropomorphisation in a socio-economic dilemma.

In the study of human behaviour, non-social targets are often used as a control for human-to-human interactions. However, the concept of anthropomorphisation suggests that human-like qualities can be attributed to non-human objects. This can prove problematic in psychological experiments, as computers are often used as non-social targets. Here, we assessed the degree of computer anthropomorphisation in a sequential and iterated prisoner's dilemma. Participants (N = 41) faced three opponents in the prisoner's dilemma paradigm-a human, a computer, and a roulette-all represented by images presented at the commencement of each round. Cooperation choice frequencies and transition probabilities were estimated within subjects, in rounds against each opponent. We found that participants anthropomorphised the computer opponent to a high degree, while the same was not found for the roulette (i.e. no cooperation choice difference vs human opponents; p = .99). The difference in participants' behaviour towards the computer vs the roulette was further potentiated by the precedent roulette round, in terms of both cooperation choice (61%, p = .007) and cooperation probability after reciprocated defection (79%, p = .007). This suggests that there could be a considerable anthropomorphisation bias towards computer opponents in social games, even for those without a human-like appearance. Conversely, a roulette may be a preferable non-social control when the opponent's abilities are not explicit or familiar.

Temporal Dynamics of Intranasal Oxytocin in Human Brain Electrophysiology.

Oxytocin (OT) is a key modulator of human social cognition, popular in behavioral neuroscience. To adequately design and interpret intranasal OT (IN-OT) research, it is crucial to know for how long it affects human brain function once administered. However, this has been mostly deduced from peripheral body fluids studies, or uncommonly used dosages. We aimed to characterize IN-OT's effects on human brain function using resting-state EEG microstates across a typical experimental session duration. Nineteen healthy males participated in a double-blind, placebo-controlled, within-subject, cross-over design of 24 IU of IN-OT in 12-min windows 15 min-to-1 h 42min after administration. We observed IN-OT effects on all microstates, across the observation span. During eyes-closed, IN-OT increased duration and contribution of A and contribution and occurrence of D, decreased duration and contribution of B and C; and increased transition probability C-to-B and C-to-D. In eyes-open, it increased A-to-C and A-to-D. As microstates A and D have been related to phonological auditory and attentional networks, respectively, we posit IN-OT may tune the brain for reception of external stimuli, particularly of social nature-tentatively supporting current neurocognitive hypotheses of OT. Moreover, we contrast our overall results against a comprehensive literature review of IN-OT time-course effects in the brain, highlighting comparability issues.

Effects of psychosis-associated genetic markers on brain volumetry: a systematic review of replicated findings and an independent validation.

BACKGROUND: Given psychotic illnesses' high heritability and associations with brain structure, numerous neuroimaging-genetics findings have been reported in the last two decades. However, few findings have been replicated. In the present independent sample we aimed to replicate any psychosis-implicated SNPs (single nucleotide polymorphisms), which had previously shown at least two main effects on brain volume. METHODS: A systematic review for SNPs showing a replicated effect on brain volume yielded 25 studies implicating seven SNPs in five genes. Their effect was then tested in 113 subjects with either schizophrenia, bipolar disorder, 'at risk mental state' or healthy state, for whole-brain and region-of-interest (ROI) associations with grey and white matter volume changes, using voxel-based morphometry. RESULTS: We found FWER-corrected (Family-wise error rate) (i.e. statistically significant) associations of: (1) CACNA1C-rs769087-A with larger bilateral hippocampus and thalamus white matter, across the whole brain; and (2) CACNA1C-rs769087-A with larger superior frontal gyrus, as ROI. Higher replication concordance with existing literature was found, in decreasing order, for: (1) CACNA1C-rs769087-A, with larger dorsolateral-prefrontal/superior frontal gyrus and hippocampi (both with anatomical and directional concordance); (2) ZNF804A-rs11681373-A, with smaller angular gyrus grey matter and rectus gyri white matter (both with anatomical and directional concordance); and (3) BDNF-rs6265-T with superior frontal and middle cingulate gyri volume change (with anatomical and allelic concordance). CONCLUSIONS: Most literature findings were not herein replicated. Nevertheless, high degree/likelihood of replication was found for two genome-wide association studies- and one candidate-implicated SNPs, supporting their involvement in psychosis and brain structure.

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.

Cultural differences in vocal emotion recognition: a behavioural and skin conductance study in Portugal and Guinea-Bissau.

Cross-cultural studies of emotion recognition in nonverbal vocalizations not only support the universality hypothesis for its innate features, but also an in-group advantage for culture-dependent features. Nevertheless, in such studies, differences in socio-economic-educational status have not always been accounted for, with idiomatic translation of emotional concepts being a limitation, and the underlying psychophysiological mechanisms still un-researched. We set out to investigate whether native residents from Guinea-Bissau (West African culture) and Portugal (Western European culture)-matched for socio-economic-educational status, sex and language-varied in behavioural and autonomic system response during emotion recognition of nonverbal vocalizations from Portuguese individuals. Overall, Guinea-Bissauans (as out-group) responded significantly less accurately (corrected p < .05), slower, and showed a trend for higher concomitant skin conductance, compared to Portuguese (as in-group)-findings which may indicate a higher cognitive effort stemming from higher difficulty in discerning emotions from another culture. Specifically, accuracy differences were particularly found for pleasure, amusement, and anger, rather than for sadness, relief or fear. Nevertheless, both cultures recognized all emotions above-chance level. The perceived authenticity, measured for the first time in nonverbal cross-cultural research, in the same vocalizations, retrieved no difference between cultures in accuracy, but still a slower response from the out-group. Lastly, we provide-to our knowledge-a first account of how skin conductance response varies between nonverbally vocalized emotions, with significant differences (p < .05). In sum, we provide behavioural and psychophysiological data, demographically and language-matched, that supports cultural and emotion effects on vocal emotion recognition and perceived authenticity, as well as the universality hypothesis.

The effect of the DISC1 Ser704Cys polymorphism on striatal dopamine synthesis capacity: an [18F]-DOPA PET study.

Whilst the role of the Disrupted-in-Schizophrenia 1 (DISC1) gene in the aetiology of major mental illnesses is debated, the characterization of its function lends it credibility as a candidate. A key aspect of this functional characterization is the determination of the role of common non-synonymous polymorphisms on normal variation within these functions. The common allele (A) of the DISC1 single-nucleotide polymorphism (SNP) rs821616 encodes a serine (ser) at the Ser704Cys polymorphism, and has been shown to increase the phosphorylation of extracellular signal-regulated protein Kinases 1 and 2 (ERK1/2) that stimulate the phosphorylation of tyrosine hydroxylase, the rate-limiting enzyme for dopamine biosynthesis. We therefore set out to test the hypothesis that human ser (A) homozygotes would show elevated dopamine synthesis capacity compared with cysteine (cys) homozygotes and heterozygotes (TT and AT) for rs821616. [18F]-DOPA positron emission tomography (PET) was used to index striatal dopamine synthesis capacity as the influx rate constant Kicer in healthy volunteers DISC1 rs821616 ser homozygotes (N = 46) and healthy volunteers DISC1 rs821616 cys homozygotes and heterozygotes (N = 56), matched for age, gender, ethnicity and using three scanners. We found DISC1 rs821616 ser homozygotes exhibited a significantly higher striatal Kicer compared with cys homozygotes and heterozygotes (P = 0.012) explaining 6.4% of the variance (partial η2 = 0.064). Our finding is consistent with its previous association with heightened activation of ERK1/2, which stimulates tyrosine hydroxylase activity for dopamine synthesis. This could be a potential mechanism mediating risk for psychosis, lending further credibility to the fact that DISC1 is of functional interest in the aetiology of major mental illness.

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.

Oxytocin modulates neural activity during early perceptual salience attribution.

Leading hypotheses of oxytocin's (OT) role in human cognition posit that it enhances salience attribution. However, whether OT exerts its effects predominantly in social (vs non-social) contexts remains debatable, and the time-course of intranasal OT's effects' on salience attribution processing is still unknown. We used the social Salience Attribution Task modified (sSAT) in a double-blind, placebo-controlled intranasal OT (inOT) administration, between-subjects design, with 54 male participants, to test existing theories of OT's role in cognition. Namely, we aimed to test whether inOT would differently affect salience attribution processing of social stimuli (expressing fearfulness) and non-social stimuli (fruits) made relevant via monetary reinforcement, and its neural processing time-course. During electroencephalography (EEG) recording, participants made speeded responses to emotional social (fearful faces) and non-emotional non-social (fruits) stimuli - which were matched for task-relevant motivational salience through their (color-dependent) probability of monetary reinforcement. InOT affected early (rather than late, P3b and LPP) EEG components, increasing N170 amplitude (p = .041) and P2b latency (p .001; albeit not of P1), regardless of stimuli's (emotional) socialness or reinforcement probability. Fear-related socialness affected salience attribution processing EEG (p .05) across time (N170, P2b and P3b), being later modulated by reinforcement probability (LPP). Our data suggest that OT's effects on neural activity during early perception, may exist irrespective of fear-related social- or reward-contexts. This partially supports the tri-phasic model of OT (which posits OT enhances salience attribution in an early perception stage regardless of socialness), and not the social salience nor the general approach-withdrawal hypotheses of OT, for early salience processing event-related potentials.

Risk variant of oligodendrocyte lineage transcription factor 2 is associated with reduced white matter integrity.

The oligodendrocyte lineage transcription factor 2 (OLIG2) regulates the genesis of oligodendrocytes, the brain cells responsible for axonal myelination. Although it has been associated with psychiatric and neurological disorders, the impact of this gene on white matter integrity has never been investigated in humans. Using diffusion tensor imaging, we examined the effect of a single nucleotide polymorphism (rs1059004) in OLIG2 previously associated with reduced gene expression, and with psychiatric disorders on fractional anisotropy in 78 healthy subjects. We found that the risk allele (A) was associated with reduced white matter integrity in the corona radiata bilaterally. This is consistent with evidence that it is a schizophrenia susceptibility gene, and suggests that it may confer increased risk through an effect on neuroanatomical connectivity.

Interaction between effects of genes coding for dopamine and glutamate transmission on striatal and parahippocampal function.

The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation.

Temporal profile of intranasal oxytocin in the human autonomic nervous system at rest: An electrocardiography and pupillometry study.

BACKGROUND: Human social behavior is modulated by oxytocin (OT). Intranasal administration of OT (IN-OT) is a noninvasive route shown to elicit changes in the autonomic nervous system (ANS) activity; however, IN-OT's effect on the temporal profile of ANS activity at rest is yet to be described. AIMS: We aimed to describe the temporal profile of IN-OT at six 10-min time windows from 15- to 100-min post-administration in 20 male participants at rest while continuously recording their pupillary in an eyes-open condition and cardiac activity in eyes-open and eyes-closed conditions. METHODS: We used a double-blind, placebo-controlled, within-subjects design study where we extracted two proxies of parasympathetic nervous system (PNS) activity: high-frequency heart rate variability (HF-HRV) and pupillary unrest index (PUI); and a proxy of sympathetic nervous system activity: sample entropy of the pupillary unrest. RESULTS: In the eyes-open condition, we found an effect of IN-OT on the proxies of PNS activity: decreased PUI in the three-time windows post-administration spanning 65-100 min, and as an exploratory finding, an increased HF-HRV in the 80-85 min time window. CONCLUSIONS: We suggest there is a role of OT in PNS regulation that may be consistent with OT's currently theorized role in the facilitation of alertness and approach behavior.

Psychosis Endophenotypes: A Gene-Set-Specific Polygenic Risk Score Analysis.

BACKGROUND AND HYPOTHESIS: Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes. STUDY DESIGN: We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications. Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for 4506 participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. STUDY RESULTS: After correction for multiple testing, we found that a reduced P300 amplitude was associated with a higher schizophrenia polygenic risk score of the forebrain regionalization gene set (mean difference per SD increase in the polygenic risk score: -1.15 µV; 95% CI: -1.70 to -0.59 µV; P = 6 × 10-5). The schizophrenia polygenic risk score of forebrain regionalization also explained more variance of the P300 amplitude (R2 = 0.032) than other polygenic risk scores, including the genome-wide polygenic risk scores. CONCLUSIONS: Our finding on reduced P300 amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later. Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models.

Effect of D-amino acid oxidase activator (DAOA; G72) on brain function during verbal fluency.

BACKGROUND: The D-Amino acid oxidase activator (G72 or DAOA) is believed to play a key role in the regulation of central glutamatergic transmission which is seen to be altered in psychosis. It is thought to regulate D-amino acid oxidase (DAO), which metabolizes D-serine, a co-agonist of NMDA-type glutamate receptors and to be involved in dendritic arborization. Linkage, genetic association and expression studies have implicated the G72 gene in both schizophrenia and bipolar disorder. AIMS: To examine the influence of G72 variation on brain function in the healthy population. METHOD: Fifty healthy volunteers were assessed using functional magnetic resonance imaging while performing a verbal fluency task. Regional brain activation and task-dependent functional connectivity during word generation was compared between different rs746187 genotypes. RESULTS: G72 rs746187 genotype had a significant effect on activation in the left postcentral and supramarginal gyri (FWE P < 0.05), and on the task-dependent functional coupling of this region with the retrosplenial cingulate gyrus (FWE P < 0.05). CONCLUSIONS: Our results may reflect an effect of G72 on glutamatergic transmission, mediated by an influence on D-amino acid oxidase activity, on brain areas particularly relevant to the hypoglutamatergic model of psychosis.

Epistasis between the DAT 3' UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia.

Dopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3' UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT x DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score = 4.3; family-wise error (FWE) p = 0.03), and in healthy volunteers alone (Z-score = 4.7; FWEp = 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis x COMT x DAT nonadditive interaction in the right orbital gyrus (Z-score = 4.3; FWEp = 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score = 4.3; FWE p = 0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.

Neuroimaging genetics of oxytocin: A transcriptomics-informed systematic review.

The last couple of decades have witnessed a rapid accumulation of studies implicating oxytocin (OT) in several neurobiological underpinnings of human behaviour and their impairment in psychiatric illness. Specifically, a neuroimaging genetics approach is helping elucidate the impact of variations in OT pathway genes on the human brain. In this review, we provide the first systematic account and discussion of all previous findings arising from human neuroimaging (epi)genetic studies of OT-related genes. To improve our mechanistic interpretation of such findings, we used data from the Genotype-Tissue Expression project to explore the functional impact the genetic variations may have on the human transcriptome. As a result, we provide an up-to-date summary of brain circuits found to be impacted by OT-relevant (epi)genetic variability, map brain pathways linking OT genes to disease, and highlight several (epi)genetic factors that modulate brain responses to intranasal OT. Finally, we provide some suggestions we believe might improve future research in the field.

Early diagnosis of Alzheimer's disease using machine learning: a multi-diagnostic, generalizable approach.

BACKGROUND: Early and accurate diagnosis of Alzheimer's disease (AD) is essential for disease management and therapeutic choices that can delay disease progression. Machine learning (ML) approaches have been extensively used in attempts to develop algorithms for reliable early diagnosis of AD, although clinical usefulness, interpretability, and generalizability of the classifiers across datasets and MRI protocols remain limited. METHODS: We report a multi-diagnostic and generalizable approach for mild cognitive impairment (MCI) and AD diagnosis using structural MRI and ML. Classifiers were trained and tested using subjects from the AD Neuroimaging Initiative (ADNI) database (n = 570) and the Open Access Series of Imaging Studies (OASIS) project database (n = 531). Several classifiers are compared and combined using voting for a decision. Additionally, we report tests of generalizability across datasets and protocols (IR-SPGR and MPRAGE), the impact of using graph theory measures on diagnostic classification performance, the relative importance of different brain regions on classification for better interpretability, and an evaluation of the potential for clinical applicability of the classifier. RESULTS: Our "healthy controls (HC) vs. AD" classifier trained and tested on the combination of ADNI and OASIS datasets obtained a balanced accuracy (BAC) of 90.6% and a Matthew's correlation coefficient (MCC) of 0.811. Our "HC vs. MCI vs. AD" classifier trained and tested on the ADNI dataset obtained a 62.1% BAC (33.3% being the by-chance cut-off) and 0.438 MCC. Hippocampal features were the strongest contributors to the classification decisions (approx. 25-45%), followed by temporal (approx. 13%), cingulate, and frontal regions (approx. 8-13% each), which is consistent with our current understanding of AD and its progression. Classifiers generalized well across both datasets and protocols. Finally, using graph theory measures did not improve classification performance. CONCLUSIONS: In sum, we present a diagnostic tool for MCI and AD trained using baseline scans and a follow-up diagnosis regardless of progression, which is multi-diagnostic, generalizable across independent data sources and acquisition protocols, and with transparently reported performance. Rated as potentially clinically applicable, our tool may be clinically useful to inform diagnostic decisions in dementia, if successful in real-world prospective clinical trials.

Sex Differences in Functional Connectivity Between Resting State Brain Networks in Autism Spectrum Disorder.

Functional brain connectivity (FBC) has previously been examined in autism spectrum disorder (ASD) between-resting-state networks (RSNs) using a highly sensitive and reproducible hypothesis-free approach. However, results have been inconsistent and sex differences have only recently been taken into consideration using this approach. We estimated main effects of diagnosis and sex and a diagnosis by sex interaction on between-RSNs FBC in 83 ASD (40 females/43 males) and 85 typically developing controls (TC; 43 females/42 males). We found increased connectivity between the default mode (DM) and (a) the executive control networks in ASD (vs. TC); (b) the cerebellum networks in males (vs. females); and (c) female-specific altered connectivity involving visual, language and basal ganglia (BG) networks in ASD-in suggestive compatibility with ASD cognitive and neuroscientific theories.

Prediction of transition to psychosis from an at-risk mental state using structural neuroimaging, genetic, and environmental data.

Introduction: Psychosis is usually preceded by a prodromal phase in which patients are clinically identified as being at in an "At Risk Mental State" (ARMS). A few studies have demonstrated the feasibility of predicting psychosis transition from an ARMS using structural magnetic resonance imaging (sMRI) data and machine learning (ML) methods. However, the reliability of these findings is unclear due to possible sampling bias. Moreover, the value of genetic and environmental data in predicting transition to psychosis from an ARMS is yet to be explored. Methods: In this study we aimed to predict transition to psychosis from an ARMS using a combination of ML, sMRI, genome-wide genotypes, and environmental risk factors as predictors, in a sample drawn from a pool of 246 ARMS subjects (60 of whom later transitioned to psychosis). First, the modality-specific values in predicting transition to psychosis were evaluated using several: (a) feature types; (b) feature manipulation strategies; (c) ML algorithms; (d) cross-validation strategies, as well as sample balancing and bootstrapping. Subsequently, the modalities whose at least 60% of the classification models showed an balanced accuracy (BAC) statistically better than chance level were included in a multimodal classification model. Results and discussion: Results showed that none of the modalities alone, i.e., neuroimaging, genetic or environmental data, could predict psychosis from an ARMS statistically better than chance and, as such, no multimodal classification model was trained/tested. These results suggest that the value of structural MRI data and genome-wide genotypes in predicting psychosis from an ARMS, which has been fostered by previous evidence, should be reconsidered.

Differential effects of DAAO on regional activation and functional connectivity in schizophrenia, bipolar disorder and controls.

Recent studies have identified DAAO as a probable susceptibility gene for schizophrenia and bipolar disorder. However, little is known about how this gene affects brain function to increase vulnerability to these disorders. We examined the impact of DAAO genotype (rs3918346) on brain function in patients with schizophrenia, patients with bipolar I disorder and healthy controls. We tested the hypothesis that a variation in DAAO genotype would be associated with altered prefrontal function and altered functional connectivity in schizophrenia and bipolar disorder. We used functional magnetic resonance imaging to measure brain responses during a verbal fluency task in a total of 121 subjects comprising 40 patients with schizophrenia, 33 patients with bipolar disorder and 48 healthy volunteers. We then used statistical parametric mapping (SPM) and psycho-physiological interaction (PPI) analyses to estimate the main effects of diagnostic group, the main effect of genotype, and their interaction on brain activation and on functional connectivity. Inferences were made at p<0.05, after correction for multiple comparisons across the whole brain. In the schizophrenia group relative to the control group, patients with one or two copies of the T allele showed lower deactivation in the left precuneus and greater activation in the right posterior cingulate gyrus than patients with two copies of the C allele. This diagnosis×genotype interaction was associated with differences in the functional connectivity of these two regions with other cortical and subcortical areas. In contrast, there were no significant effects of diagnosis or of genotype in comparisons involving bipolar patients. Our results suggest that genetic variation in DAAO has a significant impact on both regional activation and functional connectivity, and provide evidence for a diagnosis-dependent pattern of gene action.