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Background: Bipolar disorder (BD) is associated with cortical and subcortical structural brain abnormalities. It is unclear whether such alterations progressively change over time, and how this is related to the number of mood episodes. To address this question, we analyzed a large and diverse international sample with longitudinal magnetic resonance imaging (MRI) and clinical data to examine structural brain changes over time in BD. Methods: Longitudinal structural MRI and clinical data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) BD Working Group, including 307 patients with BD and 925 healthy control subjects, were collected from 14 sites worldwide. Male and female participants, aged 40 ± 17 years, underwent MRI at 2 time points. Cortical thickness, surface area, and subcortical volumes were estimated using FreeSurfer. Annualized change rates for each imaging phenotype were compared between patients with BD and healthy control subjects. Within patients, we related brain change rates to the number of mood episodes between time points and tested for effects of demographic and clinical variables. Results: Compared with healthy control subjects, patients with BD showed faster enlargement of ventricular volumes and slower thinning of the fusiform and parahippocampal cortex (0.18 < d < 0.22). More (hypo)manic episodes were associated with faster cortical thinning, primarily in the prefrontal cortex. Conclusions: In the hitherto largest longitudinal MRI study on BD, we did not detect accelerated cortical thinning but noted faster ventricular enlargements in BD. However, abnormal frontocortical thinning was observed in association with frequent manic episodes. Our study yields insights into disease progression in BD and highlights the importance of mania prevention in BD treatment.

BackgroundBipolar disorder (BD) is a familial psychiatric disorder associated with frontotemporal and subcortical brain abnormalities. It is unclear whether such abnormalities are present in relatives without BD, and little is known about structural brain trajectories in those at risk.MethodNeuroimaging was conducted at baseline and at 2-year follow-up interval in 90 high-risk individuals with a first-degree BD relative (HR), and 56 participants with no family history of mental illness who could have non-BD diagnoses. All 146 subjects were aged 12–30 years at baseline. We examined longitudinal change in gray and white matter volume, cortical thickness, and surface area in the frontotemporal cortex and subcortical regions.ResultsCompared to controls, HR participants showed accelerated cortical thinning and volume reduction in right lateralised frontal regions, including the inferior frontal gyrus, lateral orbitofrontal cortex, frontal pole and rostral middle frontal gyrus. Independent of time, the HR group had greater cortical thickness in the left caudal anterior cingulate cortex, larger volume in the right medial orbitofrontal cortex and greater area of right accumbens, compared to controls. This pattern was evident even in those without the new onset of psychopathology during the inter-scan interval.ConclusionsThis study suggests that differences previously observed in BD are developing prior to the onset of the disorder. The pattern of pathological acceleration of cortical thinning is likely consistent with a disturbance of molecular mechanisms responsible for normal cortical thinning. We also demonstrate that neuroanatomical differences in HR individuals may be progressive in some regions and stable in others.

White matter abnormalities associated with schizophrenia have been widely reported, although the consistency of findings across studies is moderate. In this study, neuroimaging was used to investigate white matter pathology and its impact on whole-brain white matter connectivity in one of the largest samples of patients with schizophrenia. Fractional anisotropy (FA) and mean diffusivity (MD) were compared between patients with schizophrenia or schizoaffective disorder (n = 326) and age-matched healthy controls (n = 197). Between-group differences in FA and MD were assessed using voxel-based analysis and permutation testing. Automated whole-brain white matter fiber tracking and the network-based statistic were used to characterize the impact of white matter pathology on the connectome and its rich club. Significant reductions in FA associated with schizophrenia were widespread, encompassing more than 40% (234ml) of cerebral white matter by volume and involving all cerebral lobes. Significant increases in MD were also widespread and distributed similarly. The corpus callosum, cingulum, and thalamic radiations exhibited the most extensive pathology according to effect size. More than 50% of cortico-cortical and cortico-subcortical white matter fiber bundles comprising the connectome were disrupted in schizophrenia. Connections between hub regions comprising the rich club were disproportionately affected. Pathology did not differ between patients with schizophrenia and schizoaffective disorder and was not mediated by medication. In conclusion, although connectivity between cerebral hubs is most extensively disturbed in schizophrenia, white matter pathology is widespread, affecting all cerebral lobes and the cerebellum, leading to disruptions in the majority of the brain's fiber bundles.

Neurobiological models explain increased risk-taking behaviours in adolescence and young adulthood as arising from staggered development of subcortical reward networks and prefrontal control networks. In this study, we examined whether individual variability in impulsivity and reward-related mechanisms is associated with higher level of engagement in risky behaviours and vulnerability to maladaptive outcomes and whether this relationship is mediated by cognitive control ability. A community sample of adolescents, young adults, and adults (age = 15-35 years) completed self-report measures and behavioural tasks of cognitive control, impulsivity, and reward-related mechanisms, and self-reported level of maladaptive outcomes. Behavioural, event-related potential (ERP), and multivariate pattern analysis (MVPA) measures of proactive control were derived from a task-switching paradigm. Adolescents, but not young adults, reported higher levels of impulsivity, reward-seeking behaviours and maladaptive outcomes than adults. They also had lower cognitive control ability, as measured by both self-report and task-based measures. Consistent with models of risk-taking behaviour, self-reported level of cognitive control mediated the relationship between self-reported levels of impulsivity and psychological distress, but the effect was not moderated by age. In contrast, there was no mediation effect of behavioural or EEG-based measures of cognitive control. These findings suggest that individual variability in cognitive control is more crucial to the relationship between risk-taking/impulsivity and outcomes than age itself. They also highlight large differences in measurement between self-report and task-based measures of cognitive control and decision-making under reward conditions, which should be considered in any studies of cognitive control.

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-d-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.

Glutamine plus glutamate (Glx), as well as N-acetylaspartate compounds, (NAAc), a marker of neuronal viability, are quantified with proton magnetic resonance spectroscopy (UsedAmongst younger (age ≤40 years-median split) bipolar-I vs HC subjects Glx was increased (p 0.001), while NAAc was reduced in WM (p 0.001). In GM, NAAc (p 0.001) and myo-inositol (p = 0.002) were reduced. Amongst older bipolar-I (vs HC) in WM regions we found reductions in: NAAc (p 0.001), glycerophospho-choline + phospho-choline (p 0.001), creatine + phospho-creatine (p 0.001) and myo-inositol (p 0.001); in GM only Glx was increased (p 0.005). Contrasts between bipolar-I and schizophrenia produced fewer results: amongst younger subjects, reduced NAAc (p 0.001) in WM and lower myo-inositol in GM (p = 0.04) in bipolar-I vs schizophrenia. In the older patients, bipolar-I had lower GM NAAc (p = 0.009) than schizophrenia.First, differential exposure to antipsychotic and mood stabilizing medication across the groups. Second, differences in substance use histories among the groups. Third, neglect of peripheral and ventral cortical and subcortical regions. Finally, limited power to detect bipolar/schizophrenia differences.Chronically-treated bipolar-I have increased Glx and reduced NAAc, suggestive of neuronal dysfunction. The NAAc reductions are more severe in bipolar-I than in schizophrenia patients.

The analysis of time-varying activity and connectivity patterns (i.e., the chronnectome) using resting-state magnetic resonance imaging has become an important part of ongoing neuroscience discussions. The majority of previous work has focused on variations of temporal coupling among fixed spatial nodes or transition of the dominant activity/connectivity pattern over time. Here, we introduce an approach to capture spatial dynamics within functional domains (FDs), as well as temporal dynamics within and between FDs. The approach models the brain as a hierarchical functional architecture with different levels of granularity, where lower levels have higher functional homogeneity and less dynamic behavior and higher levels have less homogeneity and more dynamic behavior. First, a high-order spatial independent component analysis is used to approximate functional units. A functional unit is a pattern of regions with very similar functional activity over time. Next, functional units are used to construct FDs. Finally, functional modules (FMs) are calculated from FDs, providing an overall view of brain dynamics. Results highlight the spatial fluidity within FDs, including a broad spectrum of changes in regional associations, from strong coupling to complete decoupling. Moreover, FMs capture the dynamic interplay between FDs. Patients with schizophrenia show transient reductions in functional activity and state connectivity across several FDs, particularly the subcortical domain. Activity and connectivity differences convey unique information in many cases (e.g., the default mode) highlighting their complementarity information. The proposed hierarchical model to capture FD spatiotemporal variations provides new insight into the macroscale chronnectome and identifies changes hidden from existing approaches.

Genetic and environmental etiologies may contribute to schizophrenia and its associated neurobiological profile. We examined the interaction between dopaminergic polymorphisms, childhood adversity and diagnosis (schizophrenia/schizoaffective disorder) on dopamine-related brain structures. Childhood adversity histories and structural MRI data were obtained from 249 (153 schizophrenia/schizoaffective, 96 controls) participants registered in the Australian Schizophrenia Research Bank. Polymorphisms in DRD2 and COMT were genotyped and a dopaminergic risk allelic load (RAL) was calculated. Regression analysis was used to test the main and interaction effects of RAL, childhood adversity and diagnosis on volumes of dopamine-related brain structures (caudate, putamen, nucleus accumbens, dorsolateral prefrontal cortex and hippocampus). A schizophrenia/schizoaffective diagnosis showed significant main effects on bilateral hippocampus, left dorsolateral prefrontal cortex and bilateral putamen volumes. RAL showed a significant main effect on left putamen volumes. Furthermore, across the whole sample, a significant two-way interaction between dopaminergic RAL and childhood adversity was found for left putamen volumes. No brain structure volumes were predicted by a three-way interaction that included diagnosis. Our finding suggests the left putamen may be particularly sensitive to dopaminergic gene-environment interactions regardless of diagnosis. However, larger studies are needed to assess whether these interactions are more or less pronounced in those with schizophrenia/schizoaffective disorders.

Autism spectrum disorder (ASD) is associated with atypical brain development. However, the phenotype of regionally specific increased cortical thickness observed in ASD may be driven by several independent biological processes that influence the gray/white matter boundary, such as synaptic pruning, myelination, or atypical migration. Here, we propose to use the boundary sharpness coefficient (BSC), a proxy for alterations in microstructure at the cortical gray/white matter boundary, to investigate brain differences in individuals with ASD, including factors that may influence ASD-related heterogeneity (age, sex, and intelligence quotient). Using a vertex-based meta-analysis and a large multicenter structural magnetic resonance imaging (MRI) dataset, with a total of 1136 individuals, 415 with ASD (112 female; 303 male), and 721 controls (283 female; 438 male), we observed that individuals with ASD had significantly greater BSC in the bilateral superior temporal gyrus and left inferior frontal gyrus indicating an abrupt transition (high contrast) between white matter and cortical intensities. Individuals with ASD under 18 had significantly greater BSC in the bilateral superior temporal gyrus and right postcentral gyrus; individuals with ASD over 18 had significantly increased BSC in the bilateral precuneus and superior temporal gyrus. Increases were observed in different brain regions in males and females, with larger effect sizes in females. BSC correlated with ADOS-2 Calibrated Severity Score in individuals with ASD in the right medial temporal pole. Importantly, there was a significant spatial overlap between maps of the effect of diagnosis on BSC when compared with cortical thickness. These results invite studies to use BSC as a possible new measure of cortical development in ASD and to further examine the microstructural underpinnings of BSC-related differences and their impact on measures of cortical morphology.

Altres ajuts: SRB: The Australian Schizophrenia Research Bank (ASRB) was supported by the National Health and Medical Research Council of Australia (NHMRC) (Enabling Grant, ID 386500), the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation and the Schizophrenia Research Institute. Chief Investigators for ASRB were Carr, V., Schall, U., Scott, R., Jablensky, A., Mowry, B., Michie, P., Catts, S., Henskens, F., Pantelis, C. We thank Loughland, C., the ASRB Manager, and acknowledge the help of Jason Bridge for ASRB database queries. CP was supported by NHMRC Senior Principal Research Fellowships (IDs: 628386 & 1105825); GC was supported by the Schizophrenia Research Institute utilizing infrastructure funding from the New South Wales Ministry of Health and New South Wales Ministry of Trade and Investment (Australia); JMF was supported by NHMRC project grant (1063960) and the Janette Mary O'Neil Research Fellowship; MJG was supported by NHMRC as an R.D. Wright Biomedical Career Development Fellow (1061875). MJC was supported by NHMRC Senior Research Fellowship (1121474). CASSI: CSW is funded by the NSW Ministry of Health, Office of Health and Medical Research. CSW is a recipient of a National Health and Medical Research Council (Australia) Principal Research Fellowship (PRF) (#1117079). CIAM: The CIAM study (FMH - PI) was supported by the University Research Committee, University of Cape Town and South African funding bodies National Research Foundation and Medical Research Council. COBRE: The COBRE dataset and investigators were supported by NIH grants R01EB006841 & P20GM103472, as well as NSF grant 1539067. JT (senior author) and VDC are supported by 5R01MH094524. JMS is supported by R01 AA021771 and P50 AA022534. EONCKS: This work was supported by a New Partnership for Africa's Development (NEPAD) grant through the Department of Science and Technology of South Africa, the Medical Research Council of South Africa (grant number 65174). ESO: The ESO study was funded by NPU I - LO1611 and Ministry of Health, Czech Republic - Conceptual Development of Research Organization 00023001 (IKEM). FIDMAG/Project: This work was supported by the Catalan Government and several grants from the Instituto de Salud Carlos III and co-funded by European Union (ERDF/ESF, 'Investing in your future'): Miguel Servet Research Contracts and Research Project Grants. FOR2107 Marburg: The FOR2107 Marburg study was funded by the German Research Foundation (DFG), Tilo Kircher (speaker FOR2107; DFG grant numbers KI588/14-1, KI588/14-2), Axel Krug (KR 3822/5-1, KR 3822/7-2), Igor Nenadic (NE 2254/1-2), Carsten Konrad (KO 4291/3-1). FOR2107 Muenster: The FOR2107 Muenster study was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). TH was supported by grants from the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4). Frankfurt: MRI was performed at the Frankfurt Brain Imaging Center, supported by the German Research Council (DFG) and the German Ministry for Education and Research (BMBF; Brain Imaging Center Frankfurt/Main, DLR 01GO0203). GIPSI: This study was supported by Colciencias PRISMA-U.T. Huilong1 & Huilong2: This study was funded by the National Natural Science Foundation of China (81761128021; 31671145; 81401115; 81401133), Beijing Municipal Science and Technology Commission grant (Z141107002514016) and Beijing Natural Science Foundation(7162087, Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding (XMLX201609; zylx201409). IGP: This study was funded by Project Grants from the Australian National Health and Medical Research Council of Australia (NHMRC; APP630471 and APP1081603), the Macquarie University's Australian Research Council Centre of Excellence in Cognition and its Disorders (CE110001021). Johns Hopkins: Supported by National Institutes of Health Grant Nos. MH-092443, MH-094268 (Silvio O. Conte Center), MH-105660, and MH-107730; foundation grants from Stanley, RUSK/S-R, and NARSAD/Brain and Behavior Research Foundation. Madrid: Supported by the Spanish Ministry of Science, Innovation and Universities, Instituto de Salud Carlos III, co-financed by ERDF Funds from the European Commission, "A way of making Europe", CIBERSAM. Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds and European Union Seventh Framework Program and H2020 Program; Fundación Familia Alonso, Fundación Alicia Koplowitz and Fundación Mutua Madrileña. MPRC1 & MPRC2: Support was received from NIH grants U01MH108148, 2R01EB015611, R01MH112180, R01DA027680, R01MH085646, P50MH103222 and T32MH067533, a State of Maryland contract (M00B6400091) and NSF grant (1620457). OLIN: The Olin study was supported by NIH grants R37MH43375 and R01MH074797. Oxford: The Oxford study MRC G0500092. SLF Rome: Support from the Italian Ministry of Health grants RC-12-13-14-15-16-17-18-19/A. RSCZ: RSCZ data collection was supported by RFBR 15-06-05758 grant. SCORE: This study was supported in part by grant 3232BO_119382 from the Swiss National Science Foundation. We thank the FePsy (Frueherkennung von Psychosen; early detection of psychosis) Study Group from the University of Basel, Department of Psychiatry, Switzerland, for the recruitment of the study participants. The FePsy Study was supported in part by grant No. SNF 3200-057216/1, ext./2, ext./3. Singapore: This study was supported by research grants from the National Healthcare Group, Singapore (SIG/05004; SIG/11003), and the Singapore Bioimaging Consortium (RP C-009/2006) research grants awarded to KS. SNUH: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (Grant no. 2013R1A2A1A03071089 and 2017M3C7A1029610). UCISZ: The UCISZ study was supported by the National Institutes of Mental Health grant number R21MH097196 to TGMvE. UCISZ data were processed by the UCI High Performance Computing cluster supported by Joseph Farran, Harry Mangalam, and Adam Brenner and the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant UL1 TR000153. UNIBA: The UNIBA study was supported by grant funding from the Italian Ministry of Health (PE-2011-02347951). UNIMAAS: The study was supported by Dutch Organization for Health Research and Development (ZonMw 91112002) and a personal grant to Thérèse van Amelsvoort (ZonMw-VIDI: 91712394). The data was collected in a clinical trial registered in the Dutch clinical trial registry under ID: NTR5094 (http://www.trialregister.nl). UPenn: This study was supported by the National Institute of Mental Health grants MH064045, MH 60722, MH019112, MH085096 (DHW), and R01MH112847 (RTS and TDS). Zurich: This study was supported by the Swiss National Science Foundation (105314_140351 to S.K.). Matthias Kirschner acknowledges support from the National Bank Fellowship (McGill University) and the Swiss National Foundation (P2SKP3_178175). Research reported in this publication was also supported by the following National Institutes of Health grants: U54 EB020403 to PMT, R01 MH116147, U24 RR21992, R21MH097196, and TR000153 to TGMvE, S10 OD023696 and R01EB015611 to PK, T32 AG058507and 5T32 MH073526 to CRKC, R01 MH117601 to NJ, ENIGMA's NIH Big Data to Knowledge (BD2K) initiative U54 EB020403, ENIGMA Sex Differences R01MH116147, and ENIGMA-COINSTAC: Advanced World-wide Transdiagnostic Analysis of Valence System Brain Circuits R01MH121246. A common limitation of neuroimaging studies is their small sample sizes. To overcome this hurdle, the Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium combines neuroimaging data from many institutions worldwide. However, this introduces heterogeneity due to different scanning devices and sequences. ENIGMA projects commonly address this heterogeneity with random-effects meta-analysis or mixed-effects mega-analysis. Here we tested whether the batch adjustment method, ComBat, can further reduce site-related heterogeneity and thus increase statistical power. We conducted random-effects meta-analyses, mixed-effects mega-analyses and ComBat mega-analyses to compare cortical thickness, surface area and subcortical volumes between 2897 individuals with a diagnosis of schizophrenia and 3141 healthy controls from 33 sites. Specifically, we compared the imaging data between individuals with schizophrenia and healthy controls, covarying for age and sex. The use of ComBat substantially increased the statistical significance of the findings as compared to random-effects meta-analyses. The findings were more similar when comparing ComBat with mixed-effects mega-analysis, although ComBat still slightly increased the statistical significance. ComBat also showed increased statistical power when we repeated the analyses with fewer sites. Results were nearly identical when we applied the ComBat harmonization separately for cortical thickness, cortical surface area and subcortical volumes. Therefore, we recommend applying the ComBat function to attenuate potential effects of site in ENIGMA projects and other multi-site structural imaging work. We provide easy-to-use functions in R that work even if imaging data are partially missing in some brain regions, and they can be trained with one data set and then applied to another (a requirement for some analyses such as machine learning).

Bipolar disorder is associated with cognitive deficits and cortical changes for which the developmental dynamics are not well understood. The dopamine D2 receptor (DRD2) gene has been associated with both psychiatric disorders and cognitive variability. Here we examined the mediating role of brain structure in the relationship between DRD2 genomic variation and cognitive performance, with target cortical regions selected based on evidence of association with DRD2, bipolar disorder and/or cognition from prior literature. Participants (n = 143) were aged 12–30 years and comprised 62 first-degree relatives of bipolar patients (deemed ‘at-risk’), 55 controls, and 26 patients with established bipolar disorder; all were unrelated Caucasian individuals with complete data across the three required modalities (structural magnetic resonance imaging, neuropsychological and genetic data). A DRD2 haplotype was derived from three functional polymorphisms (rs1800497, rs1076560, rs2283265) associated with alternative splicing (i.e., D2-short/-long isoforms). Moderated mediation analyses explored group differences in relationships between this DRD2 haplotype, three structural brain networks which subsume the identified cortical regions of interest (frontoparietal, dorsal-attention, and ventral-attention), and three cognitive indices (intelligence, attention, and immediate memory). Controls who were homozygous for the DRD2 major haplotype demonstrated greater cognitive performance as a result of dorsal-attention network mediation. However, this association was absent in the ‘at-risk’ group. This study provides the first evidence of a functional DRD2-brain-cognition pathway. The absence of typical brain-cognition relationships in young ‘at-risk’ individuals may reflect biological differences that precede illness onset. Further insight into early pathogenic processes may facilitate targeted early interventions.

BackgroundIdentifying clinical features that predict conversion to bipolar disorder (BD) in those at high familial risk (HR) would assist in identifying a more focused population for early intervention.MethodIn total 287 participants aged 12–30 (163 HR with a first-degree relative with BD and 124 controls (CONs)) were followed annually for a median of 5 years. We used the baseline presence of DSM-IV depressive, anxiety, behavioural and substance use disorders, as well as a constellation of specific depressive symptoms (as identified by the Probabilistic Approach to Bipolar Depression) to predict the subsequent development of hypo/manic episodes.ResultsAt baseline, HR participants were significantly more likely to report ⩾4 Probabilistic features (40.4%) when depressed than CONs (6.7%; p < .05). Nineteen HR subjects later developed either threshold (n = 8; 4.9%) or subthreshold (n = 11; 6.7%) hypo/mania. The presence of ⩾4 Probabilistic features was associated with a seven-fold increase in the risk of ‘conversion’ to threshold BD (hazard ratio = 6.9, p < .05) above and beyond the fourteen-fold increase in risk related to major depressive episodes (MDEs) per se (hazard ratio = 13.9, p < .05). Individual depressive features predicting conversion were psychomotor retardation and ⩾5 MDEs. Behavioural disorders only predicted conversion to subthreshold BD (hazard ratio = 5.23, p < .01), while anxiety and substance disorders did not predict either threshold or subthreshold hypo/mania.ConclusionsThis study suggests that specific depressive characteristics substantially increase the risk of young people at familial risk of BD going on to develop future hypo/manic episodes and may identify a more targeted HR population for the development of early intervention programs.

Contains fulltext : 191289.pdf (Publisher’s version ) (Open Access) Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen's d=-0.293; P=1.71 x 10(-21)), left fusiform gyrus (d=-0.288; P=8.25 x 10(-21)) and left rostral middle frontal cortex (d=-0.276; P=2.99 x 10(-19)). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Bipolar disorder (BD) is characterized by a dysregulation of affect and impaired integration of emotion with cognition. These traits are also expressed in probands at high genetic risk of BD. The inferior frontal gyrus (IFG) is a key cortical hub in the circuits of emotion and cognitive control, and it has been frequently associated with BD. Here, we studied resting-state functional connectivity of the left IFG in participants with BD and in those at increased genetic risk.Using resting-state functional magnetic resonance imaging we compared 49 young BD participants, 71 individuals with at least one first-degree relative with BD (at-risk), and 80 control subjects. We performed between-group analyses of the functional connectivity of the left IFG and used graph theory to study its local functional network topology. We also used machine learning to study classification based solely on the functional connectivity of the IFG.In BD, the left IFG was functionally dysconnected from a network of regions, including bilateral insulae, ventrolateral prefrontal gyri, superior temporal gyri, and the putamen (p.001). A small network incorporating neighboring insular regions and the anterior cingulate cortex showed weaker functional connectivity in at-risk than control participants (p.006). These constellations of regions overlapped with frontolimbic regions that a machine learning classifier selected as predicting group membership with an accuracy significantly greater than chance.Functional dysconnectivity of the IFG from regions involved in emotional regulation may represent a trait abnormality for BD and could potentially aid clinical diagnosis.

Although brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age.Gray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference.Significant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident.The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.

Emerging evidence suggests that psychiatric disorders are associated with disturbances in structural brain networks. Little is known, however, about brain networks in those at high risk (HR) of bipolar disorder (BD), with such disturbances carrying substantial predictive and etiological value. Whole-brain tractography was performed on diffusion-weighted images acquired from 84 unaffected HR individuals with at least one first-degree relative with BD, 38 young patients with BD and 96 matched controls (CNs) with no family history of mental illness. We studied structural connectivity differences between these groups, with a focus on highly connected hubs and networks involving emotional centres. HR participants showed lower structural connectivity in two lateralised sub-networks centred on bilateral inferior frontal gyri and left insular cortex, as well as increased connectivity in a right lateralised limbic sub-network compared with CN subjects. BD was associated with weaker connectivity in a small right-sided sub-network involving connections between fronto-temporal and temporal areas. Although these sub-networks preferentially involved structural hubs, the integrity of the highly connected structural backbone was preserved in both groups. Weaker structural brain networks involving key emotional centres occur in young people at genetic risk of BD and those with established BD. In contrast to other psychiatric disorders such as schizophrenia, the structural core of the brain remains intact, despite the local involvement of network hubs. These results add to our understanding of the neurobiological correlates of BD and provide predictions for outcomes in young people at high genetic risk for BD.

People with schizophrenia show decreased prefrontal cortex (PFC) activity during emotional response inhibition, a cognitive process sensitive to hormonal influences. Raloxifene, a selective estrogen receptor modulator, binds estrogen receptor alpha (ESR-α), improves memory, attention and normalizes cortical and hippocampal activity during learning and emotional face recognition in schizophrenia. Here, we tested the extent to which raloxifene restores neuronal activity during emotional response inhibition in schizophrenia. Since genetic variation in estrogen receptor alpha (ESR-1) determines cortical ESR-α production and correlates with cognition, we also predicted that genetic ESR-1 variation would differentially relate to increased cortical activity by raloxifene administration. Thirty people with schizophrenia participated in a thirteen-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of raloxifene administered at 120mg/day. Effects of raloxifene on brain activation were assessed based on ESR-1 genotype using functional magnetic resonance imaging during emotional word inhibition. Raloxifene increased PFC activity during inhibition of response to negative words and the raloxifene related increased PFC activity was greater in patients homozygous for ESR-1 rs9340799 AA relative to G carriers. Comparison to 23 healthy controls demonstrated that PFC activity of people with schizophrenia receiving raloxifene was more similar to controls than to their own brain activity during placebo. Estrogen receptor modulation by raloxifene restores PFC activity during emotional response inhibition in schizophrenia and ESR-1 genotype predicts degree of increased neural activity in response to raloxifene. While these preliminary results require replication, they suggest the potential for personalized pharmacotherapy using ESR-1 and estrogen receptor targeting compounds in schizophrenia.

Task-switching performance relies on a broadly distributed frontoparietal network and declines in older adults. In this study, they investigated whether this age-related decline in task switching performance was mediated by variability in global or regional white matter microstructural health. Seventy cognitively intact adults (43-87 years) completed a cued-trials task switching paradigm. Microstructural white matter measures were derived using diffusion tensor imaging (DTI) analyses on the diffusion-weighted imaging (DWI) sequence. Task switching performance decreased with increasing age and radial diffusivity (RaD), a measure of white matter microstructure that is sensitive to myelin structure. RaD mediated the relationship between age and task switching performance. However, the relationship between RaD and task switching performance remained significant when controlling for age and was stronger in the presence of cardiovascular risk factors. Variability in error and RT mixing cost were associated with RaD in global white matter and in frontoparietal white matter tracts, respectively. These findings suggest that age-related increase in mixing cost may result from both global and tract-specific disruption of cerebral white matter linked to the increased incidence of cardiovascular risks in older adults. Hum Brain Mapp 38:1588-1603, 2017. © 2016 Wiley Periodicals, Inc.

Individuals with schizophrenia who are homozygous at the c.267C>A single nucleotide polymorphism (rs2067477) within the cholinergic muscarinic M1 receptor gene have been reported to perform less well on the Wisconsin Card Sorting Test and demonstrate reduced grey matter volume in the right precentral gyrus. We investigated if rs2067477 genotype variation influenced cortical thickness and cortical surface area in a sample of 176 schizophrenia/schizoaffective disorder patients using FreeSurfer. We were unable to detect any significant changes to either surface-based measure of brain structure across genotype. Future studies should expand the focus and include SNPs that are in linkage disequilibrium with rs2067477.

WOS: 000485217300010, PubMed ID: 31443932, BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects. METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects. RESULTS: FDRs-BD had significantly larger ICV (d = +10.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects. CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct., Research Council of NorwayResearch Council of Norway [223273]; National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 MH117601, R01 MH116147, R01 MH111671, P41 EB015922, 5T32MH073526, U54EB020403, R03 MH105808]; National Institute on Aging (NIA)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [T32AG058507]; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [103703, 106469, 341717]; National Centre for Mental Health; 2010 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award [17319]; Dokuz Eylul University Department of Scientific Research Projects FundingDokuz Eylul University [2012.KB.SAG.062]; National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London; Ege University School of Medicine Research Foundation [2009-D-00017]; Medical Research CouncilMedical Research Council UK (MRC) [G0901310]; Geestkracht program of the Netherlands Organisation for Health Research and Development [10-000-1002]; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH 085667]; Nova Scotia Health Research Foundation; Dalhousie Clinical Research Scholarship; 2007 Brain and Behavior Research Foundation Young Investigator Award; Ministry of Health of the Czech RepublicMinistry of Health, Czech Republic [NR8786, NT13891]; Swedish Research CouncilSwedish Research Council [K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3]; Stockholm County CouncilStockholm County Council; Karolinska InstitutetKarolinska Institutet; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; HUBIN project; Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III [PI070066, PI1100683, PI1500467]; Fundacio Marato TV3 [091630]; ERDF Funds from the European Commission A Way of Making Europe"); Brain and Behaviour Research Foundation (NARSAD Young Investigator Award); Alicia Koplowitz Foundation; Stanley Medical Research Institute; NARSADNARSAD [20244]; Wellcome TrustWellcome Trust [064971, 085475/B/08/Z, 085475/Z/08/Z]; NARSAD Young Investigator AwardNARSAD; European CommunityEuropean Community (EC); NIMH Intramural Research ProgramUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH); NIHR Biomedical Research Centre at University College London Hospital; British Medical Association Margaret Temple Fellowship 2016; German Federal Ministry for Education and ResearchFederal Ministry of Education & Research (BMBF) [O1ZX1314B, O1ZX1314G]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [1617]; NIMHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH116147, R01 MH113619]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [U01 MH097435, R01 MH084803, R01 EB020062, R01 MH080912, R01 MH052857]; National Science FoundationNational Science Foundation (NSF) [1636893, 1734853]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [510135, 1037196, 1063960, 1066177]; ZonMwNetherlands Organization for Health Research and Development [908-02-123]; VIDINetherlands Organization for Scientific Research (NWO) [452-11-014, 917-46-370]; Janssen PharmaceuticaJohnson & Johnson USAJanssen Biotech Inc; Otsuka PharmaceuticalOtsuka Pharmaceutical; Bipolar Disorder Research Network, The researchers and studies included in this article were supported by the Research Council of Norway (Grant No. 223273), National Institutes of Health (NIH) (Grant No. R01 MH117601 [to NJ], Grant Nos. R01 MH116147, R01 MH111671, and P41 EB015922 [to PMT], Grant Nos. 5T32MH073526 and U54EB020403 [to CRKC], and Grant No. R03 MH105808 [to CEB and SCF]) and National Institute on Aging (NIA) (Grant No. T32AG058507 [to CRKC]).; C-SFS: This work was supported by Canadian Institutes of Health Research.; Cardiff: This work was supported by the National Centre for Mental Health, Bipolar Disorder Research Network, 2010 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (Grant No. 17319).; DEU: This work was supported by Dokuz Eylul University Department of Scientific Research Projects Funding (Grant No. 2012. KB. SAG. 062). This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or Department of Health.; EGEU: This work was supported by the Ege University School of Medicine Research Foundation (Grant No. 2009-D-00017).; EHRS: The Edinburgh High Risk Study was supported by the Medical Research Council.; GROUP: The infrastructure for the GROUP study was supported by the Geestkracht program of the Netherlands Organisation for Health Research and Development (Grant No. 10-000-1002).; ENBD_UT/BPO_FLB: This work was supported by the National Institute of Mental Health (Grant No. R01 MH 085667).; HHR/PHHR: This work was supported by the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 341717), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship (to TH), 2007 Brain and Behavior Research Foundation Young Investigator Award (to TH), and Ministry of Health of the Czech Republic (Grant Nos. NR8786 and NT13891).; HUBIN: This work was supported by the Swedish Research Council (Grant Nos. K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3), regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Knut and Alice Wallenberg Foundation, and HUBIN project.; IDIBAPS: This work was supported by the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI070066, PI1100683, and PI1500467) and Fundacio Marato TV3 (Grant No. 091630), co-financed by ERDF Funds from the European Commission A Way of Making Europe"), Brain and Behaviour Research Foundation (NARSAD Young Investigator Award), and Alicia Koplowitz Foundation.; IoP-BD: The Maudsley Bipolar Twin Study was supported by the Stanley Medical Research Institute and NARSAD.; IoP-SZ: This work was supported by a Wellcome Trust Research Training Fellowship (Grant No. 064971 to MMP), NARSAD Young Investigator Award (to TT), and European Community's Sixth Framework Programme through a Marie Curie Training Network called the European Twin Study Network on Schizophrenia.; Lieber Institute for Brain Development (LIBD): This work was supported by the NIMH Intramural Research Program (to DRW's laboratory). LIBD is a nonprofit research institute located in Baltimore, MD. The work performed at LIBD was performed in accordance with an NIMH material transfer agreement with LIBD.; MFS: The Maudsley Family Study cohort collection was supported by the Wellcome Trust (Grant Nos. 085475/B/08/Z and 085475/Z/08/Z), NIHR Biomedical Research Centre at University College London Hospital, Medical Research Council (Grant No. G0901310), and British Medical Association Margaret Temple Fellowship 2016.; MooDS: This work was supported by the German Federal Ministry for Education and Research grants NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) and Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e: Med program (Grant Nos. O1ZX1314B and O1ZX1314G) and Deutsche Forschungsgemeinschaft (Grant No. 1617 [to AH]).; MSSM: This work was supported by NIMH (Grant Nos. R01 MH116147 and R01 MH113619).; NU: This work was supported by NIH (Grant Nos. U01 MH097435, R01 MH084803, and R01 EB020062) and National Science Foundation (Grant Nos. 1636893 and 1734853).; OLIN: This work was supported by NIH (Grant No. R01 MH080912).; STAR: This work was supported by NIH (Grant No. R01 MH052857).; SydneyBipolarGroup: The Australian cohort collection was supported by the Australian National Health and Medical Research Council Program Grants (Grant No. 510135 [to PBM] and Grant No. 1037196 [to PBM and PRS]) and Project Grants (Grant No. 1063960 [to JMF and PRS] and Grant No. 1066177 [to JMF]).; UMCU: This work was supported by NARSAD (Grant No. 20244 [to MHJH]), ZonMw (Grant No. 908-02-123 [to HEHP]), VIDI (Grant No. 452-11-014 [to NEMvH] and Grant No. 917-46-370 [to HEHP]), and Stanley Medical Research Institute.; CliNG: We thank Anna Fanelli, Kathrin Jakob, and Maria Keil for help with data acquisition.; All authors have contributed to and approved the contents of this manuscript.; GS has received research and travel support from Janssen Pharmaceutica and Otsuka Pharmaceutical and honoraria from Adamed Pharma. NY has been an investigator in clinical studies conducted together with Janssen-Cilag, Corcept Therapeutics, and COMPASS Pathways in the last 3 years. AM-L has received consultant fees from Boehringer Ingelheim, BrainsWay, Elsevier, Lundbeck International Neuroscience Foundation, and Science Advances. CRKC has received partial research support from Biogen, Inc. (Boston, MA) for work unrelated to the topic of this manuscript. The remaining authors report no biomedical financial interests or potential conflicts of interest.

Background Internationally, from 12.2–23.4% of youth (aged 16–24 years) are not in employment, education or training (NEET). These disengaged youth are more likely to experience social exclusion, increased psychological distress and poor quality of life. Youth at risk of disengagement are less likely to access traditional support services, requiring development of innovative interventions. Methods The trial is a single blind, three arm, randomised controlled trial evaluating the effectiveness of a telephone delivered psychological intervention for disengaged youth (12–25 years). Participants will be randomised to receive either (i) SWEL, (ii) Befriending, or (iii) Single Session Psycho-Education. Therapy will be over an 8 week period with a minimum of four and maximum of eight sessions for the SWEL or Befriending conditions, or a single session for the Psycho-Education condition. Outcomes will be assessed at baseline and at 2, 8 and 14-month follow-up with the primary outcome being re-engagement in education, training or employment. Discussion This large, multi-site, randomised controlled trial will inform the delivery of services for young people at risk of disengaging from education or training. The provision of psychological therapy by telephone increases access by youth – especially those in rural and remote areas - both to the trial and the treatment, if adopted by services. The outcomes of this trial could have meaningful societal impact for a vulnerable population. It is expected that recruitment, intervention and retention will present challenges for the trial given the focus on disengaged youth. Trial registration ANZCTR, ACTRN12614001212640, Registered 18 Nov 2014. Retrospectively registered. Ethics and dissemination Ethics approval has been obtained from the participating institutions. Results of the trial will be submitted for publication in peer reviewed journals and findings presented at scientific conferences and to key service providers and policy makers.

Childhood adversity, such as physical, sexual, and verbal abuse, as well as neglect and family conflict, is a risk factor for schizophrenia. Such adversity can lead to disruptions of cognitive function during development, undermining intellectual capabilities and academic achievement. Schizophrenia is a neurodevelopmental disorder that is associated with cognitive impairments that may become evident during childhood. The Australian Schizophrenia Research Bank database comprises a large community cohort (N = 1169) in which we previously identified 3 distinct cognitive groups among people with schizophrenia: (1) Compromised, current, and estimated premorbid cognitive impairment; (2) Deteriorated, substantial decline from estimated premorbid function; and (3) Preserved, performing in the normal cognitive range without decline. The compromised group displayed the worst functional and symptom outcomes. Here, we extend our previous work by assessing the relationship among these categories of cognitive abilities and reported childhood adversity in 836 patients and healthy controls. Exploratory factor analysis of the Childhood Adversity Questionnaire revealed 3 factors (lack of parental involvement; overt abuse; family breakdown and hardship). People with schizophrenia reported significantly more childhood adversity than healthy controls on all items and factors. People with schizophrenia in the compromised group reported significantly more lack of parental involvement and family breakdown and hardship and lower socioeconomic status than those in the deteriorated group. The cognitive groups were not related to family history of psychosis. These findings identify specific social and family factors that impact cognition, highlighting the important role of these factors in the development of cognitive and functional abilities in schizophrenia.

Fathers are consistently underrepresented in parenting interventions and practitioners are an important target for change in interventions to enhance father engagement. This research examined the effects of two practitioner training programs in improving practitioner rated competencies and organizational father-inclusive practices. Two studies were conducted, each with a single group, repeated measures (pre, post and 2-month follow-up) design. Study 1 (N = 233) examined the outcomes of face-to-face training in improving practitioner ratings of competencies in engaging fathers, perceived effectiveness and use of father engagement strategies, organizational practices and rates of father engagement. Study 2 (N = 356) examined online training using the same outcome measures. Practitioners in both training formats improved in their competencies, organizational practices and rates of father engagement over time, yet those in the online format deteriorated in three competencies from post-training to follow-up. The implications for delivering practitioner training programs to enhance competencies and rates of father engagement are discussed.

Positive parenting programs have a strong evidence base for improving parent-child relationships, strengthening families, and reducing childhood behavior disturbances. Their reach is less than optimal however, with only a minority of families in need of help participating. Father involvement is particularly low. Online, self-directed programs have the potential to improve participation rates. This article examines risk factors for dropout/attrition from a free, evidence-based, self-directed, father-inclusive parenting program, Parentworks, which was made available across Australia. Parents (N = 2,967) enrolled in the program and completed preintervention questionnaires. There was a steady and consistent loss of participants through the sequence of core program modules, until a final sample of 218 completed the postintervention questionnaire. A range of demographic and parent and child variables were tested as predictors of 3 subgroups: nonstarters, partial completers, and full completers. Nonstarters (n = 1,625) tended to have older children with fewer behavioral problems and report higher psychopathology and dysfunctional parenting than those who partially (n = 1,124) or fully completed. Contrary to findings from face-to-face research, single parents had the highest completion rates. Coparticipation of partners and interparental conflict had no impact on completion rates. Fathers participated at relatively high levels. Results show that parents with the greatest need tend to engage with online programs, and online programs may be particularly useful for fathers, single parents, and those in conflicted relationships. Directions for future program design and research are discussed.

Objective: Disruptive mood dysregulation disorder is a newly proposed childhood disorder included in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition to describe children ⩽18 years of age with chronic irritability/temper outbursts. This study aimed to examine the prevalence of disruptive mood dysregulation disorder, severe mood dysregulation and chronic irritability in an Australian study of young people at increased familial risk of developing bipolar disorder (‘HR’ group) and controls (‘CON’ group). Methods: A total of 242 12- to 30-year-old HR or CON subjects were administered the severe mood dysregulation module. Of these, 42 were aged ⩽18 years at the time of assessment, with 29 subjects in the HR group and 13 in the CON group. Results: No subjects ⩽18 years – in either group – fulfilled current or lifetime criteria for disruptive mood dysregulation disorder or severe mood dysregulation, the precursor to disruptive mood dysregulation disorder. Similarly, no subjects in either group endorsed the severe mood dysregulation/disruptive mood dysregulation disorder criteria for irritable mood or marked excessive reactivity. One HR participant endorsed three severe mood dysregulation criteria (distractibility, physical restlessness and intrusiveness), while none of the comparison subjects endorsed any criteria. Exploratory studies of the broader 12- to 30-year-old sample similarly found no subjects with severe mood dysregulation/disruptive mood dysregulation disorder in either the HR or CON group and no increased rates of chronic irritability, although significantly more HR subjects reported at least one severe mood dysregulation/disruptive mood dysregulation disorder criterion (likelihood ratio = 6.17; p = 0.013); most of the reported criteria were severe mood dysregulation ‘chronic hyper-arousal’ symptoms. Conclusion: This study comprises one of the few non-US reports on the prevalence of disruptive mood dysregulation disorder and severe mood dysregulation and is the first non-US study of the prevalence of these conditions in a high-risk bipolar disorder sample. The failure to replicate the finding of higher rates of disruptive mood dysregulation disorder and chronic irritability in high-risk offspring suggests that these are not robust precursors of bipolar disorder.

Schizophrenia may be conceptualised using a dimensional approach to examine trait-like expression such as schizotypy within non-clinical populations to better understand pathophysiology. A candidate psychosis-risk marker, the auditory mismatch negativity (MMN) is thought to index the functionality of glutamatergic NMDA receptor mediated neurotransmission. Although the MMN is robustly reduced in patients with schizophrenia, the association between MMN and schizotypy in the general population is under-investigated. Thirty-five healthy participants completed the Schizotypal Personality Questionnaire (SPQ) and a multi-feature MMN paradigm (standards 82%, 50ms, 1000Hz, 80dB) with duration (100ms), frequency (1200Hz) and intensity (90dB) deviants (6% each). Spearman's correlations were used to explore the association between schizotypal personality traits and MMN amplitude. Few associations were identified between schizotypal traits and MMN. Higher Suspiciousness subscale scores tended to be correlated with larger frequency MMN amplitude. A median-split comparison of the sample on Suspiciousness scores showed larger MMN (irrespective of deviant condition) in the High compared to the Low Suspiciousness group. The trend-level association between MMN and Suspiciousness is in contrast to the robustly attenuated MMN amplitude observed in schizophrenia. Reductions in MMN may reflect a schizophrenia-disease state, whereas non-clinical schizotypy may not be subserved by similar neuropathology.

BackgroundWhite matter (WM) impairments have been reported in patients with bipolar disorder (BD) and those at high familial risk of developing BD. However, the distribution of these impairments has not been well characterized. Few studies have examined WM integrity in young people early in the course of illness and in individuals at familial risk who have not yet passed the peak age of onset.MethodWM integrity was examined in 63 BD subjects, 150 high-risk (HR) individuals and 111 participants with no family history of mental illness (CON). All subjects were aged 12 to 30 years.ResultsThis young BD group had significantly lower fractional anisotropy within the genu of the corpus callosum (CC) compared with the CON and HR groups. Moreover, the abnormality in the genu of the CC was also present in HR participants with recurrent major depressive disorder (MDD) (n = 16) compared with CON participants.ConclusionsOur findings provide important validation of interhemispheric abnormalities in BD patients. The novel finding in HR subjects with recurrent MDD – a group at particular risk of future hypo/manic episodes – suggests that this may potentially represent a trait marker for BD, though this will need to be confirmed in longitudinal follow-up studies.

BackgroundImpairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives.MethodNeurocognitive and social cognitive ability was examined in 99 young people (age range 16–30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD.ResultsOnly verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs.ConclusionsSelective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD.

Brain-Derived Neurotrophic Factor (BDNF) acts as a critical regulator of synaptogenesis and synaptic plasticity. Sex differences have been demonstrated in many aspects of schizophrenia. This study tested for sex-specific differences in peripheral BDNF levels in people with schizophrenia and healthy controls. We measured circulating plasma BDNF levels in 95 people with schizophrenia and 80 healthy controls. Plasma BDNF levels were significantly elevated in females with schizophrenia compared to males with schizophrenia and to female healthy controls. These results suggest that sex differences in peripheral BDNF levels may contribute to other sex related differences in schizophrenia.

Significant heterogeneity across aetiologies, neurobiology and clinical phenotypes have been observed in individuals with autism spectrum disorder (ASD). Neuroimaging-based neuroanatomical studies of ASD have often reported inconsistent findings which may, in part, be attributable to an insufficient understanding of the relationship between factors influencing clinical heterogeneity and their relationship to brain anatomy. To this end, we performed a large-scale examination of cortical morphometry in ASD, with a specific focus on the impact of three potential sources of heterogeneity: sex, age and full-scale intelligence (FIQ). To examine these potentially subtle relationships, we amassed a large multi-site dataset that was carefully quality controlled (yielding a final sample of 1327 from the initial dataset of 3145 magnetic resonance images; 491 individuals with ASD). Using a meta-analytic technique to account for inter-site differences, we identified greater cortical thickness in individuals with ASD relative to controls, in regions previously implicated in ASD, including the superior temporal gyrus and inferior frontal sulcus. Greater cortical thickness was observed in sex specific regions; further, cortical thickness differences were observed to be greater in younger individuals and in those with lower FIQ, and to be related to overall clinical severity. This work serves as an important step towards parsing factors that influence neuroanatomical heterogeneity in ASD and is a potential step towards establishing individual-specific biomarkers.

Brain white matter abnormalities are evident in individuals with schizophrenia, and also their first-degree relatives, suggesting that some alterations may relate to underlying genetic risk. The ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 2 (ST8SIA2) gene, which encodes the alpha-2,8-sialyltransferase 8B enzyme that aids neuronal migration and synaptic plasticity, was previously implicated as a schizophrenia susceptibility gene. This study examined the extent to which specific haplotypes in ST8SIA2 influence white matter microstructure using diffusion-weighted imaging of individuals with schizophrenia (n = 281) and healthy controls (n = 172), recruited across five Australian sites. Interactions between diagnostic status and the number of haplotype copies (0 or ≥1) were tested across all white matter voxels with cluster-based statistics. Fractional anisotropy (FA) in the right parietal lobe was found to show a significant interaction between diagnosis and ST8SIA2 protective haplotype (p ST8SIA2 risk haplotype copy number did not show any differential effects on white matter. This study provides a link between a common disease-associated haplotype and specific changes in white matter microstructure, which may relate to resilience or risk for mental illness, providing further compelling evidence for involvement of ST8SIA2 in the pathophysiology of schizophrenia.

The emotional and cognitive vulnerabilities that precede the development of bipolar disorder are poorly understood. The inferior frontal gyrus-a key cortical hub for the integration of cognitive and emotional processes-exhibits both structural and functional changes in bipolar disorder, and is also functionally impaired in unaffected first-degree relatives, showing diminished engagement during inhibition of threat-related emotional stimuli. We hypothesized that this functional impairment of the inferior frontal gyrus in those at genetic risk of bipolar disorder reflects the dysfunction of broader network dynamics underlying the coordination of emotion perception and cognitive control. To test this, we studied effective connectivity in functional magnetic resonance imaging data acquired from 41 first-degree relatives of patients with bipolar disorder, 45 matched healthy controls and 55 participants with established bipolar disorder. Dynamic causal modelling was used to model the neuronal interaction between key regions associated with fear perception (the anterior cingulate), inhibition (the left dorsolateral prefrontal cortex) and the region upon which these influences converge, namely the inferior frontal gyrus. Network models that embodied non-linear, hierarchical relationships were the most strongly supported by data from our healthy control and bipolar participants. We observed a marked difference in the hierarchical influence of the anterior cingulate on the effective connectivity from the dorsolateral prefrontal cortex to the inferior frontal gyrus that is unique to the at-risk cohort. Non-specific, non-hierarchical mechanisms appear to compensate for this network disturbance. We thus establish a specific network disturbance suggesting dysfunction in the processes that support hierarchical relationships between emotion and cognitive control in those at high genetic risk for bipolar disorder.

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.

Despite a growing number of reports, there is still limited knowledge of the clinical features that precede the onset of bipolar disorder (BD). To explore this, we investigated baseline data from a prospectively evaluated longitudinal cohort of subjects aged 12-30 years to compare: first, lifetime rates of clinical features between a) subjects at increased genetic risk for developing BD ('AR'), b) participants from families without mental illness ('controls'), and c) those with established BD; and, second, prior clinical features that predict the later onset of affective disorders in these same three groups. This is the first study to report such comparisons between these three groups (though certainly not the first to compare AR and control samples). 118 AR participants with a parent or sibling with BD (including 102 with a BD parent), 110 controls, and 44 BD subjects were assessed using semi-structured interviews. AR subjects had significantly increased lifetime risks for depressive, anxiety and behavioural disorders compared to controls. Unlike prior reports, preceding anxiety and behavioural disorders were not found to increase risk for later onset of affective disorders in the AR sample, perhaps due to limited sample size. However, preceding behavioural disorders did predict later onset of affective disorders in the BD sample. The findings that i) AR subjects had higher rates of depressive, anxiety and behavioural disorders compared to controls, and ii) prior behavioural disorders increased the risk to later development of affective disorders in the BD group, suggest the possibility of therapeutic targeting for these disorders in those at high genetic risk for BD.

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.

Parenting interventions that focus on enhancing the quality and consistency of parenting are effective for preventing and reducing externalising problems in children. There has been a recent shift towards online delivery of parenting interventions in order to increase their reach and impact on the population prevalence of child externalising problems. Parenting interventions have low rates of father participation yet research suggests that father involvement may be critical to the success of the intervention. Despite this, no online parenting interventions have been specifically developed to meet the needs and preferences of fathers, as well as mothers. This paper describes the protocol of a study examining the effectiveness of an online, father-inclusive parenting intervention called ‘ParentWorks’, which will be delivered as a universal intervention to Australian families. A single group clinical trial will be conducted to examine the effectiveness of ParentWorks for reducing child externalising problems and improving parenting, as well as to explore the impact of father engagement (in two-parent families) on child outcomes. Australian parents/caregivers with a child aged 2–16 years will be recruited. Participants will provide informed consent, complete pre-intervention measures and will then complete the intervention, which consists of five compulsory video modules and three optional modules. The primary outcomes for this study are changes in child externalising behaviour, positive and dysfunctional parenting practices and parental conflict, and the secondary outcome is changes in parental mental health. Demographic information, satisfaction with the intervention, and measures of parental engagement will also be collected. Questionnaire data will be collected at pre-intervention, post-intervention and three-month follow-up, as well as throughout the program. This paper describes the study protocol of a single group clinical trial of a national, online, father-inclusive parenting intervention. The results from this study could be used to inform public policy about providing support to parents of children with behaviour problems, and enhancing the engagement of fathers in parenting interventions. ACTRN12616001223426 , registered 05/09/2016

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.

Background Early childhood interventions can have both immediate and long-term positive effects on cognitive, behavioural, health and education outcomes. Fathers are underrepresented in interventions focusing on the well-being of children. However, father participation may be critical for intervention effectiveness, especially for parenting interventions for child externalising problems. To date, there has been very little research conducted to understand the low rates of father participation and to facilitate the development of interventions to meet the needs of fathers. This study examined fathers’ experiences of, and preferences for, parenting interventions as well as perceptions of barriers to participation. It also examined how these factors were associated with child externalising behaviour problems, and explored the predictors of participation in parenting interventions. Methods A community sample of 1001 fathers of children aged 2–16 years completed an online survey about experiences with parenting interventions, perceived barriers to participation, the importance of different factors in their decision to attend, and preferred content and delivery methods. They also completed ratings of their child’s behaviour using the Strengths and Difficulties Questionnaire. Results Overall, 15% of fathers had participated in a parenting intervention or treatment for child behaviour, with significantly higher rates of participation for fathers of children with high versus low levels of externalising problems. Fathers rated understanding what is involved in the program and knowing that the facilitator is trained as the two most important factors in their decision to participate. There were several barriers to participation that fathers of children with high-level externalising problems were more likely to endorse, across practical barriers and help-seeking attitudes, compared to fathers of children with low-level externalising problems. Almost two-thirds of fathers of children with high-level externalising behaviour had not participated in a parenting intervention or treatment. The only significant predictors of intervention participation were severity of child externalising behaviour problems and child age. Conclusions The findings have important implications for services seeking to increase father engagement and highlight a number of strategies to enhance the promotion and delivery of parenting interventions to fathers. These strategies include more public health messaging about parenting programs and the importance of father participation.

Parenting programmes are one of the best researched and most effective interventions for reducing child mental health problems. The success of such programmes, however, is largely dependent on their reach and parental engagement. Rates of parental enrolment and attendance are highly variable, and in many cases very low; this is especially true of father involvement in parenting programmes. This paper proposes a conceptual model of parental engagement in parenting programmes-the CAPE model (Connect, Attend, Participate, Enact) that builds on recent models by elaborating on the interdependent stages of engagement, and its interparental or systemic context. That is, we argue that a comprehensive model of parental engagement will best entail a process from connection to enactment of learned strategies in the child's environment, and involve consideration of individual parents (both mothers and fathers) as well as the dynamics of the parenting team. The model provides a framework for considering parent engagement as well as associated facilitators and mechanisms of parenting change such as parenting skills, self-efficacy, attributions, and the implementation context. Empirical investigation of the CAPE model could be used to further our understanding of parental engagement, its importance for programme outcomes, and mechanisms of change. This will guide future intervention refinement and developments as well as change in clinical practice.

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.

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.

Background Functional brain imaging of young people at increased genetic risk for bipolar disorder provides a means of identifying potential endophenotypes for this condition. Dysfunctional neural mechanisms for the cognitive control of emotion are implicated in the genetic predisposition to bipolar disorder, with aberrant activity in frontocortical, striatal, and limbic brain regions previously reported in subjects with established bipolar disorder during inhibitory and emotion processing tasks. Methods Functional brain activity during inhibition of emotional material in young people at increased genetic risk for bipolar disorder was investigated using a facial-emotion go/no-go task during functional magnetic resonance imaging. Data from 47 genetically high-risk individuals aged 18 to 30 years with at least one first-degree relative with bipolar disorder were compared with 49 control subjects (within the same age range but without a family history of bipolar disorder or other severe mental illness). Results Whole-brain corrected analyses revealed a highly specific and significant lack of recruitment of the inferior frontal gyrus when inhibiting responses to fearful faces in the high-risk participants compared with control subjects ( p = .011, family-wise error, peak voxel). Conclusions Impaired inhibitory function of the inferior frontal cortex may represent a trait marker of vulnerability to bipolar disorder. That this finding was revealed during inhibition of emotional material further implicates dysregulated frontolimbic brain networks as a potential neurocognitive endophenotype for bipolar disorder and provides evidence for pre-existing functional disturbances in those at high genetic risk for bipolar disorder.

BackgroundFronto-limbic structural brain abnormalities have been reported in patients with bipolar disorder (BD), but findings in individuals at increased genetic risk of developing BD have been inconsistent. We conducted a study in adolescents and young adults (12–30 years) comparing measures of fronto-limbic cortical and subcortical brain structure between individuals at increased familial risk of BD (at risk; AR), subjects with BD and controls (CON). We separately examined cortical volume, thickness and surface area as these have distinct neurodevelopmental origins and thus may reflect differential effects of genetic risk.MethodWe compared fronto-limbic measures of grey and white matter volume, cortical thickness and surface area in 72 unaffected-risk individuals with at least one first-degree relative with bipolar disorder (AR), 38 BD subjects and 72 participants with no family history of mental illness (CON).ResultsThe AR group had significantly reduced cortical thickness in the left pars orbitalis of the inferior frontal gyrus (IFG) compared with the CON group, and significantly increased left parahippocampal gyral volume compared with those with BD.ConclusionsThe finding of reduced cortical thickness of the left pars orbitalis in AR subjects is consistent with other evidence supporting the IFG as a key region associated with genetic liability for BD. The greater volume of the left parahippocampal gyrus in those at high risk is in line with some prior reports of regional increases in grey matter volume in at-risk subjects. Assessing multiple complementary morphometric measures may assist in the better understanding of abnormal developmental processes in BD.

We explored regional and total volumetric cerebellar differences in probands and their unaffected full siblings relative to typically developing participants. Participants included 94 (51 males) patients diagnosed with childhood onset schizophrenia (COS), 80 related non-psychotic siblings (37 males) and 110 (64 males) typically developing participants scanned longitudinally. The sample mean age was 16.87(S.D.=4.7; range 6.5 to 29). We performed mixed model regressions to examine group differences in trajectory and volume. The COS group had smaller bilateral anterior lobes and anterior and total vermis volumes than controls. The COS group diverged from controls over time in total, left, right, and bilateral posterior inferior cerebellum. Siblings did not have any fixed volumetric differences relative to controls but differed from controls in developmental trajectories of total and right cerebellum, left inferior posterior, left superior posterior, and superior vermis. Results are consistent with previous COS findings and several reports of decreased cerebellar volume in adult onset schizophrenia. Sibling trajectories may represent a trait marker, although the effect size for volumetric differences in early adulthood may be small.

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.

Deficits in executive function (EF) are reported to occur in individuals with Klinefelter syndrome (XXY). The degree of impairment, if any, is variable and the nature of these deficits has not been clearly elucidated in young males. In this report, we (a) examine EF skills using multiple tasks in a non-clinic referred group of youth with XXY, (b) describe the extent of EF weaknesses in XXY when this group is compared with typical males of a similar SES or typical males with similar verbal abilities, and (c) evaluate the contribution of comorbid attention-deficit/hyperactivity disorder (ADHD) to EF skills. The sample included 27 males with XXY (ages 9–25), 27 typically developing age- and vocabulary-matched males, and 22 age- and socioeconomic status-matched males. EF tasks included Verbal Fluency, the Trail Making Test, and the CANTAB Spatial Working Memory and Stockings of Cambridge tasks. Mixed model analysis of variance was used to compare the groups on EF tasks and revealed a main effect of group but no group by task interaction. Overall, the XXY group performed less well than both control groups, but performance did not differ significantly as a function of task. ADHD comorbidity in males with XXY was related to poorer EF skills. (JINS, 2011, 17, 522–530)

Twin studies indicate that both intelligence and brain structure are moderately to highly heritable. Recent bivariate studies of adult twins also suggest that intelligence and brain morphometry are influenced by shared genetic factors. The current study examines shared genetic and environmental factors between brain morphometry and intelligence in a sample of children and adolescents (twins, twin siblings, and singletons; n = 649, ages 4–19). To extend previous studies, brain morphometric data were parsed into subregions (lobar gray/white matter volumes, caudate nucleus, lateral ventricles) and intelligence into verbal and nonverbal skills (Wechsler Vocabulary and Block Design subtests). Phenotypic relationships between brain volumes and intelligence were small. Verbal skills shared unique environmental effects with gray matter volumes while nonverbal skills shared genetic effects with both global and regional gray and white matter. These results suggest that distinct mechanisms contribute to the small phenotypic relationships between brain volumes and verbal versus nonverbal intelligence.

In addition to its well established role in balance, coordination, and other motor skills, the cerebellum is increasingly recognized as a prominent contributor to a wide array of cognitive and emotional functions. Many of these capacities undergo dramatic changes during childhood and adolescence. However, accurate characterization of co-occurring anatomical changes has been hindered by lack of longitudinal data and methodologic challenges in quantifying subdivisions of the cerebellum. In this study we apply an innovative image analysis technique to quantify total cerebellar volume and 11 subdivisions (i.e. anterior, superior posterior, and inferior posterior lobes, corpus medullare, and three vermal regions) from anatomic brain MRI scans from 25 healthy females and 25 healthy males aged 5–24 years, each of whom was scanned at least three times at approximately two year intervals. Total cerebellum volume followed an inverted U shaped developmental trajectory peaking at age 11.8 years in females and 15.6 years in males. Cerebellar volume was 10% to 13% larger in males depending on the age of comparison and the sexual dimorphism remained significant after covarying for total brain volume. Subdivisions of the cerebellum had distinctive developmental trajectories with more phylogenetically recent regions maturing particularly late. The cerebellum's unique protracted developmental trajectories, sexual dimorphism, preferential vulnerability to environmental influences, and frequent implication in childhood onset disorders such as autism and ADHD make it a prime target for pediatric neuroimaging investigations.