The 2015 Middle Childhood Survey (MCS) of mental health and well-being at age 11 years in an Australian population cohort

Purpose: The Middle Childhood Survey (MCS) was designed as a computerised self-report assessment of children's mental health and well-being at approximately 11 years of age, conducted with a population cohort of 87 026 children being studied longitudinally within the New South Wales (NSW) Child Development Study. Participants: School Principals provided written consent for teachers to administer the MCS in class to year 6 students at 829 NSW schools (35.0% of eligible schools). Parent or child opt-outs from participation were received for 4.3% of children, and MCS data obtained from 27 808 children (mean age 11.5 years, SD 0.5; 49.5% female), representing 85.9% of students at participating schools. Findings to date: Demographic characteristics of participating schools and children are representative of the NSW population. Children completed items measuring Social Integration, Prosocial Behaviour, Peer Relationship Problems, Supportive Relationships (at Home, School and in the Community), Empathy, Emotional Symptoms, Conduct Problems, Aggression, Attention, Inhibitory Control, Hyperactivity-Inattention, Total Difficulties (internalising and externalising psychopathology), Perceptual Sensitivity, Psychotic-Like Experiences, Personality, Self-esteem, Daytime Sleepiness and Connection to Nature. Distributions of responses on each item and construct demarcate competencies and vulnerabilities within the population: most children report mental health and well-being, but the population distribution spanned the full range of possible scores on every construct. Future plans: Multiagency, intergenerational linkage of the MCS data with health, education, child protection, justice and early childhood development records took place late in 2016. Linked data were used to elucidate patterns of risk and protection across early and middle child development, and these data will provide a foundation for future record linkages in the cohort that will track mental and physical health, social and educational/occupational outcomes into adolescence and early adulthood.Kristin R Laurens, Stacy Tzoumakis, Kimberlie Dean, Sally A Brinkman, Miles Bore, Rhoshel K Lenroot, Maxwell Smith, Allyson Holbrook, Kim M Robinson, Robert Stevens, Felicity Harris, Vaughan J Carr, Melissa J Gree

New South Wales Child Development Study (NSW-CDS): an Australian multiagency, multigenerational, longitudinal record linkage study

Purpose: The initial aim of this multiagency, multigenerational record linkage study is to identify childhood profiles of developmental vulnerability and resilience, and to identify the determinants of these profiles. The eventual aim is to identify risk and protective factors for later childhood-onset and adolescent-onset mental health problems, and other adverse social outcomes, using subsequent waves of record linkage. The research will assist in informing the development of public policy and intervention guidelines to help prevent or mitigate adverse long-term health and social outcomes. Participants: The study comprises a population cohort of 87,026 children in the Australian State of New South Wales (NSW). The cohort was defined by entry into the first year of full-time schooling in NSW in 2009, at which time class teachers completed the Australian Early Development Census (AEDC) on each child (with 99.7% coverage in NSW). The AEDC data have been linked to the children's birth, health, school and child protection records for the period from birth to school entry, and to the health and criminal records of their parents, as well as mortality databases. Findings to date: Descriptive data summarising sex, geographic and socioeconomic distributions, and linkage rates for the various administrative databases are presented. Child data are summarised, and the mental health and criminal records data of the children's parents are provided. Future plans: In 2015, at age 11 years, a self-report mental health survey was administered to the cohort in collaboration with government, independent and Catholic primary school sectors. A second record linkage, spanning birth to age 11 years, will be undertaken to link this survey data with the aforementioned administrative databases. This will enable a further identification of putative risk and protective factors for adverse mental health and other outcomes in adolescence, which can then be tested in subsequent record linkages.Vaughan J Carr, Felicity Harris, Alessandra Raudino, Luming Luo, Maina Kariuki, Enwu Liu, Stacy Tzoumakis, Maxwell Smith, Allyson Holbrook, Miles Bore, Sally Brinkman, Rhoshel Lenroot, Katherine Dix, Kimberlie Dean, Kristin R Laurens, Melissa J Gree

Brain antibodies in the cortex and blood of people with schizophrenia and controls

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

Disambiguating ventral striatum fMRI-related bold signal during reward prediction in schizophrenia

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

Change in level of productivity in the treatment of schizophrenia with olanzapine or other antipsychotics

<p>Abstract</p> <p>Background</p> <p>When treating schizophrenia, improving patients' productivity level is a major goal considering schizophrenia is a leading cause of functional disability. Productivity level has been identified as the most preferred treatment outcome by patients with schizophrenia. However, little has been done to systematically investigate productivity levels in schizophrenia. We set out to better understand the change in productivity level among chronically ill patients with schizophrenia treated with olanzapine compared with other antipsychotic medications. We also assessed the links between productivity level and other clinical outcomes.</p> <p>Methods</p> <p>This post hoc analysis used data from 6 randomized, double-blind clinical trials of patients with schizophrenia or schizoaffective disorder, with each trial being of approximately 6 months duration. Change in productivity level was compared between olanzapine-treated patients (HGBG, n = 172; HGHJ, n = 277; HGJB, n = 171; HGLB, n = 281; HGGN, n = 159; HGDH, n = 131) and patients treated with other antipsychotic medications (separately vs. haloperidol [HGGN, n = 97; HGDH, n = 132], risperidone [HGBG, n = 167; HGGN, n = 158], quetiapine [HGJB, n = 175], ziprasidone [HGHJ, n = 271] and aripiprazole [HGLB, n = 285]). Productivity was defined as functional activities/work including working for pay, studying, housekeeping and volunteer work. Productivity level in the prior 3 months was assessed on a 5-point scale ranging from no useful functioning to functional activity/work 75% to 100% of the time.</p> <p>Results</p> <p>Chronically ill patients treated with olanzapine (OLZ) experienced significantly greater improvement in productivity when compared to patients treated with risperidone (RISP) (OLZ = 0.22 ± 1.19, RISP = -0.03 ± 1.17, p = 0.033) or ziprasidone (ZIP) (OLZ = 0.50 ± 1.38, ZIP = 0.25 ± 1.27, p = 0.026), but did not significantly differ from the quetiapine, aripiprazole or haloperidol treatment groups. Among first episode patients, OLZ therapy was associated with greater improvements in productivity levels compared to haloperidol (HAL), during the acute phase (OLZ = -0.31 ± 1.59, HAL = -0.69 ± 1.56, p = 0.011) and over the long-term (OLZ = 0.10 ± 1.50, HAL = -0.32 ± 1.91, p = 0.008). Significantly more chronically ill and first episode patients treated with olanzapine showed moderately high (>50%-75% of the time) and high levels of productivity (>75%-100% of the time) at endpoint, when compared to risperidone or haloperidol-treated patients (p < .05), respectively. Higher productivity level was associated with significantly higher study completion rates and better scores on the positive, negative, disorganized thoughts, hostility and depression subscales of the Positive and Negative Symptom Scale (PANSS).</p> <p>Conclusions</p> <p>Some antipsychotic medications significantly differed in beneficial impact on productivity level in the long-term treatment of patients with schizophrenia. Findings further highlight the link between clinical and functional outcomes, showing significant associations between higher productivity, lower symptom severity and better persistence on therapy.</p> <p>Trial Registration</p> <p>clinicaltrials.gov identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT00088049">NCT00088049</a>; <a href="http://www.clinicaltrials.gov/ct2/show/NCT00036088">NCT00036088</a></p

Genetic variants associated with longitudinal changes in brain structure across the lifespan

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging

Financial difficulties but not other types of recent negative life events show strong interactions with 5-HTTLPR genotype in the development of depressive symptoms

Several studies indicate that 5-HTTLPR mediates the effect of childhood adversity in the development of depression, while results are contradictory for recent negative life events. For childhood adversity the interaction with genotype is strongest for sexual abuse, but not for other types of childhood maltreatment; however, possible interactions with specific recent life events have not been investigated separately. The aim of our study was to investigate the effect of four distinct types of recent life events in the development of depressive symptoms in a large community sample. Interaction between different types of recent life events measured by the List of Threatening Experiences and the 5-HTTLPR genotype on current depression measured by the depression subscale and additional items of the Brief Symptom Inventory was investigated in 2588 subjects in Manchester and Budapest. Only a nominal interaction was found between life events overall and 5-HTTLPR on depression, which failed to survive correction for multiple testing. However, subcategorising life events into four categories showed a robust interaction between financial difficulties and the 5-HTTLPR genotype, and a weaker interaction in the case of illness/injury. No interaction effect for the other two life event categories was present. We investigated a general non-representative sample in a cross-sectional approach. Depressive symptoms and life event evaluations were self-reported. The 5-HTTLPR polymorphism showed a differential interaction pattern with different types of recent life events, with the strongest interaction effects of financial difficulties on depressive symptoms. This specificity of interaction with only particular types of life events may help to explain previous contradictory findings

Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = −0.42, p = 3 × 10−5), with weak evidence of IQ reductions among BD-FDRs (d = −0.23, p =.045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment

Gender Differences in White Matter Microstructure

Sexual dimorphism in human brain structure is well recognised, but little is known about gender differences in white matter microstructure. We used diffusion tensor imaging to explore differences in fractional anisotropy (FA), an index of microstructural integrity.A whole brain analysis of 135 matched subjects (90 men and 45 women) using a 1.5 T scanner. A region of interest (ROI) analysis was used to confirm those results where proximity to CSF raised the possibility of partial-volume artefact.Men had higher fractional anisotropy (FA) in cerebellar white matter and in the left superior longitudinal fasciculus; women had higher FA in the corpus callosum, confirmed by ROI.The size of the differences was substantial--of the same order as that attributed to some pathology--suggesting gender may be a potentially significant confound in unbalanced clinical studies. There are several previous reports of difference in the corpus callosum, though they disagree on the direction of difference; our findings in the cerebellum and the superior longitudinal fasciculus have not previously been noted. The higher FA in women may reflect greater efficiency of a smaller corpus callosum. The relatively increased superior longitudinal fasciculus and cerebellar FA in men may reflect their increased language lateralisation and enhanced motor development, respectively

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

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