Limited attention has been directed toward the influence of non-abusive parenting behaviour on brain structure in adolescents. It has been suggested that environmental influences during this period are likely to impact the way that the brain develops over time. The aim of this study was to investigate the association between aggressive and positive parenting behaviors on brain development from early to late adolescence, and in turn, psychological and academic functioning during late adolescence, using a multi-wave longitudinal design. Three hundred and sixty seven magnetic resonance imaging (MRI) scans were obtained over three time points from 166 adolescents (11-20 years). At the first time point, observed measures of maternal aggressive and positive behaviors were obtained. At the final time point, measures of psychological and academic functioning were obtained. Results indicated that a higher frequency of maternal aggressive behavior was associated with alterations in the development of right superior frontal and lateral parietal cortical thickness, and of nucleus accumbens volume, in males. Development of the superior frontal cortex in males mediated the relationship between maternal aggressive behaviour and measures of late adolescent functioning. We suggest that our results support an association between negative parenting and adolescent functioning, which may be mediated by immature or delayed brain maturation.

Adolescents with anxiety disorders attain poorer outcomes following extinction-based treatment compared to adults. Extinction deficit during adolescence has been identified to involve immaturity in the medial prefrontal cortex (mPFC). Findings from adult rodents suggest extinction involves dopamine signaling in the mPFC. This system changes dramatically during adolescence, but its role in adolescent extinction is unknown. Therefore, we investigated the role of prefrontal dopamine in extinction using Pavlovian fear conditioning in adolescent and adult rats. Using quantitative PCR (qPCR) analyses, we measured changes in dopamine receptor gene expression in the mPFC before and after extinction. We then enhanced dopamine 1 receptor (D1R) or dopamine 2 receptor (D2R) signaling in the infralimbic cortex (IL) of the mPFC using agonists at the time of extinction. Adolescent rats displayed a deficit in extinction retention compared to adults. Extinction induced a reduction in D1R compared to D2R gene expression in adolescent rats, whereas an increase of D1R compared to D2R gene expression was observed in adult rats. Acutely enhancing IL D1R signaling using SKF-81297 had no effect on extinction at either age. In contrast, acutely enhancing IL D2R signaling with quinpirole significantly enhanced long-term extinction in adolescents, and impaired within-session extinction in adults. Our results suggest a dissociated role for prefrontal dopamine in fear extinction during adolescence compared to adulthood. Findings highlight the dopamine system as a potential pharmacological target to improve extinction-based treatments for adolescents.

Maladaptive impulsivity is a core symptom in various psychiatric disorders. However, there is only limited evidence available on whether different measures of impulsivity represent largely unrelated aspects or a unitary construct. In a cross-species translational study, thirty rats were trained in impulsive choice (delayed reward task) and impulsive action (five-choice serial reaction time task) paradigms. The correlation between those measures was assessed during baseline performance and after pharmacological manipulations with the psychostimulant amphetamine and the norepinephrine reuptake inhibitor atomoxetine. In parallel, to validate the animal data, 101 human subjects performed analogous measures of impulsive choice (delay discounting task, DDT) and impulsive action (immediate and delayed memory task, IMT/DMT). Moreover, all subjects completed the Stop Signal Task (SST, as an additional measure of impulsive action) and filled out the Barratt impulsiveness scale (BIS-11). Correlations between DDT and IMT/DMT were determined and a principal component analysis was performed on all human measures of impulsivity. In both rats and humans measures of impulsive choice and impulsive action did not correlate. In rats the within-subject pharmacological effects of amphetamine and atomoxetine did not correlate between tasks, suggesting distinct underlying neural correlates. Furthermore, in humans, principal component analysis identified three independent factors: (1) self-reported impulsivity (BIS-11); (2) impulsive action (IMT/DMT and SST); (3) impulsive choice (DDT). This is the first study directly comparing aspects of impulsivity using a cross-species translational approach. The present data reveal the non-unitary nature of impulsivity on a behavioral and pharmacological level. Collectively, this warrants a stronger focus on the relative contribution of distinct forms of impulsivity in psychopathology.

Lithium and quetiapine are effective treatments for bipolar disorder, but their potential neuroprotective effects in humans remain unclear. A single blinded equivalence randomized controlled maintenance trial was conducted in a prospective cohort of first-episode mania (FEM) patients (n=26) to longitudinally compare the putative protective effects of lithium and quetapine on grey and white matter volume. A healthy control sample was also collected (n=20). Using structural MRI scans, voxel-wise grey and white matter volumes at baseline and changes over time in response to treatment were investigated. Patients were assessed at three time points (baseline, 3 and 12-month follow-up), whereas healthy controls were assessed at two time points (baseline and 12-month follow-up). Patients were randomized to lithium (serum level 0.6 mmol l-1, n=20) or quetiapine (flexibly dosed up to 800 mg per day, n=19) monotherapy. At baseline, compared with healthy control subjects, patients with FEM showed reduced grey matter in the orbitofrontal cortex, anterior cingulate, inferior frontal gyrus and cerebellum. In addition, patients had reduced internal capsule white matter volume bilaterally (t1,66>3.20, P<0.01). Longitudinally, there was a significant treatment × time effect only in the white matter of the left internal capsule (F2,112=8.54, P<0.01). Post hoc testing showed that, compared with baseline, lithium was more effective than quetiapine in slowing the progression of white matter volume reduction after 12 months (t1,24=3.76, P<0.01). Our data support the role of lithium but not quetiapine therapy in limiting white matter reduction early in the illness course after FEM.

Humans vary in their ability to delay gratification and impulsive decision making is a common feature in various psychiatric disorders. The level of delay discounting is a relatively stable psychological trait, and therefore neural processes implicated in delay discounting are likely to be based on the overall functional organization of the brain (under task-free conditions) in which state-dependent shifts from baseline levels occur. The current study investigated whether delay discounting can be predicted by intrinsic properties of brain functioning. Fourteen healthy male subjects performed a delay discounting task. In addition, resting state functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (¹H MRS) were used to investigate the relationship between individual differences in delay discounting and molecular and regional measures of resting state (baseline) activity of dorsal anterior cingulate cortex (dACC). Results showed that delay discounting was associated with both dACC glutamate concentrations and resting state functional connectivity of the dACC with a midbrain region including ventral tegmental area and substantia nigra. In addition, a neural pathway was established, showing that the effect of glutamate concentrations in the dACC on delay discounting is mediated by functional connectivity of the dACC with the midbrain. The current findings are important to acknowledge because spontaneous intrinsic brain processes have been proposed to be a potential promising biomarker of disease and impulsive decision making is associated with several psychiatric disorders.

BACKGROUND: A chronic course of major depressive disorder (MDD) is associated with profound alterations in brain volumes and emotional and cognitive processing. However, no neurobiological markers have been identified that prospectively predict MDD course trajectories. This study evaluated the prognostic value of different neuroimaging modalities, clinical characteristics, and their combination to classify MDD course trajectories. METHODS: One hundred eighteen MDD patients underwent structural and functional magnetic resonance imaging (MRI) (emotional facial expressions and executive functioning) and were clinically followed-up at 2 years. Three MDD trajectories (chronic n = 23, gradual improving n = 36, and fast remission n = 59) were identified based on Life Chart Interview measuring the presence of symptoms each month. Gaussian process classifiers were employed to evaluate prognostic value of neuroimaging data and clinical characteristics (including baseline severity, duration, and comorbidity). RESULTS: Chronic patients could be discriminated from patients with more favorable trajectories from neural responses to various emotional faces (up to 73% accuracy) but not from structural MRI and functional MRI related to executive functioning. Chronic patients could also be discriminated from remitted patients based on clinical characteristics (accuracy 69%) but not when age differences between the groups were taken into account. Combining different task contrasts or data sources increased prediction accuracies in some but not all cases. CONCLUSIONS: Our findings provide evidence that the prediction of naturalistic course of depression over 2 years is improved by considering neuroimaging data especially derived from neural responses to emotional facial expressions. Neural responses to emotional salient faces more accurately predicted outcome than clinical data.

INTRODUCTION: This study investigated the effects of a marine oil extract (PCSO-524®) on inattention, hyperactivity, mood and cognition in children and adolescents. PCSO-524® is a standardised lipid extract of the New Zealand green-lipped mussel and is an inflammatory modulator that inhibits the 5'-lipoxygenase and cyclooxygenase pathways and decreases concentrations of the pro-inflammatory arachidonic acid (AA). METHODS: PCSO-524® or a matched placebo was administered for 14 weeks to 144 participants (123 males/21 females; mean age 8.7 years) with high hyperactivity and inattention in a randomised, double-blind, placebo-controlled study. The primary outcome was the Conners Parent Rating Scale assessing parental reports of behavioural problems. Secondary outcomes assessed changes in cognition and mood. RESULTS: The results of the present study did not support the hypothesis that PCSO-524® improves parental reports of hyperactivity, inattention and impulsivity in children ages 6 to 14 years over placebo. Repeated measures ANOVA on post hoc subsample analysis indicated significant improvements in hyperactivity (p = 0.04), attention (p = 0.02), learning (p = 0.05) and probability of ADHD (p = 0.04) with a medium to large average effect size (d = 0.65) in those children who did not meet criteria for combined hyperactivity and inattention. Furthermore, significant improvements in the PCSO-524® group were indicated in a whole sample repeated measures ANCOVA on recognition memory between baseline and week 8 over placebo (p = 0.02, d = 0.56); this difference was not sustained at week 14. CONCLUSIONS: The results presented indicate that PCSO-524® may be beneficial in reducing levels of hyperactivity and inattention in a population of children with clinical and subclinical symptoms of ADHD.

BACKGROUND: First-episode psychosis most often has its onset during late adolescence. In caring for the young person, families endure high levels of stress and depression. Meanwhile, the social networks of families often erode. Our group has previously shown that family cognitive behaviour therapy (CBT) leads to significantly improved perceived stress compared with specialist first-episode treatment as usual; however, there are well-known barriers to the dissemination of effective family interventions. To address this, we have developed a novel online intervention entitled 'Altitudes' that fully integrates purpose-built online social networking, expert and peer moderation, and evidence-based psychoeducation within a single application. The primary aim of this trial is to evaluate the effectiveness of Altitudes in reducing stress in carers over a 6-month period. METHODS/DESIGN: We describe here a single-blinded cluster randomised controlled trial (cRCT) with permutated blocks. The clusters comprise individual families. The two treatment conditions include Altitudes plus Specialist Treatment as Usual (STAU) and STAU alone. Altitudes involves participation in our novel online programme whereas STAU comprises specialist family work at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia. We aim to recruit 160 family members of young, 15-27 year-old, patients registered for treatment for first-episode psychosis (FEP) at EPPIC. The design includes two assessment time points, namely, baseline and 6-month follow-up. The study is due for completion within 2 years including an 18-month recruitment period and a 6-month treatment phase. The primary outcome is carers' perceived stress at 6 months. Secondary outcome measures include a biomarker of stress, depressive symptoms, worry, substance use, loneliness, social support, satisfaction with life, and a range of measures that tap into coping resources. We seek to gain a dynamic picture of carer stress through our Smartphone Ecological Momentary Assessment (SEMA) tool. DISCUSSION: This is the first randomised controlled trial designed to evaluate an online intervention for carers of young people recovering from FEP. It has the potential to produce evidence in support of a highly novel, accessible, and cost-effective intervention to reduce stress in carers who are providing support to young people at a critical phase in their recovery from psychosis. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, identifier: ACTRN12616000968471 . Retrospectively registered on 22 July 2016.

BACKGROUND: Measurement of changes in health across locations is useful to compare and contrast changing epidemiological patterns against health system performance and identify specific needs for resource allocation in research, policy development, and programme decision making. Using the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we drew from two widely used summary measures to monitor such changes in population health: disability-adjusted life-years (DALYs) and healthy life expectancy (HALE). We used these measures to track trends and benchmark progress compared with expected trends on the basis of the Socio-demographic Index (SDI). METHODS: We used results from the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2016. We calculated DALYs by summing years of life lost and years of life lived with disability for each location, age group, sex, and year. We estimated HALE using age-specific death rates and years of life lived with disability per capita. We explored how DALYs and HALE differed from expected trends when compared with the SDI: the geometric mean of income per person, educational attainment in the population older than age 15 years, and total fertility rate. FINDINGS: The highest globally observed HALE at birth for both women and men was in Singapore, at 75·2 years (95% uncertainty interval 71·9-78·6) for females and 72·0 years (68·8-75·1) for males. The lowest for females was in the Central African Republic (45·6 years [42·0-49·5]) and for males was in Lesotho (41·5 years [39·0-44·0]). From 1990 to 2016, global HALE increased by an average of 6·24 years (5·97-6·48) for both sexes combined. Global HALE increased by 6·04 years (5·74-6·27) for males and 6·49 years (6·08-6·77) for females, whereas HALE at age 65 years increased by 1·78 years (1·61-1·93) for males and 1·96 years (1·69-2·13) for females. Total global DALYs remained largely unchanged from 1990 to 2016 (-2·3% [-5·9 to 0·9]), with decreases in communicable, maternal, neonatal, and nutritional (CMNN) disease DALYs offset by increased DALYs due to non-communicable diseases (NCDs). The exemplars, calculated as the five lowest ratios of observed to expected age-standardised DALY rates in 2016, were Nicaragua, Costa Rica, the Maldives, Peru, and Israel. The leading three causes of DALYs globally were ischaemic heart disease, cerebrovascular disease, and lower respiratory infections, comprising 16·1% of all DALYs. Total DALYs and age-standardised DALY rates due to most CMNN causes decreased from 1990 to 2016. Conversely, the total DALY burden rose for most NCDs; however, age-standardised DALY rates due to NCDs declined globally. INTERPRETATION: At a global level, DALYs and HALE continue to show improvements. At the same time, we observe that many populations are facing growing functional health loss. Rising SDI was associated with increases in cumulative years of life lived with disability and decreases in CMNN DALYs offset by increased NCD DALYs. Relative compression of morbidity highlights the importance of continued health interventions, which has changed in most locations in pace with the gross domestic product per person, education, and family planning. The analysis of DALYs and HALE and their relationship to SDI represents a robust framework with which to benchmark location-specific health performance. Country-specific drivers of disease burden, particularly for causes with higher-than-expected DALYs, should inform health policies, health system improvement initiatives, targeted prevention efforts, and development assistance for health, including financial and research investments for all countries, regardless of their level of sociodemographic development. The presence of countries that substantially outperform others suggests the need for increased scrutiny for proven examples of best practices, which can help to extend gains, whereas the presence of underperforming countries suggests the need for devotion of extra attention to health systems that need more robust support. FUNDING: Bill & Melinda Gates Foundation.

We examined putative microglial activation as a function of illness course in schizophrenia. Microglial activity was quantified using [11C](R)-(1-[2-chrorophynyl]-N-methyl-N-[1-methylpropyl]-3 isoquinoline carboxamide (11C-(R)-PK11195) positron emission tomography (PET) in: (i) 10 individuals at ultra-high risk (UHR) of psychosis; (ii) 18 patients recently diagnosed with schizophrenia; (iii) 15 patients chronically ill with schizophrenia; and, (iv) 27 age-matched healthy controls. Regional-binding potential (BPND) was calculated using the simplified reference-tissue model with four alternative reference inputs. The UHR, recent-onset and chronic patient groups were compared to age-matched healthy control groups to examine between-group BPND differences in 6 regions: dorsal frontal, orbital frontal, anterior cingulate, medial temporal, thalamus and insula. Correlation analysis tested for BPND associations with gray matter volume, peripheral cytokines and clinical variables. The null hypothesis of equality in BPND between patients (UHR, recent-onset and chronic) and respective healthy control groups (younger and older) was not rejected for any group comparison or region. Across all subjects, BPND was positively correlated to age in the thalamus (r=0.43, P=0.008, false discovery rate). No correlations with regional gray matter, peripheral cytokine levels or clinical symptoms were detected. We therefore found no evidence of microglial activation in groups of individuals at high risk, recently diagnosed or chronically ill with schizophrenia. While the possibility of 11C-(R)-PK11195-binding differences in certain patient subgroups remains, the patient cohorts in our study, who also displayed normal peripheral cytokine profiles, do not substantiate the assumption of microglial activation in schizophrenia as a regular and defining feature, as measured by 11C-(R)-PK11195 BPND.

BACKGROUND/OBJECTIVES: Psychiatry lacks the objective clinical tests routinely used in other specializations. Novel computerized methods to characterize complex behaviors such as speech could be used to identify and predict psychiatric illness in individuals. AIMS: In this proof-of-principle study, our aim was to test automated speech analyses combined with Machine Learning to predict later psychosis onset in youths at clinical high-risk (CHR) for psychosis. METHODS: Thirty-four CHR youths (11 females) had baseline interviews and were assessed quarterly for up to 2.5 years; five transitioned to psychosis. Using automated analysis, transcripts of interviews were evaluated for semantic and syntactic features predicting later psychosis onset. Speech features were fed into a convex hull classification algorithm with leave-one-subject-out cross-validation to assess their predictive value for psychosis outcome. The canonical correlation between the speech features and prodromal symptom ratings was computed. RESULTS: Derived speech features included a Latent Semantic Analysis measure of semantic coherence and two syntactic markers of speech complexity: maximum phrase length and use of determiners (e.g., which). These speech features predicted later psychosis development with 100% accuracy, outperforming classification from clinical interviews. Speech features were significantly correlated with prodromal symptoms. CONCLUSIONS: Findings support the utility of automated speech analysis to measure subtle, clinically relevant mental state changes in emergent psychosis. Recent developments in computer science, including natural language processing, could provide the foundation for future development of objective clinical tests for psychiatry.