ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

Background: Randomized, double-blind, placebo-controlled trials constitute the gold standard in clinical research when testing the efficacy of new psychopharmacological interventions in the treatment of major depression. However, the blinded use of placebo has been found to influence clinical trial outcomes and may bias patient selection. Discussion: To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population. Summary: We propose a list of measures to be taken to improve the external validity of double-blind, placebocontrolled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself

Interaction of C-60 molecules on Si(100)

The interactions between pairs of C60 molecules adsorbed upon the Si(1 0 0) surface have been studied via a series of DFT calculations. Configurations which have the fullerene cage located within the dimer trench bonded to four dimers (t4) have been investigated, as these have previously been found to be among the most stable for the C60 molecule. These t4 configurations are explored with all possible pairs of fullerene configuration combinations considered. We have looked at two distinct groups of separation distances between the two C60 molecules. These have the fullerene bonding sites as either adjacent to one another or separated by one Si surface dimer. Comparisons between the two groups confirm the trend of the combinations becoming more favourable at a greater fullerene separation. In the systems with adjacent bonding sites the combined pair of fullerenes were in general less favourable than the two isolated cases. At the longer fullerene separation distance this trend was reversed. The longer fullerene separation distance reflects the experimental separation observed by Moriarty et al. [P. Moriarty, Y.R. Ma, M.D. Upward, P.H. Beton, Surf. Sci. 407 (1998) 27]

Abnormal auditory tonotopy in patients with schizophrenia

Auditory hallucinations are among the most prevalent and most distressing symptoms of schizophrenia. Despite significant progress, it is still unclear whether auditory hallucinations arise from abnormalities in primary sensory processing or whether they represent failures of higher-order functions. To address this knowledge gap, we capitalized on the increased spatial resolution afforded by ultra-high field imaging at 7 Tesla to investigate the tonotopic organization of the auditory cortex in patients with schizophrenia with a history of recurrent hallucinations. Tonotopy is a fundamental feature of the functional organization of the auditory cortex that is established very early in development and predates the onset of symptoms by decades. Compared to healthy participants, patients showed abnormally increased activation and altered tonotopic organization of the auditory cortex during a purely perceptual task, which involved passive listening to tones across a range of frequencies (88-8000 Hz). These findings suggest that the predisposition to auditory hallucinations is likely to be predicated on abnormalities in the functional organization of the auditory cortex and which may serve as a biomarker for the early identification of vulnerable individuals

Strengthening of short splices in RC beams using Post-Tensioned Metal Straps

This paper investigates the effectiveness of a novel and cost-effective strengthening technique using Post-Tensioned Metal Straps (PTMS) at enhancing the bond behaviour of short lap spliced steel bars in reinforced concrete (RC) beams. Twelve RC beams with a short lap splice length of 10d b (d b = bar diameter) at the midspan zone were tested in flexure to examine the bond splitting failure. The effect of confinement (no confinement, internal steel stirrups or external PTMS), bar diameter and concrete cover were examined. The results show that, whilst unconfined control beams failed prematurely due to cover splitting, the use of PTMS confinement enhanced the bond strength of the spliced bars by up to 58 % and resulted in a less brittle behaviour. Based on the test results, a new analytical model is proposed to predict the additional bond strength provided by PTMS confinement. The model should prove useful in the strengthening design of substandard lap spliced RC elements

Reduced P300 amplitude during retrieval on a spatial working memory task in a community sample of adolescents who report psychotic symptoms.

BACKGROUND: Deficits in working memory are widely reported in schizophrenia and are considered a trait marker for the disorder. Event-related potentials (ERPs) and imaging data suggest that these differences in working memory performance may be due to aberrant functioning in the prefrontal and parietal cortices. Research suggests that many of the same risk factors for schizophrenia are shared with individuals from the general population who report psychotic symptoms. METHODS: Forty-two participants (age range 11--13 years) were divided into those who reported psychotic symptoms (N = 17) and those who reported no psychotic symptoms, i.e. the control group (N = 25). Behavioural differences in accuracy and reaction time were explored between the groups as well as electrophysiological correlates of working memory using a Spatial Working Memory Task, which was a variant of the Sternberg paradigm. Specifically, differences in the P300 component were explored across load level (low load and high load), location (positive probe i.e. in the same location as shown in the study stimulus and negative probe i.e. in a different location to the study stimulus) and between groups for the overall P300 timeframe. The effect of load was also explored at early and late timeframes of the P300 component (250-430 ms and 430-750 ms respectively). RESULTS: No between-group differences in the behavioural data were observed. Reduced amplitude of the P300 component was observed in the psychotic symptoms group relative to the control group at posterior electrode sites. Amplitude of the P300 component was reduced at high load for the late P300 timeframe at electrode sites Pz and POz. CONCLUSIONS: These results identify neural correlates of neurocognitive dysfunction associated with population level psychotic symptoms and provide insights into ERP abnormalities associated with the extended psychosis phenotype

Empirical evidence for discrete neurocognitive subgroups in bipolar disorder: clinical implications

Background. Recent data suggest trait-like neurocognitive impairments in bipolar disorder (BPD), with deficits about 1 S.D. below average, less severe than deficits noted in schizophrenia. The frequency of significant impairment in BPD is approximately 60%, with 40% of patients characterized as cognitively spared. This contrasts with a more homogeneous presentation in schizophrenia. It is not understood why some BPD patients develop deficits while others do not. Method. A total of 136 patients with BPD completed the MATRICS Consensus Cognitive Battery and data were entered into hierarchical cluster analyses to: (1) determine the optimal number of clusters (subgroups) that fit the sample; and (2) assign subjects to a specific cluster based on individual profiles. We then compared subgroups on several clinical factors and real-world community functioning. Results. Three distinct neurocognitive subgroups were found: (1) an intact group with performance comparable with healthy controls on all domains but with superior social cognition; (2) a selective impairment group with moderate deficits on processing speed, attention, verbal learning and social cognition and normal functioning in other domains; and (3) a global impairment group with severe deficits across all cognitive domains comparable with deficits in schizophrenia. Conclusions. These results suggest the presence of multiple cognitive subgroups in BPD with unique profiles and begin to address the relationships between these subgroups, several clinical factors and functional outcome. Next steps will include using these data to help guide future efforts to target these disabling symptoms with treatment

Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples

BACKGROUND: Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples. METHODS: The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant's dose and subsequently declare the maximum tolerated dose. We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies. RESULTS: In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians' time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion. CONCLUSION: Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice

Physical forcing and physical/biochemical variability of the Mediterranean Sea: a review of unresolved issues and directions for future research

This paper is the outcome of a workshop held in Rome in November 2011 on the occasion of the 25th anniversary of the POEM (Physical Oceanography of the Eastern Mediterranean) program. In the workshop discussions, a number of unresolved issues were identified for the physical and biogeochemical properties of the Mediterranean Sea as a whole, i.e., comprising the Western and Eastern sub-basins. Over the successive two years, the related ideas were discussed among the group of scientists who participated in the workshop and who have contributed to the writing of this paper. Three major topics were identified, each of them being the object of a section divided into a number of different sub-sections, each addressing a specific physical, chemical or biological issue: 1. Assessment of basin-wide physical/biochemical properties, of their variability and interactions. 2. Relative importance of external forcing functions (wind stress, heat/moisture fluxes, forcing through straits) vs. internal variability. 3. Shelf/deep sea interactions and exchanges of physical/biogeochemical properties and how they affect the sub-basin circulation and property distribution. Furthermore, a number of unresolved scientific/methodological issues were also identified and are reported in each sub-section after a short discussion of the present knowledge. They represent the collegial consensus of the scientists contributing to the paper. Naturally, the unresolved issues presented here constitute the choice of the authors and therefore they may not be exhaustive and/or complete. The overall goal is to stimulate a broader interdisciplinary discussion among the scientists of the Mediterranean oceanographic community, leading to enhanced collaborative efforts and exciting future discoveries