Synthesizing study-specific controls using generative models on open access datasets for harmonized multi-study analyses

Neuroimaging consortia can enhance reliability and generalizability of findings by pooling data across studies to achieve larger sample sizes. To adjust for site and MRI protocol effects, imaging datasets are often harmonized based on healthy controls. When data from a control group were not collected, statistical harmonization options are limited as patient characteristics and acquisition-related variables may be confounded. Here, in a multi-study neuroimaging analysis of Alzheimer's patients and controls, we tested whether it is possible to generate synthetic control MRIs. For one case-control study, we used a generative adversarial model for style-based harmonization to generate site-specific controls. Downstream feature extraction, statistical harmonization and group-level multi-study case-control and case-only analyses were performed twice, using either true or synthetic controls. All effect sizes using synthetic controls overlapped with those based on true study controls. This line of work may facilitate wider inclusion of case-only studies in multi-study consortia

A Comprehensive Corpus Callosum Segmentation Tool for Detecting Callosal Abnormalities and Genetic Associations from Multi Contrast MRIs

Structural alterations of the midsagittal corpus callosum (midCC) have been associated with a wide range of brain disorders. The midCC is visible on most MRI contrasts and in many acquisitions with a limited field-of-view. Here, we present an automated tool for segmenting and assessing the shape of the midCC from T1w, T2w, and FLAIR images. We train a UNet on images from multiple public datasets to obtain midCC segmentations. A quality control algorithm is also built-in, trained on the midCC shape features. We calculate intraclass correlations (ICC) and average Dice scores in a test-retest dataset to assess segmentation reliability. We test our segmentation on poor quality and partial brain scans. We highlight the biological significance of our extracted features using data from over 40,000 individuals from the UK Biobank; we classify clinically defined shape abnormalities and perform genetic analyses

An overview of the first 5 years of the ENIGMA obsessive–compulsive disorder working group: The power of worldwide collaboration

Abstract Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA

Rotator Cuff Tendinosis in an Animal Model: Role of Extrinsic and Overuse Factors

The rat shoulder animal model has been used previously to study the role of intrinsic injury (modeled as an acute insult to the tendon), extrinsic injury (modeled as external subacromial impingement), and overuse factors on rotator cuff tendinosis. These studies demonstrated that it is possible to produce rotator cuff tendinosis with any one of these factors in isolation. The current study uses the rat shoulder model to study the roles of extrinsic compression, overuse, and overuse in combination with extrinsic compression, on the development of rotator cuff tendinosis. The results of this study demonstrate that the injury created by overuse plus extrinsic compression is greater than the injuries created by overuse or extrinsic compression alone, particularly when important biomechanical variables are considered. While ineffective in causing a change in supraspinatus tendon properties in animals with normal cage activity, extrinsic compression had a significant and dramatic effect when it was combined with overuse activity. Without an additional factor, such as overhead activity, the extrinsic compression alone may be insufficient to cause tendinosis. The results of the present study support the role of multiple factors in the etiology of some rotator cuff injuries. © 2002 Biomedical Engineering Society.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44001/1/10439_2004_Article_482753.pd

Understanding the role of growth factors in modulating stem cell tenogenesis

Current treatments for tendon injuries often fail to fully restore joint biomechanics leading to the recurrence of symptoms, and thus resulting in a significant health problem with a relevant social impact worldwide. Cell-based approaches involving the use of stem cells might enable tailoring a successful tendon regeneration outcome. As growth factors (GFs) powerfully regulate the cell biological response, their exogenous addition can further stimulate stem cells into the tenogenic lineage, which might eventually depend on stem cells source. In the present study we investigate the tenogenic differentiation potential of human- amniotic fluid stem cells (hAFSCs) and adipose-derived stem cells (hASCs) with several GFs associated to tendon development and healing; namely, EGF, bFGF, PDGF-BB and TGF-β1. Stem cells response to biochemical stimuli was studied by screening of tendon-related genes (collagen type I, III, decorin, tenascin C and scleraxis) and proteins found in tendon extracellular matrix (ECM) (Collagen I, III, and Tenascin C). Despite the fact that GFs did not seem to influence the synthesis of tendon ECM proteins, EGF and bFGF influenced the expression of tendon-related genes in hAFSCs, while EGF and PDGF-BB stimulated the genetic expression in hASCs. Overall results on cellular alignment morphology, immunolocalization and PCR analysis indicated that both stem cell source can be biochemically induced towards tenogenic commitment, validating the potential of hASCs and hAFSCs for tendon regeneration strategies.Authors thank the Portuguese Foundation for Science and Technology (FCT) for the research project BIBS (PTDC/CVT/102972/2008) and for the post-doc fellowship grant: SFRH/BPD/86775/2012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Validation of the test for finding word retrieval deficits (WoFi) in detecting Alzheimer's disease in a naturalistic clinical setting

Background Detecting impaired naming capacity contributes to the detection of mild (MildND) and major (MajorND) neurocognitive disorder due to Alzheimer’s disease (AD). The Test for Finding Word retrieval deficits (WoFi) is a new, 50-item, auditory stimuli-based instrument. Objective The study aimed to adapt WoFi to the Greek language, to develop a short version of WoFi (WoFi-brief), to compare the item frequency and the utility of both instruments with the naming subtest of the widely used Addenbrooke’s cognitive examination III (ACEIIINaming) in detecting MildND and MajorND due to AD. Methods This cross-sectional, validation study included 99 individuals without neurocognitive disorder, as well as 114 and 49 patients with MildND and MajorND due to AD, respectively. The analyses included categorical principal components analysis using Cramer’s V, assessment of the frequency of test items based on corpora of television subtitles, comparison analyses, Kernel Fisher discriminant analysis models, proportional odds logistic regression (POLR) models and stratified repeated random subsampling used to recursive partitioning to training and validation set (70/30 ratio). Results WoFi and WoFi-brief, which consists of 16 items, have comparable item frequency and utility and outperform ACEIIINaming. According to the results of the discriminant analysis, the misclassification error was 30.9%, 33.6% and 42.4% for WoFi, WoFi-brief and ACEIIINaming, respectively. In the validation regression model including WoFi the mean misclassification error was 33%, while in those including WoFi-brief and ACEIIINaming it was 31% and 34%, respectively. Conclusions WoFi and WoFi-brief are more effective in detecting MildND and MajorND due to AD than ACEIIINaming

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