Differences in the neural correlates of schizophrenia with positive and negative formal thought disorder in patients with schizophrenia in the ENIGMA dataset.

Formal thought disorder (FTD) is a clinical key factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, the relationship between FTD symptom dimensions and patterns of regional brain volume loss in schizophrenia remains to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles by enrolling a large multi-site cohort acquired by the ENIGMA Schizophrenia Working Group (752 schizophrenia patients and 1256 controls), to unravel the neuroanatomy of FTD in schizophrenia and using virtual histology tools on implicated brain regions to investigate the cellular basis. Based on the findings of previous clinical and neuroimaging studies, we decided to separately explore positive, negative and total formal thought disorder. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but positive and negative FTD demonstrated a dissociation: negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD also showed associations with microglial cell types. These results provide an important step towards linking FTD to brain structural changes and their cellular underpinnings, providing an avenue for a better mechanistic understanding of this syndrome.

Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study.

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Neural Correlates of Positive and Negative Formal Thought Disorder in Individuals with Schizophrenia: An ENIGMA Schizophrenia Working Group Study.

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Parents' Concerns Are Associated with Early Intervention Evaluation and Eligibility Outcomes.

OBJECTIVE: To test the association of parents' concerns with early intervention (EI) developmental services outcomes including evaluation, eligibility, and enrollment in services. METHOD: We collected survey data on parents' concerns and EI service use data from a sample of 428 children referred to EI from 2016 to 2018 in 6 Oregon primary care clinics serving lower-income families as part of a developmental and autism spectrum disorder screening intervention. We assessed EI service use trajectories and associations of the presence of parent concern, age of child at the time of parents' concerns, number of concerns, and type of provider concern, with EI evaluation, EI eligibility, and enrollment in EI services, using bivariate testing and multivariable logistic regression. RESULTS: Only 22.9% of children referred to EI were enrolled in services 6 months later. Children whose parents had developmental and/or behavioral concerns were more likely to receive an EI evaluation and were also more likely to be eligible for services, compared with children whose parents had no concerns. There was no association between age, number of concerns, and type of concern with EI evaluation, eligibility, or services enrollment. CONCLUSION: Although only a minority of children referred to EI enrolled in services, the presence of parent concern is strongly associated with EI services evaluation and eligibility outcomes. Study results suggest that providers should assess the presence of parent concern when deciding on EI referrals and provide more support to parents who are not concerned at all.

Improving autism and developmental screening and referral in US primary care practices serving Latinos.

LAY ABSTRACT: Latino children experience delays in access to diagnosis and treatment of autism spectrum disorder. Primary care-based screening of all children for autism spectrum disorder and referring them for services may reduce racial/ethnic differences and improve care. REAL-START, a yearlong screening intervention, was effective in increasing screening for autism spectrum disorder and general developmental delays, increasing therapy referrals, and shortening time for developmental assessment in primary care clinics with Latino patients.

Updated report on tools to measure outcomes of clinical trials in fragile X syndrome.

OBJECTIVE: Fragile X syndrome (FXS) has been the neurodevelopmental disorder with the most active translation of preclinical breakthroughs into clinical trials. This process has led to a critical assessment of outcome measures, which resulted in a comprehensive review published in 2013. Nevertheless, the disappointing outcome of several recent phase III drug trials in FXS, and parallel efforts at evaluating behavioral endpoints for trials in autism spectrum disorder (ASD), has emphasized the need for re-assessing outcome measures and revising recommendations for FXS. METHODS: After performing an extensive database search (PubMed, Food and Drug Administration (FDA)/National Institutes of Health (NIH)'s www.ClinicalTrials.gov, etc.) to determine progress since 2013, members of the Working Groups who published the 2013 Report evaluated the available outcome measures for FXS and related neurodevelopmental disorders using the COSMIN grading system of levels of evidence. The latter has also been applied to a British survey of endpoints for ASD. In addition, we also generated an informal classification of outcome measures for use in FXS intervention studies as instruments appropriate to detect shorter- or longer-term changes. RESULTS: To date, a total of 22 double-blind controlled clinical trials in FXS have been identified through www.ClinicalTrials.gov and an extensive literature search. The vast majority of these FDA/NIH-registered clinical trials has been completed between 2008 and 2015 and has targeted the core excitatory/inhibitory imbalance present in FXS and other neurodevelopmental disorders. Limited data exist on reliability and validity for most tools used to measure cognitive, behavioral, and other problems in FXS in these trials and other studies. Overall, evidence for most tools supports a moderate tool quality grading. Data on sensitivity to treatment, currently under evaluation, could improve ratings for some cognitive and behavioral tools. Some progress has also been made at identifying promising biomarkers, mainly on blood-based and neurophysiological measures. CONCLUSION: Despite the tangible progress in implementing clinical trials in FXS, the increasing data on measurement properties of endpoints, and the ongoing process of new tool development, the vast majority of outcome measures are at the moderate quality level with limited information on reliability, validity, and sensitivity to treatment. This situation is not unique to FXS, since reviews of endpoints for ASD have arrived at similar conclusions. These findings, in conjunction with the predominance of parent-based measures particularly in the behavioral domain, indicate that endpoint development in FXS needs to continue with an emphasis on more objective measures (observational, direct testing, biomarkers) that reflect meaningful improvements in quality of life. A major continuous challenge is the development of measurement tools concurrently with testing drug safety and efficacy in clinical trials.

Calming and Focusing: Students' Perceptions of Short Classroom Strategies for Fostering Presence.

PURPOSE: Presence is the essence of professional nursing in the nurse-patient connection. Nursing students have little exposure to strategies fostering presence. This pilot study explored students' perceptions of strategies to encourage presence in the classroom. DESIGN: A three-question survey was distributed to students in the last week of classes. Faculty not teaching that course administered the survey. METHOD: Four faculty used strategies aimed at encouraging presence. These strategies included starting class with a mindfulness minute, mindful movement, singing bowl, peace and power check in, and a discussion of a current event. Each class used only one strategy consistently through the semester. Participants were undergraduate and graduate students enrolled in one of seven classes taught by these faculty. FINDINGS: Overall the students found strategies to be beneficial. In reflecting on the experience with the strategies, four themes emerged: calming/relaxing; focusing/centering; setting aside distractions; and feeling community and connection. CONCLUSION: These brief strategies were acceptable to most students and were helpful to the students in preparing for class. The response to mindfulness minute was most positive. Further research is needed on the introduction of strategies that help students in the classroom and may also increase presence at the bedside.

The real-time fMRI neurofeedback based stratification of Default Network Regulation Neuroimaging data repository.

This data descriptor describes a repository of openly shared data from an experiment to assess inter-individual differences in default mode network (DMN) activity. This repository includes cross-sectional functional magnetic resonance imaging (fMRI) data from the Multi Source Interference Task, to assess DMN deactivation, the Moral Dilemma Task, to assess DMN activation, a resting state fMRI scan, and a DMN neurofeedback paradigm, to assess DMN modulation, along with accompanying behavioral and cognitive measures. We report technical validation from n=125 participants of the final targeted sample of 180 participants. Each session includes acquisition of one whole-brain anatomical scan and whole-brain echo-planar imaging (EPI) scans, acquired during the aforementioned tasks and resting state. The data includes several self-report measures related to perseverative thinking, emotion regulation, and imaginative processes, along with a behavioral measure of rapid visual information processing. Technical validation of the data confirms that the tasks deactivate and activate the DMN as expected. Group level analysis of the neurofeedback data indicates that the participants are able to modulate their DMN with considerable inter-subject variability. Preliminary analysis of behavioral responses and specifically self-reported sleep indicate that as many as 73 participants may need to be excluded from an analysis depending on the hypothesis being tested. The present data are linked to the enhanced Nathan Kline Institute, Rockland Sample and builds on the comprehensive neuroimaging and deep phenotyping available therein. As limited information is presently available about individual differences in the capacity to directly modulate the default mode network, these data provide a unique opportunity to examine DMN modulation ability in relation to numerous phenotypic characteristics.

A Self-Administered Stress Management Intervention for Hispanic Patients Undergoing Cancer Chemotherapy.

This study evaluated whether a self-administered stress management training (SSMT) could improve quality of life (QOL) and reduce distress among Hispanics receiving chemotherapy across multiple community clinical settings. Participants were randomized to receive SSMT (n = 106) or usual care (UCO) (n = 113). The primary outcome-QOL (SF-36) and secondary outcomes depression (CES-D), and anxiety (STAI) were assessed longitudinally over four chemotherapy cycles. Acculturation (BAS) and patients' intervention adherence were assessed. About 63% of participants reported distress after the initial chemotherapy cycle. Hispanics with lower acculturation reported greater STAI-Trait scores (p = .003). No significant treatment effects on outcomes measures were observed for participants receiving SSMT. SSMT intervention techniques were reported useful and improved mental health scores were observed with patients on a psychotropic agent (p = .04). Hispanics experience an elevated level of distress, yet SSMT did not significantly improve primary outcomes. SSMT may be potentially effective when combined with a psychotropic agent. SSMT enhancing strategies are discussed.

A Tool for Interactive Data Visualization: Application to Over 10,000 Brain Imaging and Phantom MRI Data Sets.

In this paper we propose a web-based approach for quick visualization of big data from brain magnetic resonance imaging (MRI) scans using a combination of an automated image capture and processing system, nonlinear embedding, and interactive data visualization tools. We draw upon thousands of MRI scans captured via the COllaborative Imaging and Neuroinformatics Suite (COINS). We then interface the output of several analysis pipelines based on structural and functional data to a t-distributed stochastic neighbor embedding (t-SNE) algorithm which reduces the number of dimensions for each scan in the input data set to two dimensions while preserving the local structure of data sets. Finally, we interactively display the output of this approach via a web-page, based on data driven documents (D3) JavaScript library. Two distinct approaches were used to visualize the data. In the first approach, we computed multiple quality control (QC) values from pre-processed data, which were used as inputs to the t-SNE algorithm. This approach helps in assessing the quality of each data set relative to others. In the second case, computed variables of interest (e.g., brain volume or voxel values from segmented gray matter images) were used as inputs to the t-SNE algorithm. This approach helps in identifying interesting patterns in the data sets. We demonstrate these approaches using multiple examples from over 10,000 data sets including (1) quality control measures calculated from phantom data over time, (2) quality control data from human functional MRI data across various studies, scanners, sites, (3) volumetric and density measures from human structural MRI data across various studies, scanners and sites. Results from (1) and (2) show the potential of our approach to combine t-SNE data reduction with interactive color coding of variables of interest to quickly identify visually unique clusters of data (i.e., data sets with poor QC, clustering of data by site) quickly. Results from (3) demonstrate interesting patterns of gray matter and volume, and evaluate how they map onto variables including scanners, age, and gender. In sum, the proposed approach allows researchers to rapidly identify and extract meaningful information from big data sets. Such tools are becoming increasingly important as datasets grow larger.

SchizConnect: Mediating neuroimaging databases on schizophrenia and related disorders for large-scale integration.

SchizConnect (www.schizconnect.org) is built to address the issues of multiple data repositories in schizophrenia neuroimaging studies. It includes a level of mediation--translating across data sources--so that the user can place one query, e.g. for diffusion images from male individuals with schizophrenia, and find out from across participating data sources how many datasets there are, as well as downloading the imaging and related data. The current version handles the Data Usage Agreements across different studies, as well as interpreting database-specific terminologies into a common framework. New data repositories can also be mediated to bring immediate access to existing datasets. Compared with centralized, upload data sharing models, SchizConnect is a unique, virtual database with a focus on schizophrenia and related disorders that can mediate live data as information is being updated at each data source. It is our hope that SchizConnect can facilitate testing new hypotheses through aggregated datasets, promoting discovery related to the mechanisms underlying schizophrenic dysfunction.

COINS Data Exchange: An open platform for compiling, curating, and disseminating neuroimaging data.

Neuroimaging data collection is inherently expensive. Maximizing the return on investment in neuroimaging studies requires that neuroimaging data be re-used whenever possible. In an effort to further scientific knowledge, the COINS Data Exchange (DX) (http://coins.mrn.org/dx) aims to make data sharing seamless and commonplace. DX takes a three-pronged approach towards improving the overall state of data sharing within the neuroscience community. The first prong is compiling data into one location that has been collected from all over the world in many different formats. The second prong is curating the data so that it can be stored in one consistent format and so that data QA/QC measures can be assured. The third prong is disseminating the data so that it is easy to consume and straightforward to interpret. This paper explains the concepts behind each prong and describes some challenges and successes that the Data Exchange has experienced.

SchizConnect: Virtual Data Integration in Neuroimaging.

In many scientific domains, including neuroimaging studies, there is a need to obtain increasingly larger cohorts to achieve the desired statistical power for discovery. However, the economics of imaging studies make it unlikely that any single study or consortia can achieve the desired sample sizes. What is needed is an architecture that can easily incorporate additional studies as they become available. We present such architecture based on a virtual data integration approach, where data remains at the original sources, and is retrieved and harmonized in response to user queries. This is in contrast to approaches that move the data to a central warehouse. We implemented our approach in the SchizConnect system that integrates data from three neuroimaging consortia on Schizophrenia: FBIRN's Human Imaging Database (HID), MRN's Collaborative Imaging and Neuroinformatics System (COINS), and the NUSDAST project at XNAT Central. A portal providing harmonized access to these sources is publicly deployed at schizconnect.org.

Terminology development towards harmonizing multiple clinical neuroimaging research repositories.

Data sharing and mediation across disparate neuroimaging repositories requires extensive effort to ensure that the different domains of data types are referred to by commonly agreed upon terms. Within the SchizConnect project, which enables querying across decentralized databases of neuroimaging, clinical, and cognitive data from various studies of schizophrenia, we developed a model for each data domain, identified common usable terms that could be agreed upon across the repositories, and linked them to standard ontological terms where possible. We had the goal of facilitating both the current user experience in querying and future automated computations and reasoning regarding the data. We found that existing terminologies are incomplete for these purposes, even with the history of neuroimaging data sharing in the field; and we provide a model for efforts focused on querying multiple clinical neuroimaging repositories.

Survival and Toxicity Following Chemoradiation for Carcinoma of the Cervix - Impact of Multiple-phase Treatment and Shielding.

AIM: We report on outcomes and significant grade 3-4 late toxicities between January 1999 and October 2006 following introduction of multi-phase treatment and effect of shielding in treatment of cervical cancer with concurrent chemoradiation. PATIENTS AND METHODS: Radiotherapy dose by phase, recurrence, survival and toxicity data was collated by a retrospective review of clinical notes. Shielding information was retrieved from original planning films. RESULTS: 3-year survival for stages I, II and III disease were 89%,76% and 51% respectively. Local pelvic failure was 9%. Overall significant late toxicity (SLT) rate was 13%, with lower rates for post-operative treatment than primary chemoradiation (4% vs. 16%). SLT with single phase treatment was 29% versus 12% following multiphase EBRT and 16% when <2 areas were shielded versus 6% with ≥3 shielded areas (p=0.01). CONCLUSION: Shielding and multi-phase treatment not only reduce dose to organs at-risk but can also reduce late toxicity without compromising local control or survival.

Impairments in cognition and neural precursor cell proliferation in mice expressing constitutively active glycogen synthase kinase-3.

Brain glycogen synthase kinase-3 (GSK3) is hyperactive in several neurological conditions that involve impairments in both cognition and neurogenesis. This raises the hypotheses that hyperactive GSK3 may directly contribute to impaired cognition, and that this may be related to deficiencies in neural precursor cells (NPC). To study the effects of hyperactive GSK3 in the absence of disease influences, we compared adult hippocampal NPC proliferation and performance in three cognitive tasks in male and female wild-type (WT) mice and GSK3 knockin mice, which express constitutively active GSK3. NPC proliferation was ~40% deficient in both male and female GSK3 knockin mice compared with WT mice. Environmental enrichment (EE) increased NPC proliferation in male, but not female, GSK3 knockin mice and WT mice. Male and female GSK3 knockin mice exhibited impairments in novel object recognition, temporal order memory, and coordinate spatial processing compared with gender-matched WT mice. EE restored impaired novel object recognition and temporal ordering in both sexes of GSK3 knockin mice, indicating that this repair was not dependent on NPC proliferation, which was not increased by EE in female GSK3 knockin mice. Acute 1 h pretreatment with the GSK3 inhibitor TDZD-8 also improved novel object recognition and temporal ordering in male and female GSK3 knockin mice. These findings demonstrate that hyperactive GSK3 is sufficient to impair adult hippocampal NPC proliferation and to impair performance in three cognitive tasks in both male and female mice, but these changes in NPC proliferation do not directly regulate novel object recognition and temporal ordering tasks.

Harnessing modern web application technology to create intuitive and efficient data visualization and sharing tools.

Neuroscientists increasingly need to work with big data in order to derive meaningful results in their field. Collecting, organizing and analyzing this data can be a major hurdle on the road to scientific discovery. This hurdle can be lowered using the same technologies that are currently revolutionizing the way that cultural and social media sites represent and share information with their users. Web application technologies and standards such as RESTful webservices, HTML5 and high-performance in-browser JavaScript engines are being utilized to vastly improve the way that the world accesses and shares information. The neuroscience community can also benefit tremendously from these technologies. We present here a web application that allows users to explore and request the complex datasets that need to be shared among the neuroimaging community. The COINS (Collaborative Informatics and Neuroimaging Suite) Data Exchange uses web application technologies to facilitate data sharing in three phases: Exploration, Request/Communication, and Download. This paper will focus on the first phase, and how intuitive exploration of large and complex datasets is achieved using a framework that centers around asynchronous client-server communication (AJAX) and also exposes a powerful API that can be utilized by other applications to explore available data. First opened to the neuroscience community in August 2012, the Data Exchange has already provided researchers with over 2500 GB of data.

Automated collection of imaging and phenotypic data to centralized and distributed data repositories.

Accurate data collection at the ground level is vital to the integrity of neuroimaging research. Similarly important is the ability to connect and curate data in order to make it meaningful and sharable with other investigators. Collecting data, especially with several different modalities, can be time consuming and expensive. These issues have driven the development of automated collection of neuroimaging and clinical assessment data within COINS (Collaborative Informatics and Neuroimaging Suite). COINS is an end-to-end data management system. It provides a comprehensive platform for data collection, management, secure storage, and flexible data retrieval (Bockholt et al., 2010; Scott et al., 2011). It was initially developed for the investigators at the Mind Research Network (MRN), but is now available to neuroimaging institutions worldwide. Self Assessment (SA) is an application embedded in the Assessment Manager (ASMT) tool in COINS. It is an innovative tool that allows participants to fill out assessments via the web-based Participant Portal. It eliminates the need for paper collection and data entry by allowing participants to submit their assessments directly to COINS. Instruments (surveys) are created through ASMT and include many unique question types and associated SA features that can be implemented to help the flow of assessment administration. SA provides an instrument queuing system with an easy-to-use drag and drop interface for research staff to set up participants' queues. After a queue has been created for the participant, they can access the Participant Portal via the internet to fill out their assessments. This allows them the flexibility to participate from home, a library, on site, etc. The collected data is stored in a PostgresSQL database at MRN. This data is only accessible by users that have explicit permission to access the data through their COINS user accounts and access to MRN network. This allows for high volume data collection and with minimal user access to PHI (protected health information). An added benefit to using COINS is the ability to collect, store and share imaging data and assessment data with no interaction with outside tools or programs. All study data collected (imaging and assessment) is stored and exported with a participant's unique subject identifier so there is no need to keep extra spreadsheets or databases to link and keep track of the data. Data is easily exported from COINS via the Query Builder and study portal tools, which allow fine grained selection of data to be exported into comma separated value file format for easy import into statistical programs. There is a great need for data collection tools that limit human intervention and error while at the same time providing users with intuitive design. COINS aims to be a leader in database solutions for research studies collecting data from several different modalities.

Social cognition, face processing, and oxytocin receptor single nucleotide polymorphisms in typically developing children.

Recent research has provided evidence of a link between behavioral measures of social cognition (SC) and neural and genetic correlates. Differences in face processing and variations in the oxytocin receptor (OXTR) gene have been associated with SC deficits and autism spectrum disorder (ASD) traits. Much work has examined the qualitative differences between those with ASD and typically developing (TD) individuals, but very little has been done to quantify the natural variation in ASD-like traits in the typical population. The present study examines this variation in TD children using a multidimensional perspective involving behavior assessment, neural electroencephalogram (EEG) testing, and OXTR genotyping. Children completed a series of neurocognitive assessments, provided saliva samples for sequencing, and completed a face processing task while connected to an EEG. No clear pattern emerged for EEG covariates or genotypes for individual OXTR single nucleotide polymorphisms (SNPs). However, SNPs rs2254298 and rs53576 consistently interacted such that the AG/GG allele combination of these SNPs was associated with poorer performance on neurocognitive measures. These results suggest that neither SNP in isolation is risk-conferring, but rather that the combination of rs2254298(A/G) and rs53576(G/G) confers a deleterious effect on SC across several neurocognitive measures.