Robust single-trial event-related potentials differentiate between distress and fear disorders.

Recent evidence indicates that measures of brain functioning as indexed by event-related potentials (ERPs) on the electroencephalogram align more closely to transdiagnostic measures of psychopathology than to categorical taxonomies. The Hierarchical Taxonomy of Psychopathology (HiTOP) is a transdiagnostic, dimensional framework aiming to solve issues of comorbidity, symptom heterogeneity, and arbitrary diagnostic boundaries. Based on shared features, the emotional disorders are allocated into subfactors Distress and Fear. Evidence indicates that disorders that are close in the HiTOP hierarchy share etiology, symptom profiles, and treatment outcomes. However, further studies testing the biological underpinnings of the HiTOP are called for. In this study, we assessed differences between Distress and Fear in a range of well-studied ERP components. In total, 50 patients with emotional disorders were divided into two groups (Distress, N = 25; Fear, N = 25) according to HiTOP criteria and compared against 37 healthy comparison (HC) subjects. Addressing issues in traditional ERP preprocessing and analysis methods, we applied robust single-trial analysis as implemented in the EEGLAB toolbox LIMO EEG. Several ERP components were found to differ between the groups. Surprisingly, we found no difference between Fear and HC for any of the ERPs. This suggests that some well-established results from the literature, e.g., increased error-related negativity in OCD, are not a shared neurobiological correlate of the Fear subfactor. Conversely, for Distress, we found reductions compared to Fear and HC in several ERP components across paradigms. Future studies could utilize HiTOP-validated psychopathology measures to more precisely define subfactor groups.

Transdiagnostic psychopathology in the light of robust single-trial event-related potentials.

Recent evidence indicates that event-related potentials (ERPs) as measured on the electroencephalogram (EEG) are more closely related to transdiagnostic, dimensional measures of psychopathology (TDP) than to diagnostic categories. A comprehensive examination of correlations between well-studied ERPs and measures of TDP is called for. In this study, we recruited 50 patients with emotional disorders undergoing 14 weeks of transdiagnostic group psychotherapy as well as 37 healthy comparison subjects (HC) matched in age and sex. HCs were assessed once and patients three times throughout treatment (N = 172 data sets) with a battery of well-studied ERPs and psychopathology measures consistent with the TDP framework The Hierarchical Taxonomy of Psychopathology (HiTOP). ERPs were quantified using robust single-trial analysis (RSTA) methods and TDP correlations with linear regression models as implemented in the EEGLAB toolbox LIMO EEG. We found correlations at several levels of the HiTOP hierarchy. Among these, a reduced P3b was associated with the general p-factor. A reduced error-related negativity correlated strongly with worse symptomatology across the Internalizing spectrum. Increases in the correct-related negativity correlated with symptoms loading unto the Distress subfactor in the HiTOP. The Flanker N2 was related to specific symptoms of Intrusive Cognitions and Traumatic Re-experiencing and the mismatch negativity to maladaptive personality traits at the lowest levels of the HiTOP hierarchy. Our study highlights the advantages of RSTA methods and of using validated TDP constructs within a consistent framework. Future studies could utilize machine learning methods to predict TDP from a set of ERP features at the subject level.

Open and reproducible neuroimaging: From study inception to publication.

Empirical observations of how labs conduct research indicate that the adoption rate of open practices for transparent, reproducible, and collaborative science remains in its infancy. This is at odds with the overwhelming evidence for the necessity of these practices and their benefits for individual researchers, scientific progress, and society in general. To date, information required for implementing open science practices throughout the different steps of a research project is scattered among many different sources. Even experienced researchers in the topic find it hard to navigate the ecosystem of tools and to make sustainable choices. Here, we provide an integrated overview of community-developed resources that can support collaborative, open, reproducible, replicable, robust and generalizable neuroimaging throughout the entire research cycle from inception to publication and across different neuroimaging modalities. We review tools and practices supporting study inception and planning, data acquisition, research data management, data processing and analysis, and research dissemination. An online version of this resource can be found at https://oreoni.github.io. We believe it will prove helpful for researchers and institutions to make a successful and sustainable move towards open and reproducible science and to eventually take an active role in its future development.

A systematic review on the use of quantitative imaging to detect cancer therapy adverse effects in normal-appearing brain tissue.

Cancer therapy for both central nervous system (CNS) and non-CNS tumors has been previously associated with transient and long-term cognitive deterioration, commonly referred to as 'chemo fog'. This therapy-related damage to otherwise normal-appearing brain tissue is reported using post-mortem neuropathological analysis. Although the literature on monitoring therapy effects on structural magnetic resonance imaging (MRI) is well established, such macroscopic structural changes appear relatively late and irreversible. Early quantitative MRI biomarkers of therapy-induced damage would potentially permit taking these treatment side effects into account, paving the way towards a more personalized treatment planning.This systematic review (PROSPERO number 224196) provides an overview of quantitative tomographic imaging methods, potentially identifying the adverse side effects of cancer therapy in normal-appearing brain tissue. Seventy studies were obtained from the MEDLINE and Web of Science databases. Studies reporting changes in normal-appearing brain tissue using MRI, PET, or SPECT quantitative biomarkers, related to radio-, chemo-, immuno-, or hormone therapy for any kind of solid, cystic, or liquid tumor were included. The main findings of the reviewed studies were summarized, providing also the risk of bias of each study assessed using a modified QUADAS-2 tool. For each imaging method, this review provides the methodological background, and the benefits and shortcomings of each method from the imaging perspective. Finally, a set of recommendations is proposed to support future research.

The Open Brain Consent: Informing research participants and obtaining consent to share brain imaging data.

Having the means to share research data openly is essential to modern science. For human research, a key aspect in this endeavor is obtaining consent from participants, not just to take part in a study, which is a basic ethical principle, but also to share their data with the scientific community. To ensure that the participants' privacy is respected, national and/or supranational regulations and laws are in place. It is, however, not always clear to researchers what the implications of those are, nor how to comply with them. The Open Brain Consent (https://open-brain-consent.readthedocs.io) is an international initiative that aims to provide researchers in the brain imaging community with information about data sharing options and tools. We present here a short history of this project and its latest developments, and share pointers to consent forms, including a template consent form that is compliant with the EU general data protection regulation. We also share pointers to an associated data user agreement that is not only useful in the EU context, but also for any researchers dealing with personal (clinical) data elsewhere.

GliMR: Cross-Border Collaborations to Promote Advanced MRI Biomarkers for Glioma.

Purpose: There is an annual incidence of 50,000 glioma cases in Europe. The optimal treatment strategy is highly personalised, depending on tumour type, grade, spatial localization, and the degree of tissue infiltration. In research settings, advanced magnetic resonance imaging (MRI) has shown great promise as a tool to inform personalised treatment decisions. However, the use of advanced MRI in clinical practice remains scarce due to the downstream effects of siloed glioma imaging research with limited representation of MRI specialists in established consortia; and the associated lack of available tools and expertise in clinical settings. These shortcomings delay the translation of scientific breakthroughs into novel treatment strategy. As a response we have developed the network "Glioma MR Imaging 2.0" (GliMR) which we present in this article. Methods: GliMR aims to build a pan-European and multidisciplinary network of experts and accelerate the use of advanced MRI in glioma beyond the current "state-of-the-art" in glioma imaging. The Action Glioma MR Imaging 2.0 (GliMR) was granted funding by the European Cooperation in Science and Technology (COST) in June 2019. Results: GliMR's first grant period ran from September 2019 to April 2020, during which several meetings were held and projects were initiated, such as reviewing the current knowledge on advanced MRI; developing a General Data Protection Regulation (GDPR) compliant consent form; and setting up the website. Conclusion: The Action overcomes the pre-existing limitations of glioma research and is funded until September 2023. New members will be accepted during its entire duration.

A controlled comparison of thickness, volume and surface areas from multiple cortical parcellation packages.

BACKGROUND: Cortical parcellation is an essential neuroimaging tool for identifying and characterizing morphometric and connectivity brain changes occurring with age and disease. A variety of software packages have been developed for parcellating the brain's cortical surface into a variable number of regions but interpackage differences can undermine reproducibility. Using a ground truth dataset (Edinburgh_NIH10), we investigated such differences for grey matter thickness (GMth), grey matter volume (GMvol) and white matter surface area (WMsa) for the superior frontal gyrus (SFG), supramarginal gyrus (SMG), and cingulate gyrus (CG) from 4 parcellation protocols as implemented in the FreeSurfer, BrainSuite, and BrainGyrusMapping (BGM) software packages. RESULTS: Corresponding gyral definitions and morphometry approaches were not identical across the packages. As expected, there were differences in the bordering landmarks of each gyrus as well as in the manner in which variability was addressed. Rostral and caudal SFG and SMG boundaries differed, and in the event of a double CG occurrence, its upper fold was not always addressed. This led to a knock-on effect that was visible at the neighbouring gyri (e.g., knock-on effect at the SFG following CG definition) as well as gyral morphometric measurements of the affected gyri. Statistical analysis showed that the most consistent approaches were FreeSurfer's Desikan-Killiany-Tourville (DKT) protocol for GMth and BrainGyrusMapping for GMvol. Package consistency varied for WMsa, depending on the region of interest. CONCLUSIONS: Given the significance and implications that a parcellation protocol will have on the classification, and sometimes treatment, of subjects, it is essential to select the protocol which accurately represents their regions of interest and corresponding morphometrics, while embracing cortical variability.

Logical and Methodological Issues Affecting Genetic Studies of Humans Reported in Top Neuroscience Journals.

Genetics and neuroscience are two areas of science that pose particular methodological problems because they involve detecting weak signals (i.e., small effects) in noisy data. In recent years, increasing numbers of studies have attempted to bridge these disciplines by looking for genetic factors associated with individual differences in behavior, cognition, and brain structure or function. However, different methodological approaches to guarding against false positives have evolved in the two disciplines. To explore methodological issues affecting neurogenetic studies, we conducted an in-depth analysis of 30 consecutive articles in 12 top neuroscience journals that reported on genetic associations in nonclinical human samples. It was often difficult to estimate effect sizes in neuroimaging paradigms. Where effect sizes could be calculated, the studies reporting the largest effect sizes tended to have two features: (i) they had the smallest samples and were generally underpowered to detect genetic effects, and (ii) they did not fully correct for multiple comparisons. Furthermore, only a minority of studies used statistical methods for multiple comparisons that took into account correlations between phenotypes or genotypes, and only nine studies included a replication sample or explicitly set out to replicate a prior finding. Finally, presentation of methodological information was not standardized and was often distributed across Methods sections and Supplementary Material, making it challenging to assemble basic information from many studies. Space limits imposed by journals could mean that highly complex statistical methods were described in only a superficial fashion. In summary, methods that have become standard in the genetics literature-stringent statistical standards, use of large samples, and replication of findings-are not always adopted when behavioral, cognitive, or neuroimaging phenotypes are used, leading to an increased risk of false-positive findings. Studies need to correct not just for the number of phenotypes collected but also for the number of genotypes examined, genetic models tested, and subsamples investigated. The field would benefit from more widespread use of methods that take into account correlations between the factors corrected for, such as spectral decomposition, or permutation approaches. Replication should become standard practice; this, together with the need for larger sample sizes, will entail greater emphasis on collaboration between research groups. We conclude with some specific suggestions for standardized reporting in this area.

A critical analysis of neuroanatomical software protocols reveals clinically relevant differences in parcellation schemes.

A high replicability in region-of-interest (ROI) morphometric or ROI-based connectivity analyses is essential for such methods to provide biomarkers of good health or disease. In this article, we focus on package design, and more specifically on cortical parcellation protocols, for novel insight into their contribution to inter-package differences. A critical analysis of cortical parcellation protocols from FreeSurfer, BrainSuite, BrainVISA and BrainGyrusMapping revealed major limitations. Details of reference populations are generally missing, cortical variability is not always explicitly accounted for and, more importantly, definition of gyral borders can be inconsistent. We recommend that in the package selection process end users incorporate protocol suitability for the ROIs under investigation, with these particular points in mind, as inter-package differences are likely to be significant and the source of incompatibility between studies' results.

A brain imaging repository of normal structural MRI across the life course: Brain Images of Normal Subjects (BRAINS).

The Brain Images of Normal Subjects (BRAINS) Imagebank (http://www.brainsimagebank.ac.uk) is an integrated repository project hosted by the University of Edinburgh and sponsored by the Scottish Imaging Network: A Platform for Scientific Excellence (SINAPSE) collaborators. BRAINS provide sharing and archiving of detailed normal human brain imaging and relevant phenotypic data already collected in studies of healthy volunteers across the life-course. It particularly focusses on the extremes of age (currently older age, and in future perinatal) where variability is largest, and which are under-represented in existing databanks. BRAINS is a living imagebank where new data will be added when available. Currently BRAINS contains data from 808 healthy volunteers, from 15 to 81years of age, from 7 projects in 3 centres. Additional completed and ongoing studies of normal individuals from 1st to 10th decades are in preparation and will be included as they become available. BRAINS holds several MRI structural sequences, including T1, T2, T2* and fluid attenuated inversion recovery (FLAIR), available in DICOM (http://dicom.nema.org/); in future Diffusion Tensor Imaging (DTI) will be added where available. Images are linked to a wide range of 'textual data', such as age, medical history, physiological measures (e.g. blood pressure), medication use, cognitive ability, and perinatal information for pre/post-natal subjects. The imagebank can be searched to include or exclude ranges of these variables to create better estimates of 'what is normal' at different ages.

Improving data availability for brain image biobanking in healthy subjects: Practice-based suggestions from an international multidisciplinary working group.

Brain imaging is now ubiquitous in clinical practice and research. The case for bringing together large amounts of image data from well-characterised healthy subjects and those with a range of common brain diseases across the life course is now compelling. This report follows a meeting of international experts from multiple disciplines, all interested in brain image biobanking. The meeting included neuroimaging experts (clinical and non-clinical), computer scientists, epidemiologists, clinicians, ethicists, and lawyers involved in creating brain image banks. The meeting followed a structured format to discuss current and emerging brain image banks; applications such as atlases; conceptual and statistical problems (e.g. defining 'normality'); legal, ethical and technological issues (e.g. consents, potential for data linkage, data security, harmonisation, data storage and enabling of research data sharing). We summarise the lessons learned from the experiences of a wide range of individual image banks, and provide practical recommendations to enhance creation, use and reuse of neuroimaging data. Our aim is to maximise the benefit of the image data, provided voluntarily by research participants and funded by many organisations, for human health. Our ultimate vision is of a federated network of brain image biobanks accessible for large studies of brain structure and function.

Beyond differences in means: robust graphical methods to compare two groups in neuroscience.

If many changes are necessary to improve the quality of neuroscience research, one relatively simple step could have great pay-offs: to promote the adoption of detailed graphical methods, combined with robust inferential statistics. Here, we illustrate how such methods can lead to a much more detailed understanding of group differences than bar graphs and t-tests on means. To complement the neuroscientist's toolbox, we present two powerful tools that can help us understand how groups of observations differ: the shift function and the difference asymmetry function. These tools can be combined with detailed visualisations to provide complementary perspectives about the data. We provide implementations in R and MATLAB of the graphical tools, and all the examples in the article can be reproduced using R scripts.

iMap4: An open source toolbox for the statistical fixation mapping of eye movement data with linear mixed modeling.

A major challenge in modern eye movement research is to statistically map where observers are looking, by isolating the significant differences between groups and conditions. As compared to the signals from contemporary neuroscience measures, such as magneto/electroencephalography and functional magnetic resonance imaging, eye movement data are sparser, with much larger variations in space across trials and participants. As a result, the implementation of a conventional linear modeling approach on two-dimensional fixation distributions often returns unstable estimations and underpowered results, leaving this statistical problem unresolved (Liversedge, Gilchrist, & Everling, 2011). Here, we present a new version of the iMap toolbox (Caldara & Miellet, 2011) that tackles this issue by implementing a statistical framework comparable to those developed in state-of-the-art neuroimaging data-processing toolboxes. iMap4 uses univariate, pixel-wise linear mixed models on smoothed fixation data, with the flexibility of coding for multiple between- and within-subjects comparisons and performing all possible linear contrasts for the fixed effects (main effects, interactions, etc.). Importantly, we also introduced novel nonparametric tests based on resampling, to assess statistical significance. Finally, we validated this approach by using both experimental and Monte Carlo simulation data. iMap4 is a freely available MATLAB open source toolbox for the statistical fixation mapping of eye movement data, with a user-friendly interface providing straightforward, easy-to-interpret statistical graphical outputs. iMap4 matches the standards of robust statistical neuroimaging methods and represents an important step in the data-driven processing of eye movement fixation data, an important field of vision sciences.

The Glasgow Voice Memory Test: Assessing the ability to memorize and recognize unfamiliar voices.

One thousand one hundred and twenty subjects as well as a developmental phonagnosic subject (KH) along with age-matched controls performed the Glasgow Voice Memory Test, which assesses the ability to encode and immediately recognize, through an old/new judgment, both unfamiliar voices (delivered as vowels, making language requirements minimal) and bell sounds. The inclusion of non-vocal stimuli allows the detection of significant dissociations between the two categories (vocal vs. non-vocal stimuli). The distributions of accuracy and sensitivity scores (d') reflected a wide range of individual differences in voice recognition performance in the population. As expected, KH showed a dissociation between the recognition of voices and bell sounds, her performance being significantly poorer than matched controls for voices but not for bells. By providing normative data of a large sample and by testing a developmental phonagnosic subject, we demonstrated that the Glasgow Voice Memory Test, available online and accessible from all over the world, can be a valid screening tool (~5 min) for a preliminary detection of potential cases of phonagnosia and of "super recognizers" for voices.

The human voice areas: Spatial organization and inter-individual variability in temporal and extra-temporal cortices.

fMRI studies increasingly examine functions and properties of non-primary areas of human auditory cortex. However there is currently no standardized localization procedure to reliably identify specific areas across individuals such as the standard 'localizers' available in the visual domain. Here we present an fMRI 'voice localizer' scan allowing rapid and reliable localization of the voice-sensitive 'temporal voice areas' (TVA) of human auditory cortex. We describe results obtained using this standardized localizer scan in a large cohort of normal adult subjects. Most participants (94%) showed bilateral patches of significantly greater response to vocal than non-vocal sounds along the superior temporal sulcus/gyrus (STS/STG). Individual activation patterns, although reproducible, showed high inter-individual variability in precise anatomical location. Cluster analysis of individual peaks from the large cohort highlighted three bilateral clusters of voice-sensitivity, or "voice patches" along posterior (TVAp), mid (TVAm) and anterior (TVAa) STS/STG, respectively. A series of extra-temporal areas including bilateral inferior prefrontal cortex and amygdalae showed small, but reliable voice-sensitivity as part of a large-scale cerebral voice network. Stimuli for the voice localizer scan and probabilistic maps in MNI space are available for download.

Imaging learned fear circuitry in awake mice using fMRI.

Functional magnetic resonance imaging (fMRI) of learned behaviour in 'awake rodents' provides the opportunity for translational preclinical studies into the influence of pharmacological and genetic manipulations on brain function. fMRI has recently been employed to investigate learned behaviour in awake rats. Here, this methodology is translated to mice, so that future fMRI studies may exploit the vast number of genetically modified mouse lines that are available. One group of mice was conditioned to associate a flashing light (conditioned stimulus, CS) with foot shock (PG; paired group), and another group of mice received foot shock and flashing light explicitly unpaired (UG; unpaired group). The blood oxygen level-dependent signal (proxy for neuronal activation) in response to the CS was measured 24 h later in awake mice from the PG and UG using fMRI. The amygdala, implicated in fear processing, was activated to a greater degree in the PG than in the UG in response to the CS. Additionally, the nucleus accumbens was activated in the UG in response to the CS. Because the CS signalled an absence of foot shock in the UG, it is possible that this region is involved in processing the safety aspect of the CS. To conclude, the first use of fMRI to visualise brain activation in awake mice that are completing a learned emotional task is reported. This work paves the way for future preclinical fMRI studies to investigate genetic and environmental influences on brain function in transgenic mouse models of disease and aging.

Test-retest reliability of structural brain networks from diffusion MRI.

Structural brain networks constructed from diffusion MRI (dMRI) and tractography have been demonstrated in healthy volunteers and more recently in various disorders affecting brain connectivity. However, few studies have addressed the reproducibility of the resulting networks. We measured the test-retest properties of such networks by varying several factors affecting network construction using ten healthy volunteers who underwent a dMRI protocol at 1.5T on two separate occasions. Each T1-weighted brain was parcellated into 84 regions-of-interest and network connections were identified using dMRI and two alternative tractography algorithms, two alternative seeding strategies, a white matter waypoint constraint and three alternative network weightings. In each case, four common graph-theoretic measures were obtained. Network properties were assessed both node-wise and per network in terms of the intraclass correlation coefficient (ICC) and by comparing within- and between-subject differences. Our findings suggest that test-retest performance was improved when: 1) seeding from white matter, rather than grey; and 2) using probabilistic tractography with a two-fibre model and sufficient streamlines, rather than deterministic tensor tractography. In terms of network weighting, a measure of streamline density produced better test-retest performance than tract-averaged diffusion anisotropy, although it remains unclear which is a more accurate representation of the underlying connectivity. For the best performing configuration, the global within-subject differences were between 3.2% and 11.9% with ICCs between 0.62 and 0.76. The mean nodal within-subject differences were between 5.2% and 24.2% with mean ICCs between 0.46 and 0.62. For 83.3% (70/84) of nodes, the within-subject differences were smaller than between-subject differences. Overall, these findings suggest that whilst current techniques produce networks capable of characterising the genuine between-subject differences in connectivity, future work must be undertaken to improve network reliability.

Cerebral processing of voice gender studied using a continuous carryover FMRI design.

Normal listeners effortlessly determine a person's gender by voice, but the cerebral mechanisms underlying this ability remain unclear. Here, we demonstrate 2 stages of cerebral processing during voice gender categorization. Using voice morphing along with an adaptation-optimized functional magnetic resonance imaging design, we found that secondary auditory cortex including the anterior part of the temporal voice areas in the right hemisphere responded primarily to acoustical distance with the previously heard stimulus. In contrast, a network of bilateral regions involving inferior prefrontal and anterior and posterior cingulate cortex reflected perceived stimulus ambiguity. These findings suggest that voice gender recognition involves neuronal populations along the auditory ventral stream responsible for auditory feature extraction, functioning in pair with the prefrontal cortex in voice gender perception.

Single subject fMRI test-retest reliability metrics and confounding factors.

While the fMRI test-retest reliability has been mainly investigated from the point of view of group level studies, here we present analyses and results for single-subject test-retest reliability. One important aspect of group level reliability is that not only does it depend on between-session variance (test-retest), but also on between-subject variance. This has partly led to a debate regarding which reliability metric to use and how different sources of noise contribute to between-session variance. Focusing on single subject reliability allows considering between-session only. In this study, we measured test-retest reliability in four behavioural tasks (motor mapping, covert verb generation, overt word repetition, and a landmark identification task) to ensure generalisation of the results and at three levels of data processing (time-series correlation, t value variance, and overlap of thresholded maps) to understand how each step influences the other and how confounding factors influence reliability at each of these steps. The contributions of confounding factors (scanner noise, subject motion, and coregistration) were investigated using multiple regression and relative importance analyses at each step. Finally, to achieve a fuller picture of what constitutes a reliable task, we introduced a bootstrap technique of within- vs. between-subject variance. Our results show that (i) scanner noise and coregistration errors have little contribution to between-session variance (ii) subject motion (especially correlated with the stimuli) can have detrimental effects on reliability (iii) different tasks lead to different reliability results. This suggests that between-session variance in fMRI is mostly caused by the variability of underlying cognitive processes and motion correlated with the stimuli rather than technical limitations of data processing.