ReX: an integrative tool for quantifying and optimizing measurement reliability for the study of individual differences.

Characterizing multifaceted individual differences in brain function using neuroimaging is central to biomarker discovery in neuroscience. We provide an integrative toolbox, Reliability eXplorer (ReX), to facilitate the examination of individual variation and reliability as well as the effective direction for optimization of measuring individual differences in biomarker discovery. We also illustrate gradient flows, a two-dimensional field map-based approach to identifying and representing the most effective direction for optimization when measuring individual differences, which is implemented in ReX.

Connectome-wide structure-function coupling models implicate polysynaptic alterations in autism.

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental diagnoses. Although incompletely understood, structural and functional network alterations are increasingly recognized to be at the core of the condition. We utilized multimodal imaging and connectivity modeling to study structure-function coupling in ASD and probed mono- and polysynaptic mechanisms on structurally-governed network function. We examined multimodal magnetic resonance imaging data in 80 ASD and 61 neurotypical controls from the Autism Brain Imaging Data Exchange (ABIDE) II initiative. We predicted intrinsic functional connectivity from structural connectivity data in each participant using a Riemannian optimization procedure that varies the times that simulated signals can unfold along tractography-derived personalized connectomes. In both ASD and neurotypical controls, we observed improved structure-function prediction at longer diffusion time scales, indicating better modeling of brain function when polysynaptic mechanisms are accounted for. Prediction accuracy differences (∆prediction accuracy) were marked in transmodal association systems, such as the default mode network, in both neurotypical controls and ASD. Differences were, however, lower in ASD in a polysynaptic regime at higher simulated diffusion times. We compared regional differences in ∆prediction accuracy between both groups to assess the impact of polysynaptic communication on structure-function coupling. This analysis revealed that between-group differences in ∆prediction accuracy followed a sensory-to-transmodal cortical hierarchy, with an increased gap between controls and ASD in transmodal compared to sensory/motor systems. Multivariate associative techniques revealed that structure-function differences reflected inter-individual differences in autistic symptoms and verbal as well as non-verbal intelligence. Our network modeling approach sheds light on atypical structure-function coupling in autism, and suggests that polysynaptic network mechanisms are implicated in the condition and that these can help explain its wide range of associated symptoms.

QSIPrep: an integrative platform for preprocessing and reconstructing diffusion MRI data.

Diffusion-weighted magnetic resonance imaging (dMRI) is the primary method for noninvasively studying the organization of white matter in the human brain. Here we introduce QSIPrep, an integrative software platform for the processing of diffusion images that is compatible with nearly all dMRI sampling schemes. Drawing on a diverse set of software suites to capitalize on their complementary strengths, QSIPrep facilitates the implementation of best practices for processing of diffusion images.

Probing the content of affective semantic memory following caregiving-related early adversity.

Cognitive science has demonstrated that we construct knowledge about the world by abstracting patterns from routinely encountered experiences and storing them as semantic memories. This preregistered study tested the hypothesis that caregiving-related early adversities (crEAs) shape affective semantic memories to reflect the content of those adverse interpersonal-affective experiences. We also tested the hypothesis that because affective semantic memories may continue to evolve in response to later-occurring positive experiences, child-perceived attachment security will inform their content. The sample comprised 160 children (ages 6-12 at Visit 1; 87F/73 M), 66% of whom experienced crEAs (n = 105). At Visit 1, crEA exposure prior to study enrollment was operationalized as parental-reports endorsing a history of crEAs (abuse/neglect, permanent/significant parent-child separation); while child-reports assessed concurrent attachment security. A false memory task was administered online ∼2.5 years later (Visit 2) to probe the content of affective semantic memories-specifically attachment schemas. Results showed that crEA exposure (vs. no exposure) was associated with a higher likelihood of falsely endorsing insecure (vs. secure) schema scenes. Attachment security moderated the association between crEA exposure and insecure schema-based false recognition. Findings suggest that interpersonal-affective semantic schemas include representations of parent-child interactions that may capture the quality of one's own attachment experiences and that these representations shape how children remember attachment-relevant narrative events. Findings are also consistent with the hypothesis that these affective semantic memories can be modified by later experiences. Moving forward, the approach taken in this study provides a means of operationalizing Bowlby's notion of internal working models within a cognitive neuroscience framework. RESEARCH HIGHLIGHTS: Affective semantic memories representing insecure schema knowledge (child needs + needs-not-met) may be more salient, elaborated, and persistent among youths exposed to early caregiving adversity. All youths, irrespective of early caregiving adversity exposure, may possess affective semantic memories that represent knowledge of secure schemas (child needs + needs-met). Establishing secure relationships with parents following early-occurring caregiving adversity may attenuate the expression of insecure semantic memories, suggesting potential malleability. Affective semantic memories include schema representations of parent-child interactions that may capture the quality of one's own attachment experiences and shape how youths remember attachment-relevant events.

Understanding priorities and needs for child and adolescent mental health in Greece from multiple informants: an open resource dataset.

The Child and Adolescent Mental Health Initiative (CAMHI) aims to enhance mental health care capacity for children and adolescents across Greece. Considering the need for evidence-based policy, the program developed an open-resource dataset for researching the field within the country. A comprehensive, mixed-method, community-based research was conducted in 2022/2023 assessing the current state, needs, barriers, and opportunities according to multiple viewpoints. We surveyed geographically distributed samples of 1,756 caregivers, 1,201 children/adolescents, 404 schoolteachers, and 475 health professionals using validated instruments to assess mental health symptoms, mental health needs, literacy and stigma, service use and access, professional practices, training background, and training needs and preferences. Fourteen focus groups were conducted with informants from diverse populations (including underrepresented minorities) to reach an in-depth understanding of those topics. A dataset with quantitative and qualitative findings is now available for researchers, policymakers, and society [ https://osf.io/crz6h/ and https://rpubs.com/camhi/sdashboard ]. This resource offers valuable data for assessing the needs and priorities for child and adolescent mental health care in Greece. It is now freely available to consult, and is expected to inform upcoming research and evidence-based professional training. This initiative may inspire similar ones in other countries, informing methodological strategies for researching mental health needs.

Omnipresence of the sensorimotor-association axis topography in the human connectome.

Low-dimensional representations are increasingly used to study meaningful organizational principles within the human brain. Most notably, the sensorimotor-association axis consistently explains the most variance in the human connectome as its so-called principal gradient, suggesting that it represents a fundamental organizational principle. While recent work indicates these low dimensional representations are relatively robust, they are limited by modeling only certain aspects of the functional connectivity structure. To date, the majority of studies have restricted these approaches to the strongest connections in the brain, treating weaker or negative connections as noise despite evidence of meaningful structure among them. The present work examines connectivity gradients of the human connectome across a full range of connectivity strengths and explores the implications for outcomes of individual differences, identifying potential dependencies on thresholds and opportunities to improve prediction tasks. Interestingly, the sensorimotor-association axis emerged as the principal gradient of the human connectome across the entire range of connectivity levels. Moreover, the principal gradient of connections at intermediate strengths encoded individual differences, better followed individual-specific anatomical features, and was also more predictive of intelligence. Taken together, our results add to evidence of the sensorimotor-association axis as a fundamental principle of the brain's functional organization, since it is evident even in the connectivity structure of more lenient connectivity thresholds. These more loosely coupled connections further appear to contain valuable and potentially important information that could be used to improve our understanding of individual differences, diagnosis, and the prediction of treatment outcomes.

Deviations from a typical development of the cerebellum in youth are associated with psychopathology, executive functions and educational outcomes.

BACKGROUND: Understanding deviations from typical brain development is a promising approach to comprehend pathophysiology in childhood and adolescence. We investigated if cerebellar volumes different than expected for age and sex could predict psychopathology, executive functions and academic achievement. METHODS: Children and adolescents aged 6-17 years from the Brazilian High-Risk Cohort Study for Mental Conditions had their cerebellar volume estimated using Multiple Automatically Generated Templates from T1-weighted images at baseline (n = 677) and at 3-year follow-up (n = 447). Outcomes were assessed using the Child Behavior Checklist and standardized measures of executive functions and school achievement. Models of typically developing cerebellum were based on a subsample not exposed to risk factors and without mental-health conditions (n = 216). Deviations from this model were constructed for the remaining individuals (n = 461) and standardized variation from age and sex trajectory model was used to predict outcomes in cross-sectional, longitudinal and mediation analyses. RESULTS: Cerebellar volumes higher than expected for age and sex were associated with lower externalizing specific factor and higher executive functions. In a longitudinal analysis, deviations from typical development at baseline predicted inhibitory control at follow-up, and cerebellar deviation changes from baseline to follow-up predicted changes in reading and writing abilities. The association between deviations in cerebellar volume and academic achievement was mediated by inhibitory control. CONCLUSIONS: Deviations in the cerebellar typical development are associated with outcomes in youth that have long-lasting consequences. This study highlights both the potential of typical developing models and the important role of the cerebellum in mental health, cognition and education.

Shared and distinct patterns of atypical cortical morphometry in children with autism and anxiety.

Autism spectrum disorder (ASD) and anxiety disorders (ANX) are common neurodevelopmental conditions with several overlapping symptoms. Notably, many children and adolescents with ASD also have an ANX diagnosis, suggesting shared pathological mechanisms. Here, we leveraged structural imaging and phenotypic data from 112 youth (33 ASD, 37 ANX, 42 typically developing controls) to assess shared and distinct cortical thickness patterns of the disorders. ANX was associated with widespread increases in cortical thickness, while ASD related to a mixed pattern of subtle increases and decreases across the cortical mantle. Despite the qualitative difference in the case-control contrasts, the statistical maps from the ANX-vs-controls and ASD-vs-controls analyses were significantly correlated when correcting for spatial autocorrelation. Dimensional analysis, regressing trait anxiety and social responsiveness against cortical thickness measures, partially recapitulated diagnosis-based findings. Collectively, our findings provide evidence for a common axis of neurodevelopmental disturbances as well as distinct effects of ASD and ANX on cortical thickness.

The science of child and adolescent mental health in Greece: a nationwide systematic review.

Evidence-based information is essential for effective mental health care, yet the extent and accessibility of the scientific literature are critical barriers for professionals and policymakers. To map the necessities and make validated resources accessible, we undertook a systematic review of scientific evidence on child and adolescent mental health in Greece encompassing three research topics: prevalence estimates, assessment instruments, and interventions. We searched Pubmed, Web of Science, PsycINFO, Google Scholar, and IATPOTEK from inception to December 16th, 2021. We included studies assessing the prevalence of conditions, reporting data on assessment tools, and experimental interventions. For each area, manuals informed data extraction and the methodological quality were ascertained using validated tools. This review was registered in protocols.io [68583]. We included 104 studies reporting 533 prevalence estimates, 223 studies informing data on 261 assessment instruments, and 34 intervention studies. We report the prevalence of conditions according to regions within the country. A repository of locally validated instruments and their psychometrics was compiled. An overview of interventions provided data on their effectiveness. The outcomes are made available in an interactive resource online [ https://rpubs.com/camhi/sysrev_table ]. Scientific evidence on child and adolescent mental health in Greece has now been cataloged and appraised. This timely and accessible compendium of up-to-date evidence offers valuable resources for clinical practice and policymaking in Greece and may encourage similar assessments in other countries.

Curation of BIDS (CuBIDS): A workflow and software package for streamlining reproducible curation of large BIDS datasets.

The Brain Imaging Data Structure (BIDS) is a specification accompanied by a software ecosystem that was designed to create reproducible and automated workflows for processing neuroimaging data. BIDS Apps flexibly build workflows based on the metadata detected in a dataset. However, even BIDS valid metadata can include incorrect values or omissions that result in inconsistent processing across sessions. Additionally, in large-scale, heterogeneous neuroimaging datasets, hidden variability in metadata is difficult to detect and classify. To address these challenges, we created a Python-based software package titled "Curation of BIDS" (CuBIDS), which provides an intuitive workflow that helps users validate and manage the curation of their neuroimaging datasets. CuBIDS includes a robust implementation of BIDS validation that scales to large samples and incorporates DataLad--a version control software package for data--as an optional dependency to ensure reproducibility and provenance tracking throughout the entire curation process. CuBIDS provides tools to help users perform quality control on their images' metadata and identify unique combinations of imaging parameters. Users can then execute BIDS Apps on a subset of participants that represent the full range of acquisition parameters that are present, accelerating pipeline testing on large datasets.

Heterogeneity in caregiving-related early adversity: Creating stable dimensions and subtypes.

Early psychosocial adversities exist at many levels, including caregiving-related, extrafamilial, and sociodemographic, which despite their high interrelatedness may have unique impacts on development. In this paper, we focus on caregiving-related early adversities (crEAs) and parse the heterogeneity of crEAs via data reduction techniques that identify experiential cooccurrences. Using network science, we characterized crEA cooccurrences to represent the comorbidity of crEA experiences across a sample of school-age children (n = 258; 6-12 years old) with a history of crEAs. crEA dimensions (variable level) and crEA subtypes (subject level) were identified using parallel factor analysis/principal component analysis and graph-based Louvain community detection. Bagging enhancement with cross-validation provided estimates of robustness. These data-driven dimensions/subtypes showed evidence of stability, transcended traditional sociolegally defined groups, were more homogenous than sociolegally defined groups, and reduced statistical correlations with sociodemographic factors. Finally, random forests showed both unique and common predictive importance of the crEA dimensions/subtypes for childhood mental health symptoms and academic skills. These data-driven outcomes provide additional tools and recommendations for crEA data reduction to inform precision medicine efforts in this area.

Impact of concatenating fMRI data on reliability for functional connectomics.

Compelling evidence suggests the need for more data per individual to reliably map the functional organization of the human connectome. As the notion that 'more data is better' emerges as a golden rule for functional connectomics, researchers find themselves grappling with the challenges of how to obtain the desired amounts of data per participant in a practical manner, particularly for retrospective data aggregation. Increasingly, the aggregation of data across all fMRI scans available for an individual is being viewed as a solution, regardless of scan condition (e.g., rest, task, movie). A number of open questions exist regarding the aggregation process and the impact of different decisions on the reliability of resultant aggregate data. We leveraged the availability of highly sampled test-retest datasets to systematically examine the impact of data aggregation strategies on the reliability of cortical functional connectomics. Specifically, we compared functional connectivity estimates derived after concatenating from: 1) multiple scans under the same state, 2) multiple scans under different states (i.e. hybrid or general functional connectivity), and 3) subsets of one long scan. We also varied connectivity processing (i.e. global signal regression, ICA-FIX, and task regression) and estimation procedures. When the total number of time points is equal, and the scan state held constant, concatenating multiple shorter scans had a clear advantage over a single long scan. However, this was not necessarily true when concatenating across different fMRI states (i.e. task conditions), where the reliability from the aggregate data varied across states. Concatenating fewer numbers of states that are more reliable tends to yield higher reliability. Our findings provide an overview of multiple dependencies of data concatenation that should be considered to optimize reliability in analysis of functional connectivity data.

Mapping functional gradients of the striatal circuit using simultaneous microelectric stimulation and ultrahigh-field fMRI in non-human primates.

Advances in functional magnetic resonance imaging (fMRI) have significantly enhanced our understanding of the striatal system of both humans and non-human primates (NHP) over the last few decades. However, its circuit-level functional anatomy remains poorly understood, partly because in-vivo fMRI cannot directly perturb a brain system and map its casual input-output relationship. Also, routine 3T fMRI has an insufficient spatial resolution. We performed electrical microstimulation (EM) of the striatum in lightly-anesthetized NHPs while simultaneously mapping whole-brain activation, using contrast-enhanced fMRI at ultra-high-field 7T. By stimulating multiple positions along the striatum's main (dorsal-to-ventral) axis, we revealed its complex functional circuit concerning mutually connected subsystems in both cortical and subcortical areas. Indeed, within the striatum, there were distinct brain activation patterns across different stimulation sites. Specifically, dorsal stimulation revealed a medial-to-lateral elongated shape of activation in upper caudate and putamen areas, whereas ventral stimulation evoked areas confined to the medial and lower caudate. Such dorsoventral gradients also appeared in neocortical and thalamic activations, indicating consistent embedding profiles of the striatal system across the whole brain. These findings reflect different forms of within-circuit and inter-regional neuronal connectivity between the dorsal and ventromedial striatum. These patterns both shared and contrasted with previous anatomical tract-tracing and in-vivo resting-state fMRI studies. Our approach of combining microstimulation and whole-brain fMRI mapping in NHPs provides a unique opportunity to integrate our understanding of a targeted brain area's meso- and macro-scale functional systems.

Stability and similarity of the pediatric connectome as developmental measures.

Patterns of functional connectivity are unique at the individual level, enabling test-retest matching algorithms to identify a subject from among a group using only their functional connectome. Recent findings show that accuracies of these algorithms in children increase with age. Relatedly, the persistence of functional connectivity (FC) patterns across tasks and rest also increases with age. This study investigated the hypothesis that within-subject stability and between-subject similarity of the whole-brain pediatric connectome are developmentally relevant outcomes. Using data from 210 help-seeking children and adolescents, ages 6-21 years (Healthy Brain Network Biobank), we computed whole-brain FC matrices for each participant during two different movies (MovieDM and MovieTP) and two runs of task-free rest (all from a single scan session) and fed these matrices to a test-retest matching algorithm. We replicated the finding that matching accuracies for children and youth (ages 6-21 years) are low (18-44%), and that cross-state and cross-movie accuracies were the lowest. Results also showed that parcellation resolution and the number of volumes used in each matrix affect fingerprinting accuracies. Next, we calculated three measures of whole-connectome stability for each subject: cross-rest (Rest1-Rest2), cross-state (MovieDM-Rest1), and cross-movie (MovieDM-MovieTP), and three measures of within-state between-subject connectome similarity for Rest1, MovieDM, and MovieTP. We show that stability and similarity were correlated, but that these measures were not related to age. A principal component analysis of these measures yielded two components that we used to test for brain-behavior correlations with IQ, general psychopathology, and social skills measures (n = 119). The first component was significantly correlated with the social skills measure (r=-0.26, p = 0.005). Post hoc correlations showed that the social skills measure correlated with both cross-rest stability (r=-0.29, p = 0.001) and with connectome similarity during MovieDM (r=-0.28, p = 0.002). These findings suggest that the stability and similarity of the whole-brain connectome relate to the development of social skills. We infer that the maturation of the functional connectome simultaneously achieves patterns of FC that are distinct at the individual subject level, that are shared across individuals, and that are persistent across states and across runs-features which presumably combine to optimize neural processing during development. Future longitudinal work could reveal the developmental trajectories of stability and similarity of the connectome.

Measurement reliability for individual differences in multilayer network dynamics: Cautions and considerations.

Multilayer network models have been proposed as an effective means of capturing the dynamic configuration of distributed neural circuits and quantitatively describing how communities vary over time. Beyond general insights into brain function, a growing number of studies have begun to employ these methods for the study of individual differences. However, test-retest reliabilities for multilayer network measures have yet to be fully quantified or optimized, potentially limiting their utility for individual difference studies. Here, we systematically evaluated the impact of multilayer community detection algorithms, selection of network parameters, scan duration, and task condition on test-retest reliabilities of multilayer network measures (i.e., flexibility, integration, and recruitment). A key finding was that the default method used for community detection by the popular generalized Louvain algorithm can generate erroneous results. Although available, an updated algorithm addressing this issue is yet to be broadly adopted in the neuroimaging literature. Beyond the algorithm, the present work identified parameter selection as a key determinant of test-retest reliability; however, optimization of these parameters and expected reliabilities appeared to be dataset-specific. Once parameters were optimized, consistent with findings from the static functional connectivity literature, scan duration was a much stronger determinant of reliability than scan condition. When the parameters were optimized and scan duration was sufficient, both passive (i.e., resting state, Inscapes, and movie) and active (i.e., flanker) tasks were reliable, although reliability in the movie watching condition was significantly higher than in the other three tasks. The minimal data requirement for achieving reliable measures for the movie watching condition was 20 min, and 30 min for the other three tasks. Our results caution the field against the use of default parameters without optimization based on the specific datasets to be employed - a process likely to be limited for most due to the lack of test-retest samples to enable parameter optimization.

U-net model for brain extraction: Trained on humans for transfer to non-human primates.

Brain extraction (a.k.a. skull stripping) is a fundamental step in the neuroimaging pipeline as it can affect the accuracy of downstream preprocess such as image registration, tissue classification, etc. Most brain extraction tools have been designed for and applied to human data and are often challenged by non-human primates (NHP) data. Amongst recent attempts to improve performance on NHP data, deep learning models appear to outperform the traditional tools. However, given the minimal sample size of most NHP studies and notable variations in data quality, the deep learning models are very rarely applied to multi-site samples in NHP imaging. To overcome this challenge, we used a transfer-learning framework that leverages a large human imaging dataset to pretrain a convolutional neural network (i.e. U-Net Model), and then transferred this to NHP data using a small NHP training sample. The resulting transfer-learning model converged faster and achieved more accurate performance than a similar U-Net Model trained exclusively on NHP samples. We improved the generalizability of the model by upgrading the transfer-learned model using additional training datasets from multiple research sites in the Primate Data-Exchange (PRIME-DE) consortium. Our final model outperformed brain extraction routines from popular MRI packages (AFNI, FSL, and FreeSurfer) across a heterogeneous sample from multiple sites in the PRIME-DE with less computational cost (20 s~10 min). We also demonstrated the transfer-learning process enables the macaque model to be updated for use with scans from chimpanzees, marmosets, and other mammals (e.g. pig). Our model, code, and the skull-stripped mask repository of 136 macaque monkeys are publicly available for unrestricted use by the neuroimaging community at https://github.com/HumanBrainED/NHP-BrainExtraction.

A collaborative resource platform for non-human primate neuroimaging.

Neuroimaging non-human primates (NHPs) is a growing, yet highly specialized field of neuroscience. Resources that were primarily developed for human neuroimaging often need to be significantly adapted for use with NHPs or other animals, which has led to an abundance of custom, in-house solutions. In recent years, the global NHP neuroimaging community has made significant efforts to transform the field towards more open and collaborative practices. Here we present the PRIMatE Resource Exchange (PRIME-RE), a new collaborative online platform for NHP neuroimaging. PRIME-RE is a dynamic community-driven hub for the exchange of practical knowledge, specialized analytical tools, and open data repositories, specifically related to NHP neuroimaging. PRIME-RE caters to both researchers and developers who are either new to the field, looking to stay abreast of the latest developments, or seeking to collaboratively advance the field .

Remote Digital Psychiatry for Mobile Mental Health Assessment and Therapy: MindLogger Platform Development Study.

BACKGROUND: Universal access to assessment and treatment of mental health and learning disorders remains a significant and unmet need. There are many people without access to care because of economic, geographic, and cultural barriers, as well as the limited availability of clinical experts who could help advance our understanding and treatment of mental health. OBJECTIVE: This study aims to create an open, configurable software platform to build clinical measures, mobile assessments, tasks, and interventions without programming expertise. Specifically, our primary requirements include an administrator interface for creating and scheduling recurring and customized questionnaires where end users receive and respond to scheduled notifications via an iOS or Android app on a mobile device. Such a platform would help relieve overwhelmed health systems and empower remote and disadvantaged subgroups in need of accurate and effective information, assessment, and care. This platform has the potential to advance scientific research by supporting the collection of data with instruments tailored to specific scientific questions from large, distributed, and diverse populations. METHODS: We searched for products that satisfy these requirements. We designed and developed a new software platform called MindLogger, which exceeds the requirements. To demonstrate the platform's configurability, we built multiple applets (collections of activities) within the MindLogger mobile app and deployed several of them, including a comprehensive set of assessments underway in a large-scale, longitudinal mental health study. RESULTS: Of the hundreds of products we researched, we found 10 that met our primary requirements with 4 that support end-to-end encryption, 2 that enable restricted access to individual users' data, 1 that provides open-source software, and none that satisfy all three. We compared features related to information presentation and data capture capabilities; privacy and security; and access to the product, code, and data. We successfully built MindLogger mobile and web applications, as well as web browser-based tools for building and editing new applets and for administering them to end users. MindLogger has end-to-end encryption, enables restricted access, is open source, and supports a variety of data collection features. One applet is currently collecting data from children and adolescents in our mental health study, and other applets are in different stages of testing and deployment for use in clinical and research settings. CONCLUSIONS: We demonstrated the flexibility and applicability of the MindLogger platform through its deployment in a large-scale, longitudinal, mobile mental health study and by building a variety of other mental health-related applets. With this release, we encourage a broad range of users to apply the MindLogger platform to create and test applets to advance health care and scientific research. We hope that increasing the availability of applets designed to assess and administer interventions will facilitate access to health care in the general population.

Toward a connectivity gradient-based framework for reproducible biomarker discovery.

Despite myriad demonstrations of feasibility, the high dimensionality of fMRI data remains a critical barrier to its utility for reproducible biomarker discovery. Recent efforts to address this challenge have capitalized on dimensionality reduction techniques applied to resting-state fMRI, identifying principal components of intrinsic connectivity which describe smooth transitions across different cortical systems, so called "connectivity gradients". These gradients recapitulate neurocognitively meaningful organizational principles that are present in both human and primate brains, and also appear to differ among individuals and clinical populations. Here, we provide a critical assessment of the suitability of connectivity gradients for biomarker discovery. Using the Human Connectome Project (discovery subsample=209; two replication subsamples= 209 × 2) and the Midnight scan club (n = 9), we tested the following key biomarker traits - reliability, reproducibility and predictive validity - of functional gradients. In doing so, we systematically assessed the effects of three analytical settings, including i) dimensionality reduction algorithms (i.e., linear vs. non-linear methods), ii) input data types (i.e., raw time series, [un-]thresholded functional connectivity), and iii) amount of the data (resting-state fMRI time-series lengths). We found that the reproducibility of functional gradients across algorithms and subsamples is generally higher for those explaining more variances of whole-brain connectivity data, as well as those having higher reliability. Notably, among different analytical settings, a linear dimensionality reduction (principal component analysis in our study), more conservatively thresholded functional connectivity (e.g., 95-97%) and longer time-series data (at least ≥20mins) was found to be preferential conditions to obtain higher reliability. Those gradients with higher reliability were able to predict unseen phenotypic scores with a higher accuracy, highlighting reliability as a critical prerequisite for validity. Importantly, prediction accuracy with connectivity gradients exceeded that observed with more traditional edge-based connectivity measures, suggesting the added value of a low-dimensional and multivariate gradient approach. Finally, the present work highlights the importance and benefits of systematically exploring the parameter space for new imaging methods before widespread deployment.

Functional connectivity of EEG is subject-specific, associated with phenotype, and different from fMRI.

A variety of psychiatric, behavioral and cognitive phenotypes have been linked to brain ''functional connectivity'' -- the pattern of correlation observed between different brain regions. Most commonly assessed using functional magnetic resonance imaging (fMRI), here, we investigate the connectivity-phenotype associations with functional connectivity measured with electroencephalography (EEG), using phase-coupling. We analyzed data from the publicly available Healthy Brain Network Biobank. This database compiles a growing sample of children and adolescents, currently encompassing 1657 individuals. Among a variety of assessment instruments we focus on ten phenotypic and additional demographic measures that capture most of the variance in this sample. The largest effect sizes are found for age and sex for both fMRI and EEG. We replicate previous findings of an association of Intelligence Quotient (IQ) and Attention Deficit Hyperactivity Disorder (ADHD) with the pattern of fMRI functional connectivity. We also find an association with socioeconomic status, anxiety and the Child Behavior Checklist Score. For EEG we find a significant connectivity-phenotype relationship with IQ. The actual spatial patterns of functional connectivity are quite different between fMRI and source-space EEG. However, within EEG we observe clusters of functional connectivity that are consistent across frequency bands. Additionally we analyzed reproducibility of functional connectivity. We compare connectivity obtained with different tasks, including resting state, a video and a visual flicker task. For both EEG and fMRI the variation between tasks was smaller than the variability observed between subjects. We also found an increase of reliability with increasing frequency of the EEG, and increased sampling duration. We conclude that, while the patterns of functional connectivity are distinct between fMRI and phase-coupling of EEG, they are nonetheless similar in their robustness to the task, and similar in that idiosyncratic patterns of connectivity predict individual phenotypes.