SAN: Mitigating spatial covariance heterogeneity in cortical thickness data collected from multiple scanners or sites.

In neuroimaging studies, combining data collected from multiple study sites or scanners is becoming common to increase the reproducibility of scientific discoveries. At the same time, unwanted variations arise by using different scanners (inter-scanner biases), which need to be corrected before downstream analyses to facilitate replicable research and prevent spurious findings. While statistical harmonization methods such as ComBat have become popular in mitigating inter-scanner biases in neuroimaging, recent methodological advances have shown that harmonizing heterogeneous covariances results in higher data quality. In vertex-level cortical thickness data, heterogeneity in spatial autocorrelation is a critical factor that affects covariance heterogeneity. Our work proposes a new statistical harmonization method called spatial autocorrelation normalization (SAN) that preserves homogeneous covariance vertex-level cortical thickness data across different scanners. We use an explicit Gaussian process to characterize scanner-invariant and scanner-specific variations to reconstruct spatially homogeneous data across scanners. SAN is computationally feasible, and it easily allows the integration of existing harmonization methods. We demonstrate the utility of the proposed method using cortical thickness data from the Social Processes Initiative in the Neurobiology of the Schizophrenia(s) (SPINS) study. SAN is publicly available as an R package.

Searching Reproducible Brain Features using NeuroMark: Templates for Different Age Populations and Imaging Modalities.

A primary challenge to the data-driven analysis is the balance between poor generalizability of population-based research and characterizing more subject-, study- and population-specific variability. We previously introduced a fully automated spatially constrained independent component analysis (ICA) framework called NeuroMark and its functional MRI (fMRI) template. NeuroMark has been successfully applied in numerous studies, identifying brain markers reproducible across datasets and disorders. The first NeuroMark template was constructed based on young adult cohorts. We recently expanded on this initiative by creating a standardized normative multi-spatial-scale functional template using over 100,000 subjects, aiming to improve generalizability and comparability across studies involving diverse cohorts. While a unified template across the lifespan is desirable, a comprehensive investigation of the similarities and differences between components from different age populations might help systematically transform our understanding of the human brain by revealing the most well-replicated and variable network features throughout the lifespan. In this work, we introduced two significant expansions of NeuroMark templates first by generating replicable fMRI templates for infants, adolescents, and aging cohorts, and second by incorporating structural MRI (sMRI) and diffusion MRI (dMRI) modalities. Specifically, we built spatiotemporal fMRI templates based on 6,000 resting-state scans from four datasets. This is the first attempt to create robust ICA templates covering dynamic brain development across the lifespan. For the sMRI and dMRI data, we used two large publicly available datasets including more than 30,000 scans to build reliable templates. We employed a spatial similarity analysis to identify replicable templates and investigate the degree to which unique and similar patterns are reflective in different age populations. Our results suggest remarkably high similarity of the resulting adapted components, even across extreme age differences. With the new templates, the NeuroMark framework allows us to perform age-specific adaptations and to capture features adaptable to each modality, therefore facilitating biomarker identification across brain disorders. In sum, the present work demonstrates the generalizability of NeuroMark templates and suggests the potential of new templates to boost accuracy in mental health research and advance our understanding of lifespan and cross-modal alterations.

Combining neuropsychological assessment and structural neuroimaging to identify early Alzheimer's disease in a memory clinic cohort.

INTRODUCTION: The current study examined the contributions of comprehensive neuropsychological assessment and volumetric assessment of selected mesial temporal subregions on structural magnetic resonance imaging (MRI) to identify patients with amnestic mild cognitive impairment (aMCI) and mild probable Alzheimer's disease (AD) dementia in a memory clinic cohort. METHODS: Comprehensive neuropsychological assessment and automated entorhinal, transentorhinal, and hippocampal volume measurements were conducted in 40 healthy controls, 38 patients with subjective memory symptoms, 16 patients with aMCI, 16 patients with mild probable AD dementia. Multinomial logistic regression was used to compare the neuropsychological and MRI measures. RESULTS: Combining the neuropsychological and MRI measures improved group membership prediction over the MRI measures alone but did not improve group membership prediction over the neuropsychological measures alone. CONCLUSION: Comprehensive neuropsychological assessment was an important tool to evaluate cognitive impairment. The mesial temporal volumetric MRI measures contributed no diagnostic value over and above the determinations made through neuropsychological assessment.

Improving 3D edge detection for visual inspection of MRI coregistration and alignment.

BACKGROUND: Visualizing edges is critical for neuroimaging. For example, edge maps enable quality assurance for the automatic alignment of an image from one modality (or individual) to another. NEW METHOD: We suggest that using the second derivative (difference of Gaussian, or DoG) provides robust edge detection. This method is tuned by size (which is typically known in neuroimaging) rather than intensity (which is relative). RESULTS: We demonstrate that this method performs well across a broad range of imaging modalities. The edge contours produced consistently form closed surfaces, whereas alternative methods may generate disconnected lines, introducing potential ambiguity in contiguity. COMPARISON WITH EXISTING METHODS: Current methods for computing edges are based on either the first derivative of the image (FSL), or a variation of the Canny Edge detection method (AFNI). These methods suffer from two primary limitations. First, the crucial tuning parameter for each of these methods relates to the image intensity. Unfortunately, image intensity is relative for most neuroimaging modalities making the performance of these methods unreliable. Second, these existing approaches do not necessarily generate a closed edge/surface, which can reduce the ability to determine the correspondence between a represented edge and another image. CONCLUSION: The second derivative is well suited for neuroimaging edge detection. We include this method as part of both the AFNI and FSL software packages, standalone code and online.

Multimodal active subspace analysis for computing assessment oriented subspaces from neuroimaging data.

BACKGROUND: For successful biomarker discovery, it is essential to develop computational frameworks that summarize high-dimensional neuroimaging data in terms of involved sub-systems of the brain, while also revealing underlying heterogeneous functional and structural changes covarying with specific cognitive and biological traits. However, unsupervised decompositions do not inculcate clinical assessment information, while supervised approaches extract only individual feature importance, thereby impeding qualitative interpretation at the level of subspaces. NEW METHOD: We present a novel framework to extract robust multimodal brain subspaces associated with changes in a given cognitive or biological trait. Our approach involves active subspace learning on the gradients of a trained machine learning model followed by clustering to extract and summarize the most salient and consistent subspaces associated with the target variable. RESULTS: Through a rigorous cross-validation procedure on an Alzheimer's disease (AD) dataset, our framework successfully extracts multimodal subspaces specific to a given clinical assessment (e.g., memory and other cognitive skills), and also retains predictive performance in standard machine learning algorithms. We also show that the salient active subspace directions occur consistently across randomly sub-sampled repetitions of the analysis. COMPARISON WITH EXISTING METHOD(S): Compared to existing unsupervised decompositions based on principle component analysis, the subspace components in our framework retain higher predictive information. CONCLUSIONS: As an important step towards biomarker discovery, our framework not only uncovers AD-related brain regions in the associated brain subspaces, but also enables automated identification of multiple underlying structural and functional sub-systems of the brain that collectively characterize changes in memory and proficiency in cognitive skills related to brain disorders like AD.

Potential of neuroimaging as a biomarker in amyotrophic lateral sclerosis: from structure to metabolism.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron degeneration. The development of ALS involves metabolite alterations leading to tissue lesions in the nervous system. Recent advances in neuroimaging have significantly improved our understanding of the underlying pathophysiology of ALS, with findings supporting the corticoefferent axonal disease progression theory. Current studies on neuroimaging in ALS have demonstrated inconsistencies, which may be due to small sample sizes, insufficient statistical power, overinterpretation of findings, and the inherent heterogeneity of ALS. Deriving meaningful conclusions solely from individual imaging metrics in ALS studies remains challenging, and integrating multimodal imaging techniques shows promise for detecting valuable ALS biomarkers. In addition to giving an overview of the principles and techniques of different neuroimaging modalities, this review describes the potential of neuroimaging biomarkers in the diagnosis and prognostication of ALS. We provide an insight into the underlying pathology, highlighting the need for standardized protocols and multicenter collaborations to advance ALS research.

Attention-guided deep learning for gestational age prediction using fetal brain MRI.

Magnetic resonance imaging offers unrivaled visualization of the fetal brain, forming the basis for establishing age-specific morphologic milestones. However, gauging age-appropriate neural development remains a difficult task due to the constantly changing appearance of the fetal brain, variable image quality, and frequent motion artifacts. Here we present an end-to-end, attention-guided deep learning model that predicts gestational age with R2 score of 0.945, mean absolute error of 6.7 days, and concordance correlation coefficient of 0.970. The convolutional neural network was trained on a heterogeneous dataset of 741 developmentally normal fetal brain images ranging from 19 to 39 weeks in gestational age. We also demonstrate model performance and generalizability using independent datasets from four academic institutions across the U.S. and Turkey with R2 scores of 0.81-0.90 after minimal fine-tuning. The proposed regression algorithm provides an automated machine-enabled tool with the potential to better characterize in utero neurodevelopment and guide real-time gestational age estimation after the first trimester.

Accurate brain-age models for routine clinical MRI examinations.

Convolutional neural networks (CNN) can accurately predict chronological age in healthy individuals from structural MRI brain scans. Potentially, these models could be applied during routine clinical examinations to detect deviations from healthy ageing, including early-stage neurodegeneration. This could have important implications for patient care, drug development, and optimising MRI data collection. However, existing brain-age models are typically optimised for scans which are not part of routine examinations (e.g., volumetric T1-weighted scans), generalise poorly (e.g., to data from different scanner vendors and hospitals etc.), or rely on computationally expensive pre-processing steps which limit real-time clinical utility. Here, we sought to develop a brain-age framework suitable for use during routine clinical head MRI examinations. Using a deep learning-based neuroradiology report classifier, we generated a dataset of 23,302 'radiologically normal for age' head MRI examinations from two large UK hospitals for model training and testing (age range = 18-95 years), and demonstrate fast (< 5 s), accurate (mean absolute error [MAE] < 4 years) age prediction from clinical-grade, minimally processed axial T2-weighted and axial diffusion-weighted scans, with generalisability between hospitals and scanner vendors (Δ MAE < 1 year). The clinical relevance of these brain-age predictions was tested using 228 patients whose MRIs were reported independently by neuroradiologists as showing atrophy 'excessive for age'. These patients had systematically higher brain-predicted age than chronological age (mean predicted age difference = +5.89 years, 'radiologically normal for age' mean predicted age difference = +0.05 years, p < 0.0001). Our brain-age framework demonstrates feasibility for use as a screening tool during routine hospital examinations to automatically detect older-appearing brains in real-time, with relevance for clinical decision-making and optimising patient pathways.

Impact of MRI on decision-making in ICU patients with disorders of consciousness.

BACKGROUND: Recovery of consciousness is the most important survival factor in patients with acute brain injury and disorders of consciousness (DoC). Since most deaths in the intensive care unit (ICU) occur after withdrawal of life-support, medical decision-making is crucial for acute DoC patients. Neuroimaging informs decision-making, yet the precise effects of MRI on decision-making in the ICU are poorly understood. We investigated the impact of brain MRI on prognostication, therapeutic decisions and physician confidence in ICU patients with DoC. METHODS: In this simulated decision-making study utilizing a prospective ICU cohort, a panel of neurocritical experts first reviewed clinical information (without MRI) from 75 acute DoC patients and made decisions about diagnosis, prognosis and treatment. Following review of the MRI, the panel then decided if the initial decisions needed revision. In parallel, a blinded neuroradiologist reassessed all neuroimaging. RESULTS: MRI led to changes in clinical management of 57 (76%) of patients (Number-Needed-to-Test for any change: 1.32), including revised diagnoses (20%), levels of care (21%), diagnostic confidence (43%) and prognostications (33%). Decisions were revised more often with stroke than with other brain injuries (p = 0.02). However, although MRI revealed additional pathology in 81%, this did not predict revised clinical decision-making (p-values ≥0.08). CONCLUSION: MRI results changed decision-making in 3 of 4 ICU patients, but radiological findings were not predictive of clinical decision-making. This highlights the need to better understand the effects of neuroimaging on management decisions. How MRI influences decision-making in the ICU is an important avenue for research to improve acute DoC management.

Predicting alcohol dependence from multi-site brain structural measures.

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.

Testing a convolutional neural network-based hippocampal segmentation method in a stroke population.

As stroke mortality rates decrease, there has been a surge of effort to study poststroke dementia (PSD) to improve long-term quality of life for stroke survivors. Hippocampal volume may be an important neuroimaging biomarker in poststroke dementia, as it has been associated with many other forms of dementia. However, studying hippocampal volume using MRI requires hippocampal segmentation. Advances in automated segmentation methods have allowed for studying the hippocampus on a large scale, which is important for robust results in the heterogeneous stroke population. However, most of these automated methods use a single atlas-based approach and may fail in the presence of severe structural abnormalities common in stroke. Hippodeep, a new convolutional neural network-based hippocampal segmentation method, does not rely solely on a single atlas-based approach and thus may be better suited for stroke populations. Here, we compared quality control and the accuracy of segmentations generated by Hippodeep and two well-accepted hippocampal segmentation methods on stroke MRIs (FreeSurfer 6.0 whole hippocampus and FreeSurfer 6.0 sum of hippocampal subfields). Quality control was performed using a stringent protocol for visual inspection of the segmentations, and accuracy was measured as volumetric correlation with manual segmentations. Hippodeep performed significantly better than both FreeSurfer methods in terms of quality control. All three automated segmentation methods had good correlation with manual segmentations and no one method was significantly more correlated than the others. Overall, this study suggests that both Hippodeep and FreeSurfer may be useful for hippocampal segmentation in stroke rehabilitation research, but Hippodeep may be more robust to stroke lesion anatomy.

Reproducibility in the absence of selective reporting: An illustration from large-scale brain asymmetry research.

The problem of poor reproducibility of scientific findings has received much attention over recent years, in a variety of fields including psychology and neuroscience. The problem has been partly attributed to publication bias and unwanted practices such as p-hacking. Low statistical power in individual studies is also understood to be an important factor. In a recent multisite collaborative study, we mapped brain anatomical left-right asymmetries for regional measures of surface area and cortical thickness, in 99 MRI datasets from around the world, for a total of over 17,000 participants. In the present study, we revisited these hemispheric effects from the perspective of reproducibility. Within each dataset, we considered that an effect had been reproduced when it matched the meta-analytic effect from the 98 other datasets, in terms of effect direction and significance threshold. In this sense, the results within each dataset were viewed as coming from separate studies in an "ideal publishing environment," that is, free from selective reporting and p hacking. We found an average reproducibility rate of 63.2% (SD = 22.9%, min = 22.2%, max = 97.0%). As expected, reproducibility was higher for larger effects and in larger datasets. Reproducibility was not obviously related to the age of participants, scanner field strength, FreeSurfer software version, cortical regional measurement reliability, or regional size. These findings constitute an empirical illustration of reproducibility in the absence of publication bias or p hacking, when assessing realistic biological effects in heterogeneous neuroscience data, and given typically-used sample sizes.

Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

White matter hyperintensities segmentation using an ensemble of neural networks.

White matter hyperintensities (WMHs) represent the most common neuroimaging marker of cerebral small vessel disease (CSVD). The volume and location of WMHs are important clinical measures. We present a pipeline using deep fully convolutional network and ensemble models, combining U-Net, SE-Net, and multi-scale features, to automatically segment WMHs and estimate their volumes and locations. We evaluated our method in two datasets: a clinical routine dataset comprising 60 patients (selected from Chinese National Stroke Registry, CNSR) and a research dataset composed of 60 patients (selected from MICCAI WMH Challenge, MWC). The performance of our pipeline was compared with four freely available methods: LGA, LPA, UBO detector, and U-Net, in terms of a variety of metrics. Additionally, to access the model generalization ability, another research dataset comprising 40 patients (from Older Australian Twins Study and Sydney Memory and Aging Study, OSM), was selected and tested. The pipeline achieved the best performance in both research dataset and the clinical routine dataset with DSC being significantly higher than other methods (p < .001), reaching .833 and .783, respectively. The results of model generalization ability showed that the model trained on the research dataset (DSC = 0.736) performed higher than that trained on the clinical dataset (DSC = 0.622). Our method outperformed widely used pipelines in WMHs segmentation. This system could generate both image and text outputs for whole brain, lobar and anatomical automatic labeling WMHs. Additionally, software and models of our method are made publicly available at https://www.nitrc.org/projects/what_v1.

FreeSurfer-based segmentation of hippocampal subfields: A review of methods and applications, with a novel quality control procedure for ENIGMA studies and other collaborative efforts.

Structural hippocampal abnormalities are common in many neurological and psychiatric disorders, and variation in hippocampal measures is related to cognitive performance and other complex phenotypes such as stress sensitivity. Hippocampal subregions are increasingly studied, as automated algorithms have become available for mapping and volume quantification. In the context of the Enhancing Neuro Imaging Genetics through Meta Analysis Consortium, several Disease Working Groups are using the FreeSurfer software to analyze hippocampal subregion (subfield) volumes in patients with neurological and psychiatric conditions along with data from matched controls. In this overview, we explain the algorithm's principles, summarize measurement reliability studies, and demonstrate two additional aspects (subfield autocorrelation and volume/reliability correlation) with illustrative data. We then explain the rationale for a standardized hippocampal subfield segmentation quality control (QC) procedure for improved pipeline harmonization. To guide researchers to make optimal use of the algorithm, we discuss how global size and age effects can be modeled, how QC steps can be incorporated and how subfields may be aggregated into composite volumes. This discussion is based on a synopsis of 162 published neuroimaging studies (01/2013-12/2019) that applied the FreeSurfer hippocampal subfield segmentation in a broad range of domains including cognition and healthy aging, brain development and neurodegeneration, affective disorders, psychosis, stress regulation, neurotoxicity, epilepsy, inflammatory disease, childhood adversity and posttraumatic stress disorder, and candidate and whole genome (epi-)genetics. Finally, we highlight points where FreeSurfer-based hippocampal subfield studies may be optimized.

Hyperbolic trade-off: The importance of balancing trial and subject sample sizes in neuroimaging.

Here we investigate the crucial role of trials in task-based neuroimaging from the perspectives of statistical efficiency and condition-level generalizability. Big data initiatives have gained popularity for leveraging a large sample of subjects to study a wide range of effect magnitudes in the brain. On the other hand, most task-based FMRI designs feature a relatively small number of subjects, so that resulting parameter estimates may be associated with compromised precision. Nevertheless, little attention has been given to another important dimension of experimental design, which can equally boost a study's statistical efficiency: the trial sample size. The common practice of condition-level modeling implicitly assumes no cross-trial variability. Here, we systematically explore the different factors that impact effect uncertainty, drawing on evidence from hierarchical modeling, simulations and an FMRI dataset of 42 subjects who completed a large number of trials of cognitive control task. We find that, due to an approximately symmetric hyperbola-relationship between trial and subject sample sizes in the presence of relatively large cross-trial variability, 1) trial sample size has nearly the same impact as subject sample size on statistical efficiency; 2) increasing both the number of trials and subjects improves statistical efficiency more effectively than focusing on subjects alone; 3) trial sample size can be leveraged alongside subject sample size to improve the cost-effectiveness of an experimental design; 4) for small trial sample sizes, trial-level modeling, rather than condition-level modeling through summary statistics, may be necessary to accurately assess the standard error of an effect estimate. We close by making practical suggestions for improving experimental designs across neuroimaging and behavioral studies.

Mitigating site effects in covariance for machine learning in neuroimaging data.

To acquire larger samples for answering complex questions in neuroscience, researchers have increasingly turned to multi-site neuroimaging studies. However, these studies are hindered by differences in images acquired across multiple sites. These effects have been shown to bias comparison between sites, mask biologically meaningful associations, and even introduce spurious associations. To address this, the field has focused on harmonizing data by removing site-related effects in the mean and variance of measurements. Contemporaneously with the increase in popularity of multi-center imaging, the use of machine learning (ML) in neuroimaging has also become commonplace. These approaches have been shown to provide improved sensitivity, specificity, and power due to their modeling the joint relationship across measurements in the brain. In this work, we demonstrate that methods for removing site effects in mean and variance may not be sufficient for ML. This stems from the fact that such methods fail to address how correlations between measurements can vary across sites. Data from the Alzheimer's Disease Neuroimaging Initiative is used to show that considerable differences in covariance exist across sites and that popular harmonization techniques do not address this issue. We then propose a novel harmonization method called Correcting Covariance Batch Effects (CovBat) that removes site effects in mean, variance, and covariance. We apply CovBat and show that within-site correlation matrices are successfully harmonized. Furthermore, we find that ML methods are unable to distinguish scanner manufacturer after our proposed harmonization is applied, and that the CovBat-harmonized data retain accurate prediction of disease group.

Ironsmith: An automated pipeline for QSM-based data analyses.

Quantitative susceptibility mapping (QSM) is an MRI-based, computational method for anatomically localizing and measuring concentrations of specific biomarkers in tissue such as iron. Growing research suggests QSM is a viable method for evaluating the impact of iron overload in neurological disorders and on cognitive performance in aging. Several software toolboxes are currently available to reconstruct QSM maps from 3D GRE MR Images. However, few if any software packages currently exist that offer fully automated pipelines for QSM-based data analyses: from DICOM images to region-of-interest (ROI) based QSM values. Even less QSM-based software exist that offer quality control measures for evaluating the QSM output. Here, we address these gaps in the field by introducing and demonstrating the reliability and external validity of Ironsmith; an open-source, fully automated pipeline for creating and processing QSM maps, extracting QSM values from subcortical and cortical brain regions (89 ROIs) and evaluating the quality of QSM data using SNR measures and assessment of outlier regions on phase images. Ironsmith also features automatic filtering of QSM outlier values and precise CSF-only QSM reference masks that minimize partial volume effects. Testing of Ironsmith revealed excellent intra- and inter-rater reliability. Finally, external validity of Ironsmith was demonstrated via an anatomically selective relationship between motor performance and Ironsmith-derived QSM values in motor cortex. In sum, Ironsmith provides a freely-available, reliable, turn-key pipeline for QSM-based data analyses to support research on the impact of brain iron in aging and neurodegenerative disease.

Reliability of structural MRI measurements: The effects of scan session, head tilt, inter-scan interval, acquisition sequence, FreeSurfer version and processing stream.

BACKGROUND: Large-scale longitudinal and multi-centre studies are used to explore neuroimaging markers of normal ageing, and neurodegenerative and mental health disorders. Longitudinal changes in brain structure are typically small, therefore the reliability of automated techniques is crucial. Determining the effects of different factors on reliability allows investigators to control those adversely affecting reliability, calculate statistical power, or even avoid particular brain measures with low reliability. This study examined the impact of several image acquisition and processing factors and documented the test-retest reliability of structural MRI measurements. METHODS: In Phase I, 20 healthy adults (11 females; aged 20-30 years) were scanned on two occasions three weeks apart on the same scanner using the ADNI-3 protocol. On each occasion, individuals were scanned twice (repetition), after re-entering the scanner (reposition) and after tilting their head forward. At one year follow-up, nine returning individuals and 11 new volunteers were recruited for Phase II (11 females; aged 22-31 years). Scans were acquired on two different scanners using the ADNI-2 and ADNI-3 protocols. Structural images were processed using FreeSurfer (v5.3.0, 6.0.0 and 7.1.0) to provide subcortical and cortical volume, cortical surface area and thickness measurements. Intra-class correlation coefficients (ICC) were calculated to estimate test-retest reliability. We examined the effect of repetition, reposition, head tilt, time between scans, MRI sequence and scanner on reliability of structural brain measurements. Mean percentage differences were also calculated in supplementary analyses. RESULTS: Using the FreeSurfer v7.1.0 longitudinal pipeline, we observed high reliability for subcortical and cortical volumes, and cortical surface areas at repetition, reposition, three weeks and one year (mean ICCs>0.97). Cortical thickness reliability was lower (mean ICCs>0.82). Head tilt had the greatest adverse impact on ICC estimates, for example reducing mean right cortical thickness to ICC=0.74. In contrast, changes in ADNI sequence or MRI scanner had a minimal effect. We observed an increase in reliability for updated FreeSurfer versions, with the longitudinal pipeline consistently having a higher reliability than the cross-sectional pipeline. DISCUSSION: Longitudinal studies should monitor or control head tilt to maximise reliability. We provided the ICC estimates and mean percentage differences for all FreeSurfer brain regions, which may inform power analyses for clinical studies and have implications for the design of future longitudinal studies.

Mental health in the UK Biobank: A roadmap to self-report measures and neuroimaging correlates.

The UK Biobank (UKB) is a highly promising dataset for brain biomarker research into population mental health due to its unprecedented sample size and extensive phenotypic, imaging, and biological measurements. In this study, we aimed to provide a shared foundation for UKB neuroimaging research into mental health with a focus on anxiety and depression. We compared UKB self-report measures and revealed important timing effects between scan acquisition and separate online acquisition of some mental health measures. To overcome these timing effects, we introduced and validated the Recent Depressive Symptoms (RDS-4) score which we recommend for state-dependent and longitudinal research in the UKB. We furthermore tested univariate and multivariate associations between brain imaging-derived phenotypes (IDPs) and mental health. Our results showed a significant multivariate relationship between IDPs and mental health, which was replicable. Conversely, effect sizes for individual IDPs were small. Test-retest reliability of IDPs was stronger for measures of brain structure than for measures of brain function. Taken together, these results provide benchmarks and guidelines for future UKB research into brain biomarkers of mental health.