Identification of causal effects of neuroanatomy on cognitive decline requires modeling unobserved confounders.

INTRODUCTION: Carrying out a randomized controlled trial to estimate the causal effects of regional brain atrophy due to Alzheimer's disease (AD) is impossible. Instead, we must estimate causal effects from observational data. However, this generally requires knowing and having recorded all confounders, which is often unrealistic. METHODS: We provide an approach that leverages the dependencies among multiple neuroanatomical measures to estimate causal effects from observational neuroimaging data without the need to know and record all confounders. RESULTS: Our analyses of N = 732 $N=732$ subjects from the Alzheimer's Disease Neuroimaging Initiative demonstrate that using our approach results in biologically meaningful conclusions, whereas ignoring unobserved confounding yields results that conflict with established knowledge on cognitive decline due to AD. DISCUSSION: The findings provide evidence that the impact of unobserved confounding can be substantial. To ensure trustworthy scientific insights, future AD research can account for unobserved confounding via the proposed approach.

DAFT: A universal module to interweave tabular data and 3D images in CNNs.

Prior work on Alzheimer's Disease (AD) has demonstrated that convolutional neural networks (CNNs) can leverage the high-dimensional image information for diagnosing patients. Beside such data-driven approaches, many established biomarkers exist and are typically represented as tabular data, such as demographics, genetic alterations, or laboratory measurements from cerebrospinal fluid. However, little research has focused on the effective integration of tabular data into existing CNN architectures to improve patient diagnosis. We introduce the Dynamic Affine Feature Map Transform (DAFT), a general-purpose module for CNNs that incites or represses high-level concepts learned from a 3D image by conditioning feature maps of a convolutional layer on both a patient's image and tabular clinical information. This is achieved by using an auxiliary neural network that outputs a scaling factor and offset to dynamically apply an affine transformation to the feature maps of a convolutional layer. In our experiments on AD diagnosis and time-to-dementia prediction, we show that the DAFT is highly effective in combining 3D image and tabular information by achieving a mean balanced accuracy of 0.622 for diagnosis, and mean c-index of 0.748 for time-to-dementia prediction, thus outperforming all baseline methods. Finally, our extensive ablation study and empirical experiments reveal that the performance improvement due to the DAFT is robust with respect to many design choices.

AbdomenNet: deep neural network for abdominal organ segmentation in epidemiologic imaging studies.

BACKGROUND: Whole-body imaging has recently been added to large-scale epidemiological studies providing novel opportunities for investigating abdominal organs. However, the segmentation of these organs is required beforehand, which is time consuming, particularly on such a large scale. METHODS: We introduce AbdomentNet, a deep neural network for the automated segmentation of abdominal organs on two-point Dixon MRI scans. A pre-processing pipeline enables to process MRI scans from different imaging studies, namely the German National Cohort, UK Biobank, and Kohorte im Raum Augsburg. We chose a total of 61 MRI scans across the three studies for training an ensemble of segmentation networks, which segment eight abdominal organs. Our network presents a novel combination of octave convolutions and squeeze and excitation layers, as well as training with stochastic weight averaging. RESULTS: Our experiments demonstrate that it is beneficial to combine data from different imaging studies to train deep neural networks in contrast to training separate networks. Combining the water and opposed-phase contrasts of the Dixon sequence as input channels, yields the highest segmentation accuracy, compared to single contrast inputs. The mean Dice similarity coefficient is above 0.9 for larger organs liver, spleen, and kidneys, and 0.71 and 0.74 for gallbladder and pancreas, respectively. CONCLUSIONS: Our fully automated pipeline provides high-quality segmentations of abdominal organs across population studies. In contrast, a network that is only trained on a single dataset does not generalize well to other datasets.

Effect of MRI acquisition acceleration via compressed sensing and parallel imaging on brain volumetry.

OBJECTIVES: To investigate the effect of compressed SENSE (CS), an acceleration technique combining parallel imaging and compressed sensing, on potential bias and precision of brain volumetry and evaluate it in the context of normative brain volumetry. MATERIALS AND METHODS: In total, 171 scans from scan-rescan experiments on three healthy subjects were analyzed. Each subject received 3D-T1-weighted brain MRI scans at increasing degrees of acceleration (CS-factor = 1/4/8/12/16/20/32). Single-scan acquisition times ranged from 00:41 min (CS-factor = 32) to 21:52 min (CS-factor = 1). Brain segmentation and volumetry was performed using two different software tools: md.brain, a proprietary software based on voxel-based morphometry, and FreeSurfer, an open-source software based on surface-based morphometry. Four sub-volumes were analyzed: brain parenchyma (BP), total gray matter, total white matter, and cerebrospinal fluid (CSF). Coefficient of variation (CoV) of the repeated measurements as a measure of intra-subject reliability was calculated. Intraclass correlation coefficient (ICC) with regard to increasing CS-factor was calculated as another measure of reliability. Noise-to-contrast ratio as a measure of image quality was calculated for each dataset to analyze the association between acceleration factor, noise and volumetric brain measurements. RESULTS: For all sub-volumes, there is a systematic bias proportional to the CS-factor which is dependent on the utilized software and subvolume. Measured volumes deviated significantly from the reference standard (CS-factor = 1), e.g. ranging from 1 to 13% for BP. The CS-induced systematic bias is driven by increased image noise. Except for CSF, reliability of brain volumetry remains high, demonstrated by low CoV (< 1% for CS-factor up to 20) and good to excellent ICC for CS-factor up to 12. CONCLUSION: CS-acceleration has a systematic biasing effect on volumetric brain measurements.

Neuroimage signature from salient keypoints is highly specific to individuals and shared by close relatives.

Neuroimaging studies typically adopt a common feature space for all data, which may obscure aspects of neuroanatomy only observable in subsets of a population, e.g. cortical folding patterns unique to individuals or shared by close relatives. Here, we propose to model individual variability using a distinctive keypoint signature: a set of unique, localized patterns, detected automatically in each image by a generic saliency operator. The similarity of an image pair is then quantified by the proportion of keypoints they share using a novel Jaccard-like measure of set overlap. Experiments demonstrate the keypoint method to be highly efficient and accurate, using a set of 7536 T1-weighted MRIs pooled from four public neuroimaging repositories, including twins, non-twin siblings, and 3334 unique subjects. All same-subject image pairs are identified by a similarity threshold despite confounds including aging and neurodegenerative disease progression. Outliers reveal previously unknown data labeling inconsistencies, demonstrating the usefulness of the keypoint signature as a computational tool for curating large neuroimage datasets.

Bayesian QuickNAT: Model uncertainty in deep whole-brain segmentation for structure-wise quality control.

We introduce Bayesian QuickNAT for the automated quality control of whole-brain segmentation on MRI T1 scans. Next to the Bayesian fully convolutional neural network, we also present inherent measures of segmentation uncertainty that allow for quality control per brain structure. For estimating model uncertainty, we follow a Bayesian approach, wherein, Monte Carlo (MC) samples from the posterior distribution are generated by keeping the dropout layers active at test time. Entropy over the MC samples provides a voxel-wise model uncertainty map, whereas expectation over the MC predictions provides the final segmentation. Next to voxel-wise uncertainty, we introduce four metrics to quantify structure-wise uncertainty in segmentation for quality control. We report experiments on four out-of-sample datasets comprising of diverse age range, pathology and imaging artifacts. The proposed structure-wise uncertainty metrics are highly correlated with the Dice score estimated with manual annotation and therefore present an inherent measure of segmentation quality. In particular, the intersection over union over all the MC samples is a suitable proxy for the Dice score. In addition to quality control at scan-level, we propose to incorporate the structure-wise uncertainty as a measure of confidence to do reliable group analysis on large data repositories. We envisage that the introduced uncertainty metrics would help assess the fidelity of automated deep learning based segmentation methods for large-scale population studies, as they enable automated quality control and group analyses in processing large data repositories.

QuickNAT: A fully convolutional network for quick and accurate segmentation of neuroanatomy.

Whole brain segmentation from structural magnetic resonance imaging (MRI) is a prerequisite for most morphological analyses, but is computationally intense and can therefore delay the availability of image markers after scan acquisition. We introduce QuickNAT, a fully convolutional, densely connected neural network that segments a MRI brain scan in 20 s. To enable training of the complex network with millions of learnable parameters using limited annotated data, we propose to first pre-train on auxiliary labels created from existing segmentation software. Subsequently, the pre-trained model is fine-tuned on manual labels to rectify errors in auxiliary labels. With this learning strategy, we are able to use large neuroimaging repositories without manual annotations for training. In an extensive set of evaluations on eight datasets that cover a wide age range, pathology, and different scanners, we demonstrate that QuickNAT achieves superior segmentation accuracy and reliability in comparison to state-of-the-art methods, while being orders of magnitude faster. The speed up facilitates processing of large data repositories and supports translation of imaging biomarkers by making them available within seconds for fast clinical decision making.

DeepNAT: Deep convolutional neural network for segmenting neuroanatomy.

We introduce DeepNAT, a 3D Deep convolutional neural network for the automatic segmentation of NeuroAnaTomy in T1-weighted magnetic resonance images. DeepNAT is an end-to-end learning-based approach to brain segmentation that jointly learns an abstract feature representation and a multi-class classification. We propose a 3D patch-based approach, where we do not only predict the center voxel of the patch but also neighbors, which is formulated as multi-task learning. To address a class imbalance problem, we arrange two networks hierarchically, where the first one separates foreground from background, and the second one identifies 25 brain structures on the foreground. Since patches lack spatial context, we augment them with coordinates. To this end, we introduce a novel intrinsic parameterization of the brain volume, formed by eigenfunctions of the Laplace-Beltrami operator. As network architecture, we use three convolutional layers with pooling, batch normalization, and non-linearities, followed by fully connected layers with dropout. The final segmentation is inferred from the probabilistic output of the network with a 3D fully connected conditional random field, which ensures label agreement between close voxels. The roughly 2.7million parameters in the network are learned with stochastic gradient descent. Our results show that DeepNAT compares favorably to state-of-the-art methods. Finally, the purely learning-based method may have a high potential for the adaptation to young, old, or diseased brains by fine-tuning the pre-trained network with a small training sample on the target application, where the availability of larger datasets with manual annotations may boost the overall segmentation accuracy in the future.

Gaussian process uncertainty in age estimation as a measure of brain abnormality.

Multivariate regression models for age estimation are a powerful tool for assessing abnormal brain morphology associated to neuropathology. Age prediction models are built on cohorts of healthy subjects and are built to reflect normal aging patterns. The application of these multivariate models to diseased subjects usually results in high prediction errors, under the hypothesis that neuropathology presents a similar degenerative pattern as that of accelerated aging. In this work, we propose an alternative to the idea that pathology follows a similar trajectory than normal aging. Instead, we propose the use of metrics which measure deviations from the mean aging trajectory. We propose to measure these deviations using two different metrics: uncertainty in a Gaussian process regression model and a newly proposed age weighted uncertainty measure. Consequently, our approach assumes that pathologic brain patterns are different to those of normal aging. We present results for subjects with autism, mild cognitive impairment and Alzheimer's disease to highlight the versatility of the approach to different diseases and age ranges. We evaluate volume, thickness, and VBM features for quantifying brain morphology. Our evaluations are performed on a large number of images obtained from a variety of publicly available neuroimaging databases. Across all features, our uncertainty based measurements yield a better separation between diseased subjects and healthy individuals than the prediction error. Finally, we illustrate differences in the disease pattern to normal aging, supporting the application of uncertainty as a measure of neuropathology.

Whole-brain analysis reveals increased neuroanatomical asymmetries in dementia for hippocampus and amygdala.

Structural magnetic resonance imaging data are frequently analysed to reveal morphological changes of the human brain in dementia. Most contemporary imaging biomarkers are scalar values, such as the volume of a structure, and may miss the localized morphological variation of early presymptomatic disease progression. Neuroanatomical shape descriptors, however, can represent complex geometric information of individual anatomical regions and may demonstrate increased sensitivity in association studies. Yet, they remain largely unexplored. In this article, we introduce a novel technique to study shape asymmetries of neuroanatomical structures across subcortical and cortical brain regions. We demonstrate that neurodegeneration of subcortical structures in Alzheimer's disease is not symmetric. The hippocampus shows a significant increase in asymmetry longitudinally and both hippocampus and amygdala show a significantly higher asymmetry cross-sectionally concurrent with disease severity above and beyond an ageing effect. Our results further suggest that the asymmetry in these structures is undirectional and that primarily the anterior hippocampus becomes asymmetric. Based on longitudinal asymmetry measures we subsequently study the progression from mild cognitive impairment to dementia, demonstrating that shape asymmetry in hippocampus, amygdala, caudate and cortex is predictive of disease onset. The same analyses on scalar volume measurements did not produce any significant results, indicating that shape asymmetries, potentially induced by morphometric changes in subnuclei, rather than size asymmetries are associated with disease progression and can yield a powerful imaging biomarker for the early presymptomatic classification and prediction of Alzheimer's disease. Because literature has focused on contralateral volume differences, subcortical disease lateralization may have been overlooked thus far.

Domain adaptation for Alzheimer's disease diagnostics.

With the increasing prevalence of Alzheimer's disease, research focuses on the early computer-aided diagnosis of dementia with the goal to understand the disease process, determine risk and preserving factors, and explore preventive therapies. By now, large amounts of data from multi-site studies have been made available for developing, training, and evaluating automated classifiers. Yet, their translation to the clinic remains challenging, in part due to their limited generalizability across different datasets. In this work, we describe a compact classification approach that mitigates overfitting by regularizing the multinomial regression with the mixed ℓ1/ℓ2 norm. We combine volume, thickness, and anatomical shape features from MRI scans to characterize neuroanatomy for the three-class classification of Alzheimer's disease, mild cognitive impairment and healthy controls. We demonstrate high classification accuracy via independent evaluation within the scope of the CADDementia challenge. We, furthermore, demonstrate that variations between source and target datasets can substantially influence classification accuracy. The main contribution of this work addresses this problem by proposing an approach for supervised domain adaptation based on instance weighting. Integration of this method into our classifier allows us to assess different strategies for domain adaptation. Our results demonstrate (i) that training on only the target training set yields better results than the naïve combination (union) of source and target training sets, and (ii) that domain adaptation with instance weighting yields the best classification results, especially if only a small training component of the target dataset is available. These insights imply that successful deployment of systems for computer-aided diagnostics to the clinic depends not only on accurate classifiers that avoid overfitting, but also on a dedicated domain adaptation strategy.

BrainPrint: a discriminative characterization of brain morphology.

We introduce BrainPrint, a compact and discriminative representation of brain morphology. BrainPrint captures shape information of an ensemble of cortical and subcortical structures by solving the eigenvalue problem of the 2D and 3D Laplace-Beltrami operator on triangular (boundary) and tetrahedral (volumetric) meshes. This discriminative characterization enables new ways to study the similarity between brains; the focus can either be on a specific brain structure of interest or on the overall brain similarity. We highlight four applications for BrainPrint in this article: (i) subject identification, (ii) age and sex prediction, (iii) brain asymmetry analysis, and (iv) potential genetic influences on brain morphology. The properties of BrainPrint require the derivation of new algorithms to account for the heterogeneous mix of brain structures with varying discriminative power. We conduct experiments on three datasets, including over 3000 MRI scans from the ADNI database, 436 MRI scans from the OASIS dataset, and 236 MRI scans from the VETSA twin study. All processing steps for obtaining the compact representation are fully automated, making this processing framework particularly attractive for handling large datasets.

Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: the CADDementia challenge.

Algorithms for computer-aided diagnosis of dementia based on structural MRI have demonstrated high performance in the literature, but are difficult to compare as different data sets and methodology were used for evaluation. In addition, it is unclear how the algorithms would perform on previously unseen data, and thus, how they would perform in clinical practice when there is no real opportunity to adapt the algorithm to the data at hand. To address these comparability, generalizability and clinical applicability issues, we organized a grand challenge that aimed to objectively compare algorithms based on a clinically representative multi-center data set. Using clinical practice as the starting point, the goal was to reproduce the clinical diagnosis. Therefore, we evaluated algorithms for multi-class classification of three diagnostic groups: patients with probable Alzheimer's disease, patients with mild cognitive impairment and healthy controls. The diagnosis based on clinical criteria was used as reference standard, as it was the best available reference despite its known limitations. For evaluation, a previously unseen test set was used consisting of 354 T1-weighted MRI scans with the diagnoses blinded. Fifteen research teams participated with a total of 29 algorithms. The algorithms were trained on a small training set (n=30) and optionally on data from other sources (e.g., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of aging). The best performing algorithm yielded an accuracy of 63.0% and an area under the receiver-operating-characteristic curve (AUC) of 78.8%. In general, the best performances were achieved using feature extraction based on voxel-based morphometry or a combination of features that included volume, cortical thickness, shape and intensity. The challenge is open for new submissions via the web-based framework: http://caddementia.grand-challenge.org.

Multi-modal robust inverse-consistent linear registration.

Registration performance can significantly deteriorate when image regions do not comply with model assumptions. Robust estimation improves registration accuracy by reducing or ignoring the contribution of voxels with large intensity differences, but existing approaches are limited to monomodal registration. In this work, we propose a robust and inverse-consistent technique for cross-modal, affine image registration. The algorithm is derived from a contextual framework of image registration. The key idea is to use a modality invariant representation of images based on local entropy estimation, and to incorporate a heteroskedastic noise model. This noise model allows us to draw the analogy to iteratively reweighted least squares estimation and to leverage existing weighting functions to account for differences in local information content in multimodal registration. Furthermore, we use the nonparametric windows density estimator to reliably calculate entropy of small image patches. Finally, we derive the Gauss-Newton update and show that it is equivalent to the efficient second-order minimization for the fully symmetric registration approach. We illustrate excellent performance of the proposed methods on datasets containing outliers for alignment of brain tumor, full head, and histology images.

Blockface histology with optical coherence tomography: a comparison with Nissl staining.

Spectral domain optical coherence tomography (SD-OCT) is a high resolution imaging technique that generates excellent contrast based on intrinsic optical properties of the tissue, such as neurons and fibers. The SD-OCT data acquisition is performed directly on the tissue block, diminishing the need for cutting, mounting and staining. We utilized SD-OCT to visualize the laminar structure of the isocortex and compared cortical cytoarchitecture with the gold standard Nissl staining, both qualitatively and quantitatively. In histological processing, distortions routinely affect registration to the blockface image and prevent accurate 3D reconstruction of regions of tissue. We compared blockface registration to SD-OCT and Nissl, respectively, and found that SD-OCT-blockface registration was significantly more accurate than Nissl-blockface registration. Two independent observers manually labeled cortical laminae (e.g. III, IV and V) in SD-OCT images and Nissl stained sections. Our results show that OCT images exhibit sufficient contrast in the cortex to reliably differentiate the cortical layers. Furthermore, the modalities were compared with regard to cortical laminar organization and showed good agreement. Taken together, these SD-OCT results suggest that SD-OCT contains information comparable to standard histological stains such as Nissl in terms of distinguishing cortical layers and architectonic areas. Given these data, we propose that SD-OCT can be used to reliably generate 3D reconstructions of multiple cubic centimeters of cortex that can be used to accurately and semi-automatically perform standard histological analyses.

Neural deformation fields for template-based reconstruction of cortical surfaces from MRI.

The reconstruction of cortical surfaces is a prerequisite for quantitative analyses of the cerebral cortex in magnetic resonance imaging (MRI). Existing segmentation-based methods separate the surface registration from the surface extraction, which is computationally inefficient and prone to distortions. We introduce Vox2Cortex-Flow (V2C-Flow), a deep mesh-deformation technique that learns a deformation field from a brain template to the cortical surfaces of an MRI scan. To this end, we present a geometric neural network that models the deformation-describing ordinary differential equation in a continuous manner. The network architecture comprises convolutional and graph-convolutional layers, which allows it to work with images and meshes at the same time. V2C-Flow is not only very fast, requiring less than two seconds to infer all four cortical surfaces, but also establishes vertex-wise correspondences to the template during reconstruction. In addition, V2C-Flow is the first approach for cortex reconstruction that models white matter and pial surfaces jointly, therefore avoiding intersections between them. Our comprehensive experiments on internal and external test data demonstrate that V2C-Flow results in cortical surfaces that are state-of-the-art in terms of accuracy. Moreover, we show that the established correspondences are more consistent than in FreeSurfer and that they can directly be utilized for cortex parcellation and group analyses of cortical thickness.

Deep learning for the prediction of type 2 diabetes mellitus from neck-to-knee Dixon MRI in the UK biobank.

Rationale and objectives: We evaluate the automatic identification of type 2 diabetes from neck-to-knee, two-point Dixon MRI scans with 3D convolutional neural networks on a large, population-based dataset. To this end, we assess the best combination of MRI contrasts and stations for diabetes prediction, and the benefit of integrating risk factors. Materials and methods: Subjects with type 2 diabetes mellitus have been identified in the prospective UK Biobank Imaging study, and a matched control sample has been created to avoid confounding bias. Five-fold cross-validation is used for the evaluation. All scans from the two-point Dixon neck-to-knee sequence have been standardized. A neural network that considers multi-channel MRI input was developed and integrates clinical information in tabular format. An ensemble strategy is used to combine multi-station MRI predictions. A subset with quantitative fat measurements is identified for comparison to prior approaches. Results: MRI scans from 3406 subjects (mean age, 66.2 years ± 7.1 [standard deviation]; 1128 women) were analyzed with 1703 diabetics. A balanced accuracy of 78.7 %, AUC ROC of 0.872, and an average precision of 0.878 was obtained for the classification of diabetes. The ensemble over multiple Dixon MRI stations yields better performance than selecting the individually best station. Moreover, combining fat and water scans as multi-channel inputs to the networks improves upon just using single contrasts as input. Integrating clinical information about known risk factors of diabetes in the network boosts the performance across all stations and the ensemble. The neural network achieved superior results compared to the prediction based on quantitative MRI measurements. Conclusions: The developed deep learning model accurately predicted type 2 diabetes from neck-to-knee two-point Dixon MRI scans.

Abdominal organ segmentation via deep diffeomorphic mesh deformations.

Abdominal organ segmentation from CT and MRI is an essential prerequisite for surgical planning and computer-aided navigation systems. It is challenging due to the high variability in the shape, size, and position of abdominal organs. Three-dimensional numeric representations of abdominal shapes with point-wise correspondence to a template are further important for quantitative and statistical analyses thereof. Recently, template-based surface extraction methods have shown promising advances for direct mesh reconstruction from volumetric scans. However, the generalization of these deep learning-based approaches to different organs and datasets, a crucial property for deployment in clinical environments, has not yet been assessed. We close this gap and employ template-based mesh reconstruction methods for joint liver, kidney, pancreas, and spleen segmentation. Our experiments on manually annotated CT and MRI data reveal limited generalization capabilities of previous methods to organs of different geometry and weak performance on small datasets. We alleviate these issues with a novel deep diffeomorphic mesh-deformation architecture and an improved training scheme. The resulting method, UNetFlow, generalizes well to all four organs and can be easily fine-tuned on new data. Moreover, we propose a simple registration-based post-processing that aligns voxel and mesh outputs to boost segmentation accuracy.

Can we diagnose mental disorders in children? A large-scale assessment of machine learning on structural neuroimaging of 6916 children in the adolescent brain cognitive development study.

Background: Prediction of mental disorders based on neuroimaging is an emerging area of research with promising first results in adults. However, research on the unique demographic of children is underrepresented and it is doubtful whether findings obtained on adults can be transferred to children. Methods: Using data from 6916 children aged 9-10 in the multicenter Adolescent Brain Cognitive Development study, we extracted 136 regional volume and thickness measures from structural magnetic resonance images to rigorously evaluate the capabilities of machine learning to predict 10 different psychiatric disorders: major depressive disorder, bipolar disorder (BD), psychotic symptoms, attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder, conduct disorder, post-traumatic stress disorder, obsessive-compulsive disorder, generalized anxiety disorder, and social anxiety disorder. For each disorder, we performed cross-validation and assessed whether models discovered a true pattern in the data via permutation testing. Results: Two of 10 disorders can be detected with statistical significance when using advanced models that (i) allow for non-linear relationships between neuroanatomy and disorder, (ii) model interdependencies between disorders, and (iii) avoid confounding due to sociodemographic factors: ADHD (AUROC = 0.567, p = 0.002) and BD (AUROC = 0.551, p = 0.002). In contrast, traditional models perform consistently worse and predict only ADHD with statistical significance (AUROC = 0.529, p = 0.002). Conclusion: While the modest absolute classification performance does not warrant application in the clinic, our results provide empirical evidence that embracing and explicitly accounting for the complexities of mental disorders via advanced machine learning models can discover patterns that would remain hidden with traditional models.

Emotion regulation in adolescents with major depression - Evidence from a combined EEG and eye-tracking study.

BACKGROUND: Adolescent major depression (MD) is characterized by deficits in emotion regulation (ER). Little is known about the neurophysiological correlates that are associated with these deficits. Moreover, the additional examination of visual attention during ER would allow a more in-depth understanding of ER deficits but has not yet been applied simultaneously. METHODS: N = 33 adolescents with MD and n = 35 healthy controls (HCs) aged 12-18 years performed an ER task during which they either a) down-regulated their negative affective response to negative images via cognitive reappraisal or b) attended the images without changing their affective response. During the task, the Late Positive Potential (LPP), gaze fixations on emotional image aspects, and self-reported affective responses were collected simultaneously. RESULTS: Compared to HCs, adolescents with MD demonstrated reduced ER success based on self-report but did not differ in LPP amplitudes. Participants in both groups showed increased amplitudes in the middle LPP window when they reappraised negative pictures compared to when they attended them. Only in the HC group, increased LPP amplitudes during reappraisal were paralleled by more positive affective responses. LIMITATION: The applied stimuli were part of picture databases and might therefore have limited self-relevance. CONCLUSIONS: Increased LPP amplitude during ER in both groups might be specific to adolescence and might suggest that ER at this age is challenging and requires a high amount of cognitive resources. These findings provide an important starting point for future interventional studies in youth MD.