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Many longitudinal neuroimaging studies aim to improve the understanding of brain aging and diseases by studying the dynamic interactions between brain function and cognition. Doing so requires accurate encoding of their multidimensional relationship while accounting for individual variability over time. For this purpose, we propose an unsupervised learning model (called \underline{\textbf{Co}}ntrastive Learning-based \underline{\textbf{Gra}}ph Generalized \underline{\textbf{Ca}}nonical Correlation Analysis (CoGraCa)) that encodes their relationship via Graph Attention Networks and generalized Canonical Correlational Analysis. To create brain-cognition fingerprints reflecting unique neural and cognitive phenotype of each person, the model also relies on individualized and multimodal contrastive learning. We apply CoGraCa to longitudinal dataset of healthy individuals consisting of resting-state functional MRI and cognitive measures acquired at multiple visits for each participant. The generated fingerprints effectively capture significant individual differences and outperform current single-modal and CCA-based multimodal models in identifying sex and age. More importantly, our encoding provides interpretable interactions between those two modalities.

Deep learning models generating structural brain MRIs have the potential to significantly accelerate discovery of neuroscience studies. However, their use has been limited in part by the way their quality is evaluated. Most evaluations of generative models focus on metrics originally designed for natural images (such as structural similarity index and Frechet inception distance). As we show in a comparison of 6 state-of-the-art generative models trained and tested on over 3000 MRIs, these metrics are sensitive to the experimental setup and inadequately assess how well brain MRIs capture macrostructural properties of brain regions (i.e., anatomical plausibility). This shortcoming of the metrics results in inconclusive findings even when qualitative differences between the outputs of models are evident. We therefore propose a framework for evaluating models generating brain MRIs, which requires uniform processing of the real MRIs, standardizing the implementation of the models, and automatically segmenting the MRIs generated by the models. The segmentations are used for quantifying the plausibility of anatomy displayed in the MRIs. To ensure meaningful quantification, it is crucial that the segmentations are highly reliable. Our framework rigorously checks this reliability, a step often overlooked by prior work. Only 3 of the 6 generative models produced MRIs, of which at least 95% had highly reliable segmentations. More importantly, the assessment of each model by our framework is in line with qualitative assessments, reinforcing the validity of our approach., Comment: Accepted MICCAI 20224

The number of samples in structural brain MRI studies is often too small to properly train deep learning models. Generative models show promise in addressing this issue by effectively learning the data distribution and generating high-fidelity MRI. However, they struggle to produce diverse, high-quality data outside the distribution defined by the training data. One way to address the issue is using causal models developed for 3D volume counterfactuals. However, accurately modeling causality in high-dimensional spaces is a challenge so that these models generally generate 3D brain MRIS of lower quality. To address these challenges, we propose a two-stage method that constructs a Structural Causal Model (SCM) within the latent space. In the first stage, we employ a VQ-VAE to learn a compact embedding of the MRI volume. Subsequently, we integrate our causal model into this latent space and execute a three-step counterfactual procedure using a closed-form Generalized Linear Model (GLM). Our experiments conducted on real-world high-resolution MRI data (1mm) demonstrate that our method can generate high-quality 3D MRI counterfactuals.

Logical anomalies (LA) refer to data violating underlying logical constraints e.g., the quantity, arrangement, or composition of components within an image. Detecting accurately such anomalies requires models to reason about various component types through segmentation. However, curation of pixel-level annotations for semantic segmentation is both time-consuming and expensive. Although there are some prior few-shot or unsupervised co-part segmentation algorithms, they often fail on images with industrial object. These images have components with similar textures and shapes, and a precise differentiation proves challenging. In this study, we introduce a novel component segmentation model for LA detection that leverages a few labeled samples and unlabeled images sharing logical constraints. To ensure consistent segmentation across unlabeled images, we employ a histogram matching loss in conjunction with an entropy loss. As segmentation predictions play a crucial role, we propose to enhance both local and global sample validity detection by capturing key aspects from visual semantics via three memory banks: class histograms, component composition embeddings and patch-level representations. For effective LA detection, we propose an adaptive scaling strategy to standardize anomaly scores from different memory banks in inference. Extensive experiments on the public benchmark MVTec LOCO AD reveal our method achieves 98.1% AUROC in LA detection vs. 89.6% from competing methods., Comment: Accepted in AAAI2024

Generative AI models hold great potential in creating synthetic brain MRIs that advance neuroimaging studies by, for example, enriching data diversity. However, the mainstay of AI research only focuses on optimizing the visual quality (such as signal-to-noise ratio) of the synthetic MRIs while lacking insights into their relevance to neuroscience. To gain these insights with respect to T1-weighted MRIs, we first propose a new generative model, BrainSynth, to synthesize metadata-conditioned (e.g., age- and sex-specific) MRIs that achieve state-of-the-art visual quality. We then extend our evaluation with a novel procedure to quantify anatomical plausibility, i.e., how well the synthetic MRIs capture macrostructural properties of brain regions, and how accurately they encode the effects of age and sex. Results indicate that more than half of the brain regions in our synthetic MRIs are anatomically accurate, i.e., with a small effect size between real and synthetic MRIs. Moreover, the anatomical plausibility varies across cortical regions according to their geometric complexity. As is, our synthetic MRIs can significantly improve the training of a Convolutional Neural Network to identify accelerated aging effects in an independent study. These results highlight the opportunities of using generative AI to aid neuroimaging research and point to areas for further improvement.

Interpretability is a key issue when applying deep learning models to longitudinal brain MRIs. One way to address this issue is by visualizing the high-dimensional latent spaces generated by deep learning via self-organizing maps (SOM). SOM separates the latent space into clusters and then maps the cluster centers to a discrete (typically 2D) grid preserving the high-dimensional relationship between clusters. However, learning SOM in a high-dimensional latent space tends to be unstable, especially in a self-supervision setting. Furthermore, the learned SOM grid does not necessarily capture clinically interesting information, such as brain age. To resolve these issues, we propose the first self-supervised SOM approach that derives a high-dimensional, interpretable representation stratified by brain age solely based on longitudinal brain MRIs (i.e., without demographic or cognitive information). Called Longitudinally-consistent Self-Organized Representation learning (LSOR), the method is stable during training as it relies on soft clustering (vs. the hard cluster assignments used by existing SOM). Furthermore, our approach generates a latent space stratified according to brain age by aligning trajectories inferred from longitudinal MRIs to the reference vector associated with the corresponding SOM cluster. When applied to longitudinal MRIs of the Alzheimer's Disease Neuroimaging Initiative (ADNI, N=632), LSOR generates an interpretable latent space and achieves comparable or higher accuracy than the state-of-the-art representations with respect to the downstream tasks of classification (static vs. progressive mild cognitive impairment) and regression (determining ADAS-Cog score of all subjects). The code is available at https://github.com/ouyangjiahong/longitudinal-som-single-modality.

Publicly available data sets of structural MRIs might not contain specific measurements of brain Regions of Interests (ROIs) that are important for training machine learning models. For example, the curvature scores computed by Freesurfer are not released by the Adolescent Brain Cognitive Development (ABCD) Study. One can address this issue by simply reapplying Freesurfer to the data set. However, this approach is generally computationally and labor intensive (e.g., requiring quality control). An alternative is to impute the missing measurements via a deep learning approach. However, the state-of-the-art is designed to estimate randomly missing values rather than entire measurements. We therefore propose to re-frame the imputation problem as a prediction task on another (public) data set that contains the missing measurements and shares some ROI measurements with the data sets of interest. A deep learning model is then trained to predict the missing measurements from the shared ones and afterwards is applied to the other data sets. Our proposed algorithm models the dependencies between ROI measurements via a graph neural network (GNN) and accounts for demographic differences in brain measurements (e.g. sex) by feeding the graph encoding into a parallel architecture. The architecture simultaneously optimizes a graph decoder to impute values and a classifier in predicting demographic factors. We test the approach, called Demographic Aware Graph-based Imputation (DAGI), on imputing those missing Freesurfer measurements of ABCD (N=3760) by training the predictor on those publicly released by the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA, N=540)..., Comment: Accepted at the 6th workshop on PRedictive Intelligence in Medicine (PRIME 2023) - MICCAI 2023

One of the hallmark symptoms of Parkinson's Disease (PD) is the progressive loss of postural reflexes, which eventually leads to gait difficulties and balance problems. Identifying disruptions in brain function associated with gait impairment could be crucial in better understanding PD motor progression, thus advancing the development of more effective and personalized therapeutics. In this work, we present an explainable, geometric, weighted-graph attention neural network (xGW-GAT) to identify functional networks predictive of the progression of gait difficulties in individuals with PD. xGW-GAT predicts the multi-class gait impairment on the MDS Unified PD Rating Scale (MDS-UPDRS). Our computational- and data-efficient model represents functional connectomes as symmetric positive definite (SPD) matrices on a Riemannian manifold to explicitly encode pairwise interactions of entire connectomes, based on which we learn an attention mask yielding individual- and group-level explainability. Applied to our resting-state functional MRI (rs-fMRI) dataset of individuals with PD, xGW-GAT identifies functional connectivity patterns associated with gait impairment in PD and offers interpretable explanations of functional subnetworks associated with motor impairment. Our model successfully outperforms several existing methods while simultaneously revealing clinically-relevant connectivity patterns. The source code is available at https://github.com/favour-nerrise/xGW-GAT ., Comment: Accepted by the 26th International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI 2023). MICCAI Student-Author Registration (STAR) Award. 11 pages, 2 figures, 1 table, appendix. Source Code: https://github.com/favour-nerrise/xGW-GAT

As acquiring MRIs is expensive, neuroscience studies struggle to attain a sufficient number of them for properly training deep learning models. This challenge could be reduced by MRI synthesis, for which Generative Adversarial Networks (GANs) are popular. GANs, however, are commonly unstable and struggle with creating diverse and high-quality data. A more stable alternative is Diffusion Probabilistic Models (DPMs) with a fine-grained training strategy. To overcome their need for extensive computational resources, we propose a conditional DPM (cDPM) with a memory-efficient process that generates realistic-looking brain MRIs. To this end, we train a 2D cDPM to generate an MRI subvolume conditioned on another subset of slices from the same MRI. By generating slices using arbitrary combinations between condition and target slices, the model only requires limited computational resources to learn interdependencies between slices even if they are spatially far apart. After having learned these dependencies via an attention network, a new anatomy-consistent 3D brain MRI is generated by repeatedly applying the cDPM. Our experiments demonstrate that our method can generate high-quality 3D MRIs that share a similar distribution to real MRIs while still diversifying the training set. The code is available at https://github.com/xiaoiker/mask3DMRI_diffusion and also will be released as part of MONAI, at https://github.com/Project-MONAI/GenerativeModels.

The white-matter (micro-)structural architecture of the brain promotes synchrony among neuronal populations, giving rise to richly patterned functional connections. A fundamental problem for systems neuroscience is determining the best way to relate structural and functional networks quantified by diffusion tensor imaging and resting-state functional MRI. As one of the state-of-the-art approaches for network analysis, graph convolutional networks (GCN) have been separately used to analyze functional and structural networks, but have not been applied to explore inter-network relationships. In this work, we propose to couple the two networks of an individual by adding inter-network edges between corresponding brain regions, so that the joint structure-function graph can be directly analyzed by a single GCN. The weights of inter-network edges are learnable, reflecting non-uniform structure-function coupling strength across the brain. We apply our Joint-GCN to predict age and sex of 662 participants from the public dataset of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) based on their functional and micro-structural white-matter networks. Our results support that the proposed Joint-GCN outperforms existing multi-modal graph learning approaches for analyzing structural and functional networks.

For the first time, we propose using a multiple instance learning based convolution-free transformer model, called Multiple Instance Neuroimage Transformer (MINiT), for the classification of T1weighted (T1w) MRIs. We first present several variants of transformer models adopted for neuroimages. These models extract non-overlapping 3D blocks from the input volume and perform multi-headed self-attention on a sequence of their linear projections. MINiT, on the other hand, treats each of the non-overlapping 3D blocks of the input MRI as its own instance, splitting it further into non-overlapping 3D patches, on which multi-headed self-attention is computed. As a proof-of-concept, we evaluate the efficacy of our model by training it to identify sex from T1w-MRIs of two public datasets: Adolescent Brain Cognitive Development (ABCD) and the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA). The learned attention maps highlight voxels contributing to identifying sex differences in brain morphometry. The code is available at https://github.com/singlaayush/MINIT.

A fundamental approach in neuroscience research is to test hypotheses based on neuropsychological and behavioral measures, i.e., whether certain factors (e.g., related to life events) are associated with an outcome (e.g., depression). In recent years, deep learning has become a potential alternative approach for conducting such analyses by predicting an outcome from a collection of factors and identifying the most "informative" ones driving the prediction. However, this approach has had limited impact as its findings are not linked to statistical significance of factors supporting hypotheses. In this article, we proposed a flexible and scalable approach based on the concept of permutation testing that integrates hypothesis testing into the data-driven deep learning analysis. We apply our approach to the yearly self-reported assessments of 621 adolescent participants of the National Consortium of Alcohol and Neurodevelopment in Adolescence (NCANDA) to predict negative valence, a symptom of major depressive disorder according to the NIMH Research Domain Criteria (RDoC). Our method successfully identifies categories of risk factors that further explain the symptom., Comment: Accepted at the 5th workshop on PRedictive Intelligence in Medicine (PRIME 2022) - MICCAI 2022

Translating machine learning algorithms into clinical applications requires addressing challenges related to interpretability, such as accounting for the effect of confounding variables (or metadata). Confounding variables affect the relationship between input training data and target outputs. When we train a model on such data, confounding variables will bias the distribution of the learned features. A recent promising solution, MetaData Normalization (MDN), estimates the linear relationship between the metadata and each feature based on a non-trainable closed-form solution. However, this estimation is confined by the sample size of a mini-batch and thereby may cause the approach to be unstable during training. In this paper, we extend the MDN method by applying a Penalty approach (referred to as PDMN). We cast the problem into a bi-level nested optimization problem. We then approximate this optimization problem using a penalty method so that the linear parameters within the MDN layer are trainable and learned on all samples. This enables PMDN to be plugged into any architectures, even those unfit to run batch-level operations, such as transformers and recurrent models. We show improvement in model accuracy and greater independence from confounders using PMDN over MDN in a synthetic experiment and a multi-label, multi-site dataset of magnetic resonance images (MRIs).

Parkinson's disease (PD) is a neurological disorder that has a variety of observable motor-related symptoms such as slow movement, tremor, muscular rigidity, and impaired posture. PD is typically diagnosed by evaluating the severity of motor impairments according to scoring systems such as the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Automated severity prediction using video recordings of individuals provides a promising route for non-intrusive monitoring of motor impairments. However, the limited size of PD gait data hinders model ability and clinical potential. Because of this clinical data scarcity and inspired by the recent advances in self-supervised large-scale language models like GPT-3, we use human motion forecasting as an effective self-supervised pre-training task for the estimation of motor impairment severity. We introduce GaitForeMer, Gait Forecasting and impairment estimation transforMer, which is first pre-trained on public datasets to forecast gait movements and then applied to clinical data to predict MDS-UPDRS gait impairment severity. Our method outperforms previous approaches that rely solely on clinical data by a large margin, achieving an F1 score of 0.76, precision of 0.79, and recall of 0.75. Using GaitForeMer, we show how public human movement data repositories can assist clinical use cases through learning universal motion representations. The code is available at https://github.com/markendo/GaitForeMer ., Comment: Accepted as a conference paper at MICCAI (Medical Image Computing and Computer Assisted Intervention) 2022

Starting from childhood, the human brain restructures and rewires throughout life. Characterizing such complex brain development requires effective analysis of longitudinal and multi-modal neuroimaging data. Here, we propose such an analysis approach named Longitudinal Correlation Analysis (LCA). LCA couples the data of two modalities by first reducing the input from each modality to a latent representation based on autoencoders. A self-supervised strategy then relates the two latent spaces by jointly disentangling two directions, one in each space, such that the longitudinal changes in latent representations along those directions are maximally correlated between modalities. We applied LCA to analyze the longitudinal T1-weighted and diffusion-weighted MRIs of 679 youths from the National Consortium on Alcohol and Neurodevelopment in Adolescence. Unlike existing approaches that focus on either cross-sectional or single-modal modeling, LCA successfully unraveled coupled macrostructural and microstructural brain development from morphological and diffusivity features extracted from the data. A retesting of LCA on raw 3D image volumes of those subjects successfully replicated the findings from the feature-based analysis. Lastly, the developmental effects revealed by LCA were inline with the current understanding of maturational patterns of the adolescent brain.

Batch Normalization (BN) and its variants have delivered tremendous success in combating the covariate shift induced by the training step of deep learning methods. While these techniques normalize feature distributions by standardizing with batch statistics, they do not correct the influence on features from extraneous variables or multiple distributions. Such extra variables, referred to as metadata here, may create bias or confounding effects (e.g., race when classifying gender from face images). We introduce the Metadata Normalization (MDN) layer, a new batch-level operation which can be used end-to-end within the training framework, to correct the influence of metadata on feature distributions. MDN adopts a regression analysis technique traditionally used for preprocessing to remove (regress out) the metadata effects on model features during training. We utilize a metric based on distance correlation to quantify the distribution bias from the metadata and demonstrate that our method successfully removes metadata effects on four diverse settings: one synthetic, one 2D image, one video, and one 3D medical image dataset., Comment: Accepted to CVPR 2021. Project page: https://mml.stanford.edu/MDN/

Longitudinal MRIs are often used to capture the gradual deterioration of brain structure and function caused by aging or neurological diseases. Analyzing this data via machine learning generally requires a large number of ground-truth labels, which are often missing or expensive to obtain. Reducing the need for labels, we propose a self-supervised strategy for representation learning named Longitudinal Neighborhood Embedding (LNE). Motivated by concepts in contrastive learning, LNE explicitly models the similarity between trajectory vectors across different subjects. We do so by building a graph in each training iteration defining neighborhoods in the latent space so that the progression direction of a subject follows the direction of its neighbors. This results in a smooth trajectory field that captures the global morphological change of the brain while maintaining the local continuity. We apply LNE to longitudinal T1w MRIs of two neuroimaging studies: a dataset composed of 274 healthy subjects, and Alzheimer's Disease Neuroimaging Initiative (ADNI, N=632). The visualization of the smooth trajectory vector field and superior performance on downstream tasks demonstrate the strength of the proposed method over existing self-supervised methods in extracting information associated with normal aging and in revealing the impact of neurodegenerative disorders. The code is available at \url{https://github.com/ouyangjiahong/longitudinal-neighbourhood-embedding.git}., Comment: Provisional Accepted by Medical Image Computing and Computer Assisted Intervention (MICCAI) 2021

Multi-modal MRIs are widely used in neuroimaging applications since different MR sequences provide complementary information about brain structures. Recent works have suggested that multi-modal deep learning analysis can benefit from explicitly disentangling anatomical (shape) and modality (appearance) information into separate image presentations. In this work, we challenge mainstream strategies by showing that they do not naturally lead to representation disentanglement both in theory and in practice. To address this issue, we propose a margin loss that regularizes the similarity in relationships of the representations across subjects and modalities. To enable robust training, we further use a conditional convolution to design a single model for encoding images of all modalities. Lastly, we propose a fusion function to combine the disentangled anatomical representations as a set of modality-invariant features for downstream tasks. We evaluate the proposed method on three multi-modal neuroimaging datasets. Experiments show that our proposed method can achieve superior disentangled representations compared to existing disentanglement strategies. Results also indicate that the fused anatomical representation has potential in the downstream task of zero-dose PET reconstruction and brain tumor segmentation. The code is available at \url{https://github.com/ouyangjiahong/representation-disentanglement}., Comment: Accepted by Information Processing in Medical Imaging (IPMI) 2021

Interpretability is a critical factor in applying complex deep learning models to advance the understanding of brain disorders in neuroimaging studies. To interpret the decision process of a trained classifier, existing techniques typically rely on saliency maps to quantify the voxel-wise or feature-level importance for classification through partial derivatives. Despite providing some level of localization, these maps are not human-understandable from the neuroscience perspective as they do not inform the specific meaning of the alteration linked to the brain disorder. Inspired by the image-to-image translation scheme, we propose to train simulator networks that can warp a given image to inject or remove patterns of the disease. These networks are trained such that the classifier produces consistently increased or decreased prediction logits for the simulated images. Moreover, we propose to couple all the simulators into a unified model based on conditional convolution. We applied our approach to interpreting classifiers trained on a synthetic dataset and two neuroimaging datasets to visualize the effect of the Alzheimer's disease and alcohol use disorder. Compared to the saliency maps generated by baseline approaches, our simulations and visualizations based on the Jacobian determinants of the warping field reveal meaningful and understandable patterns related to the diseases.