Qingyu Zhao

Favour Nerrise, Qingyu Zhao, Kathleen L. Poston et al.

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 .

Yixin Wang, Wei Peng, Susan F. Tapert et al.

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)...

Wei Peng, Tomas Bosschieter, Jiahong Ouyang et al.

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.

Yixin Wang, Wei Peng, Yu Zhang et al.

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.

Bahram Jafrasteh, Wei Peng, Cheng Wan et al.

Generative models enhance neuroimaging through data augmentation, quality improvement, and rare condition studies. Despite advances in realistic synthetic MRIs, evaluations focus on texture and perception, lacking sensitivity to crucial anatomical fidelity. This study proposes a new metric, called WASABI (Wasserstein-Based Anatomical Brain Index), to assess the anatomical realism of synthetic brain MRIs. WASABI leverages \textit{SynthSeg}, a deep learning-based brain parcellation tool, to derive volumetric measures of brain regions in each MRI and uses the multivariate Wasserstein distance to compare distributions between real and synthetic anatomies. Based on controlled experiments on two real datasets and synthetic MRIs from five generative models, WASABI demonstrates higher sensitivity in quantifying anatomical discrepancies compared to traditional image-level metrics, even when synthetic images achieve near-perfect visual quality. Our findings advocate for shifting the evaluation paradigm beyond visual inspection and conventional metrics, emphasizing anatomical fidelity as a crucial benchmark for clinically meaningful brain MRI synthesis. Our code is available at https://github.com/BahramJafrasteh/wasabi-mri.

Jiahong Ouyang, Qingyu Zhao, Ehsan Adeli et al.

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}.

Jiahong Ouyang, Qingyu Zhao, Edith V Sullivan et al.

Many neurological diseases are characterized by gradual deterioration of brain structure and function. Large longitudinal MRI datasets have revealed such deterioration, in part, by applying machine and deep learning to predict diagnosis. A popular approach is to apply Convolutional Neural Networks (CNN) to extract informative features from each visit of the longitudinal MRI and then use those features to classify each visit via Recurrent Neural Networks (RNNs). Such modeling neglects the progressive nature of the disease, which may result in clinically implausible classifications across visits. To avoid this issue, we propose to combine features across visits by coupling feature extraction with a novel longitudinal pooling layer and enforce consistency of the classification across visits in line with disease progression. We evaluate the proposed method on the longitudinal structural MRIs from three neuroimaging datasets: Alzheimer's Disease Neuroimaging Initiative (ADNI, N=404), a dataset composed of 274 normal controls and 329 patients with Alcohol Use Disorder (AUD), and 255 youths from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA). In all three experiments our method is superior to other widely used approaches for longitudinal classification thus making a unique contribution towards more accurate tracking of the impact of conditions on the brain. The code is available at https://github.com/ouyangjiahong/longitudinal-pooling.

Ehsan Adeli, Qingyu Zhao, Adolf Pfefferbaum et al.

Presence of bias (in datasets or tasks) is inarguably one of the most critical challenges in machine learning applications that has alluded to pivotal debates in recent years. Such challenges range from spurious associations between variables in medical studies to the bias of race in gender or face recognition systems. Controlling for all types of biases in the dataset curation stage is cumbersome and sometimes impossible. The alternative is to use the available data and build models incorporating fair representation learning. In this paper, we propose such a model based on adversarial training with two competing objectives to learn features that have (1) maximum discriminative power with respect to the task and (2) minimal statistical mean dependence with the protected (bias) variable(s). Our approach does so by incorporating a new adversarial loss function that encourages a vanished correlation between the bias and the learned features. We apply our method to synthetic data, medical images (containing task bias), and a dataset for gender classification (containing dataset bias). Our results show that the learned features by our method not only result in superior prediction performance but also are unbiased. The code is available at https://github.com/QingyuZhao/BR-Net/.

Jensen Hwa, Qingyu Zhao, Aditya Lahiri et al.

Conditional independence (CI) constraints are critical for defining and evaluating fairness in machine learning, as well as for learning unconfounded or causal representations. Traditional methods for ensuring fairness either blindly learn invariant features with respect to a protected variable (e.g., race when classifying sex from face images) or enforce CI relative to the protected attribute only on the model output (e.g., the sex label). Neither of these methods are effective in enforcing CI in high-dimensional feature spaces. In this paper, we focus on a nascent approach characterizing the CI constraint in terms of two Jensen-Shannon divergence terms, and we extend it to high-dimensional feature spaces using a novel dynamic sampling strategy. In doing so, we introduce a new training paradigm that can be applied to any encoder architecture. We are able to enforce conditional independence of the diffusion autoencoder latent representation with respect to any protected attribute under the equalized odds constraint and show that this approach enables causal image generation with controllable latent spaces. Our experimental results demonstrate that our approach can achieve high accuracy on downstream tasks while upholding equality of odds.

Qingyu Zhao, Ehsan Adeli, Kilian M. Pohl

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.

Mandy Lu, Qingyu Zhao, Jiequan Zhang et al.

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.

Zixuan Liu, Ehsan Adeli, Kilian M. Pohl et al.

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.

Qingyu Zhao, Zixuan Liu, Ehsan Adeli et al.

Machine learning analysis of longitudinal neuroimaging data is typically based on supervised learning, which requires a large number of ground-truth labels to be informative. As ground-truth labels are often missing or expensive to obtain in neuroscience, we avoid them in our analysis by combing factor disentanglement with self-supervised learning to identify changes and consistencies across the multiple MRIs acquired of each individual over time. Specifically, we propose a new definition of disentanglement by formulating a multivariate mapping between factors (e.g., brain age) associated with an MRI and a latent image representation. Then, factors that evolve across acquisitions of longitudinal sequences are disentangled from that mapping by self-supervised learning in such a way that changes in a single factor induce change along one direction in the representation space. We implement this model, named Longitudinal Self-Supervised Learning (LSSL), via a standard autoencoding structure with a cosine loss to disentangle brain age from the image representation. We apply LSSL to two longitudinal neuroimaging studies to highlight its strength in extracting the brain-age information from MRI and revealing informative characteristics associated with neurodegenerative and neuropsychological disorders. Moreover, the representations learned by LSSL facilitate supervised classification by recording faster convergence and higher (or similar) prediction accuracy compared to several other representation learning techniques.

Soham Gadgil, Qingyu Zhao, Adolf Pfefferbaum et al.

The Blood-Oxygen-Level-Dependent (BOLD) signal of resting-state fMRI (rs-fMRI) records the temporal dynamics of intrinsic functional networks in the brain. However, existing deep learning methods applied to rs-fMRI either neglect the functional dependency between different brain regions in a network or discard the information in the temporal dynamics of brain activity. To overcome those shortcomings, we propose to formulate functional connectivity networks within the context of spatio-temporal graphs. We train a spatio-temporal graph convolutional network (ST-GCN) on short sub-sequences of the BOLD time series to model the non-stationary nature of functional connectivity. Simultaneously, the model learns the importance of graph edges within ST-GCN to gain insight into the functional connectivities contributing to the prediction. In analyzing the rs-fMRI of the Human Connectome Project (HCP, N=1,091) and the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA, N=773), ST-GCN is significantly more accurate than common approaches in predicting gender and age based on BOLD signals. Furthermore, the brain regions and functional connections significantly contributing to the predictions of our model are important markers according to the neuroscience literature.

Qingyu Zhao, Ehsan Adeli, Adolf Pfefferbaum et al.

With recent advances in deep learning, neuroimaging studies increasingly rely on convolutional networks (ConvNets) to predict diagnosis based on MR images. To gain a better understanding of how a disease impacts the brain, the studies visualize the salience maps of the ConvNet highlighting voxels within the brain majorly contributing to the prediction. However, these salience maps are generally confounded, i.e., some salient regions are more predictive of confounding variables (such as age) than the diagnosis. To avoid such misinterpretation, we propose in this paper an approach that aims to visualize confounder-free saliency maps that only highlight voxels predictive of the diagnosis. The approach incorporates univariate statistical tests to identify confounding effects within the intermediate features learned by ConvNet. The influence from the subset of confounded features is then removed by a novel partial back-propagation procedure. We use this two-step approach to visualize confounder-free saliency maps extracted from synthetic and two real datasets. These experiments reveal the potential of our visualization in producing unbiased model-interpretation.

Qingyu Zhao, Ehsan Adeli, Nicolas Honnorat et al.

While unsupervised variational autoencoders (VAE) have become a powerful tool in neuroimage analysis, their application to supervised learning is under-explored. We aim to close this gap by proposing a unified probabilistic model for learning the latent space of imaging data and performing supervised regression. Based on recent advances in learning disentangled representations, the novel generative process explicitly models the conditional distribution of latent representations with respect to the regression target variable. Performing a variational inference procedure on this model leads to joint regularization between the VAE and a neural-network regressor. In predicting the age of 245 subjects from their structural Magnetic Resonance (MR) images, our model is more accurate than state-of-the-art methods when applied to either region-of-interest (ROI) measurements or raw 3D volume images. More importantly, unlike simple feed-forward neural-networks, disentanglement of age in latent representations allows for intuitive interpretation of the structural developmental patterns of the human brain.

Qingyu Zhao, Nicolas Honnorat, Ehsan Adeli et al.

Variation Autoencoder (VAE) has become a powerful tool in modeling the non-linear generative process of data from a low-dimensional latent space. Recently, several studies have proposed to use VAE for unsupervised clustering by using mixture models to capture the multi-modal structure of latent representations. This strategy, however, is ineffective when there are outlier data samples whose latent representations are meaningless, yet contaminating the estimation of key major clusters in the latent space. This exact problem arises in the context of resting-state fMRI (rs-fMRI) analysis, where clustering major functional connectivity patterns is often hindered by heavy noise of rs-fMRI and many minor clusters (rare connectivity patterns) of no interest to analysis. In this paper we propose a novel generative process, in which we use a Gaussian-mixture to model a few major clusters in the data, and use a non-informative uniform distribution to capture the remaining data. We embed this truncated Gaussian-Mixture model in a Variational AutoEncoder framework to obtain a general joint clustering and outlier detection approach, called tGM-VAE. We demonstrated the applicability of tGM-VAE on the MNIST dataset and further validated it in the context of rs-fMRI connectivity analysis.