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Multi-site structural MRI is increasingly used in neuroimaging studies to diversify subject cohorts. However, combining MR images acquired from various sites/centers may introduce site-related non-biological variations. Retrospective image harmonization helps address this issue, but current methods usually perform harmonization on pre-extracted hand-crafted radiomic features, limiting downstream applicability. Several image-level approaches focus on 2D slices, disregarding inherent volumetric information, leading to suboptimal outcomes. To this end, we propose a novel 3D MRI Harmonization framework through Conditional Latent Diffusion (HCLD) by explicitly considering image style and brain anatomy. It comprises a generalizable 3D autoencoder that encodes and decodes MRIs through a 4D latent space, and a conditional latent diffusion model that learns the latent distribution and generates harmonized MRIs with anatomical information from source MRIs while conditioned on target image style. This enables efficient volume-level MRI harmonization through latent style translation, without requiring paired images from target and source domains during training. The HCLD is trained and evaluated on 4,158 T1-weighted brain MRIs from three datasets in three tasks, assessing its ability to remove site-related variations while retaining essential biological features. Qualitative and quantitative experiments suggest the effectiveness of HCLD over several state-of-the-arts

Major depressive disorder (MDD) is a common mental disorder that typically affects a person's mood, cognition, behavior, and physical health. Resting-state functional magnetic resonance imaging (rs-fMRI) data are widely used for computer-aided diagnosis of MDD. While multi-site fMRI data can provide more data for training reliable diagnostic models, significant cross-site data heterogeneity would result in poor model generalizability. Many domain adaptation methods are designed to reduce the distributional differences between sites to some extent, but usually ignore overfitting problem of the model on the source domain. Intuitively, target data augmentation can alleviate the overfitting problem by forcing the model to learn more generalized features and reduce the dependence on source domain data. In this work, we propose a new augmentation-based unsupervised cross-domain fMRI adaptation (AUFA) framework for automatic diagnosis of MDD. The AUFA consists of 1) a graph representation learning module for extracting rs-fMRI features with spatial attention, 2) a domain adaptation module for feature alignment between source and target data, 3) an augmentation-based self-optimization module for alleviating model overfitting on the source domain, and 4) a classification module. Experimental results on 1,089 subjects suggest that AUFA outperforms several state-of-the-art methods in MDD identification. Our approach not only reduces data heterogeneity between different sites, but also localizes disease-related functional connectivity abnormalities and provides interpretability for the model.

Functional magnetic resonance imaging (fMRI) has been increasingly employed to investigate functional brain activity. Many fMRI-related software/toolboxes have been developed, providing specialized algorithms for fMRI analysis. However, existing toolboxes seldom consider fMRI data augmentation, which is quite useful, especially in studies with limited or imbalanced data. Moreover, current studies usually focus on analyzing fMRI using conventional machine learning models that rely on human-engineered fMRI features, without investigating deep learning models that can automatically learn data-driven fMRI representations. In this work, we develop an open-source toolbox, called Augmentation and Computation Toolbox for braIn netwOrk aNalysis (ACTION), offering comprehensive functions to streamline fMRI analysis. The ACTION is a Python-based and cross-platform toolbox with graphical user-friendly interfaces. It enables automatic fMRI augmentation, covering blood-oxygen-level-dependent (BOLD) signal augmentation and brain network augmentation. Many popular methods for brain network construction and network feature extraction are included. In particular, it supports constructing deep learning models, which leverage large-scale auxiliary unlabeled data (3,800+ resting-state fMRI scans) for model pretraining to enhance model performance for downstream tasks. To facilitate multi-site fMRI studies, it is also equipped with several popular federated learning strategies. Furthermore, it enables users to design and test custom algorithms through scripting, greatly improving its utility and extensibility. We demonstrate the effectiveness and user-friendliness of ACTION on real fMRI data and present the experimental results. The software, along with its source code and manual, can be accessed online., Comment: 14 pages, 5 figures, 5 tables

Magnetic resonance imaging (MRI) and positron emission tomography (PET) are increasingly used in multimodal analysis of neurodegenerative disorders. While MRI is broadly utilized in clinical settings, PET is less accessible. Many studies have attempted to use deep generative models to synthesize PET from MRI scans. However, they often suffer from unstable training and inadequately preserve brain functional information conveyed by PET. To this end, we propose a functional imaging constrained diffusion (FICD) framework for 3D brain PET image synthesis with paired structural MRI as input condition, through a new constrained diffusion model (CDM). The FICD introduces noise to PET and then progressively removes it with CDM, ensuring high output fidelity throughout a stable training phase. The CDM learns to predict denoised PET with a functional imaging constraint introduced to ensure voxel-wise alignment between each denoised PET and its ground truth. Quantitative and qualitative analyses conducted on 293 subjects with paired T1-weighted MRI and 18F-fluorodeoxyglucose (FDG)-PET scans suggest that FICD achieves superior performance in generating FDG-PET data compared to state-of-the-art methods. We further validate the effectiveness of the proposed FICD on data from a total of 1,262 subjects through three downstream tasks, with experimental results suggesting its utility and generalizability.

Image noise and motion artifacts greatly affect the quality of brain MRI and negatively influence downstream medical image analysis. Previous studies often focus on 2D methods that process each volumetric MR image slice-by-slice, thus losing important 3D anatomical information. Additionally, these studies generally treat image denoising and artifact correction as two standalone tasks, without considering their potential relationship, especially on low-quality images where severe noise and motion artifacts occur simultaneously. To address these issues, we propose a Joint image Denoising and motion Artifact Correction (JDAC) framework via iterative learning to handle noisy MRIs with motion artifacts, consisting of an adaptive denoising model and an anti-artifact model. In the adaptive denoising model, we first design a novel noise level estimation strategy, and then adaptively reduce the noise through a U-Net backbone with feature normalization conditioning on the estimated noise variance. The anti-artifact model employs another U-Net for eliminating motion artifacts, incorporating a novel gradient-based loss function designed to maintain the integrity of brain anatomy during the motion correction process. These two models are iteratively employed for joint image denoising and artifact correction through an iterative learning framework. An early stopping strategy depending on noise level estimation is applied to accelerate the iteration process. The denoising model is trained with 9,544 T1-weighted MRIs with manually added Gaussian noise as supervision. The anti-artifact model is trained on 552 T1-weighted MRIs with motion artifacts and paired motion-free images. Experimental results on a public dataset and a clinical study suggest the effectiveness of JDAC in both tasks of denoising and motion artifact correction, compared with several state-of-the-art methods.

Brain magnetic resonance imaging (MRI) has been extensively employed across clinical and research fields, but often exhibits sensitivity to site effects arising from non-biological variations such as differences in field strength and scanner vendors. Numerous retrospective MRI harmonization techniques have demonstrated encouraging outcomes in reducing the site effects at the image level. However, existing methods generally suffer from high computational requirements and limited generalizability, restricting their applicability to unseen MRIs. In this paper, we design a novel disentangled latent energy-based style translation (DLEST) framework for unpaired image-level MRI harmonization, consisting of (a) site-invariant image generation (SIG), (b) site-specific style translation (SST), and (c) site-specific MRI synthesis (SMS). Specifically, the SIG employs a latent autoencoder to encode MRIs into a low-dimensional latent space and reconstruct MRIs from latent codes. The SST utilizes an energy-based model to comprehend the global latent distribution of a target domain and translate source latent codes toward the target domain, while SMS enables MRI synthesis with a target-specific style. By disentangling image generation and style translation in latent space, the DLEST can achieve efficient style translation. Our model was trained on T1-weighted MRIs from a public dataset (with 3,984 subjects across 58 acquisition sites/settings) and validated on an independent dataset (with 9 traveling subjects scanned in 11 sites/settings) in four tasks: histogram and feature visualization, site classification, brain tissue segmentation, and site-specific structural MRI synthesis. Qualitative and quantitative results demonstrate the superiority of our method over several state-of-the-arts.

Resting-state functional MRI (rs-fMRI) is increasingly employed in multi-site research to aid neurological disorder analysis. Existing studies usually suffer from significant cross-site/domain data heterogeneity caused by site effects such as differences in scanners/protocols. Many methods have been proposed to reduce fMRI heterogeneity between source and target domains, heavily relying on the availability of source data. But acquiring source data is challenging due to privacy concerns and/or data storage burdens in multi-site studies. To this end, we design a source-free collaborative domain adaptation (SCDA) framework for fMRI analysis, where only a pretrained source model and unlabeled target data are accessible. Specifically, a multi-perspective feature enrichment method (MFE) is developed for target fMRI analysis, consisting of multiple collaborative branches to dynamically capture fMRI features of unlabeled target data from multiple views. Each branch has a data-feeding module, a spatiotemporal feature encoder, and a class predictor. A mutual-consistency constraint is designed to encourage pair-wise consistency of latent features of the same input generated from these branches for robust representation learning. To facilitate efficient cross-domain knowledge transfer without source data, we initialize MFE using parameters of a pretrained source model. We also introduce an unsupervised pretraining strategy using 3,806 unlabeled fMRIs from three large-scale auxiliary databases, aiming to obtain a general feature encoder. Experimental results on three public datasets and one private dataset demonstrate the efficacy of our method in cross-scanner and cross-study prediction tasks. The model pretrained on large-scale rs-fMRI data has been released to the public., Comment: 12 pages, 5 figures

Resting-state functional magnetic resonance imaging (rs-fMRI) offers a non-invasive approach to examining abnormal brain connectivity associated with brain disorders. Graph neural network (GNN) gains popularity in fMRI representation learning and brain disorder analysis with powerful graph representation capabilities. Training a general GNN often necessitates a large-scale dataset from multiple imaging centers/sites, but centralizing multi-site data generally faces inherent challenges related to data privacy, security, and storage burden. Federated Learning (FL) enables collaborative model training without centralized multi-site fMRI data. Unfortunately, previous FL approaches for fMRI analysis often ignore site-specificity, including demographic factors such as age, gender, and education level. To this end, we propose a specificity-aware federated graph learning (SFGL) framework for rs-fMRI analysis and automated brain disorder identification, with a server and multiple clients/sites for federated model aggregation and prediction. At each client, our model consists of a shared and a personalized branch, where parameters of the shared branch are sent to the server while those of the personalized branch remain local. This can facilitate knowledge sharing among sites and also helps preserve site specificity. In the shared branch, we employ a spatio-temporal attention graph isomorphism network to learn dynamic fMRI representations. In the personalized branch, we integrate vectorized demographic information (i.e., age, gender, and education years) and functional connectivity networks to preserve site-specific characteristics. Representations generated by the two branches are then fused for classification. Experimental results on two fMRI datasets with a total of 1,218 subjects suggest that SFGL outperforms several state-of-the-art approaches.

Resting-state functional magnetic resonance imaging (rs-fMRI) can reflect spontaneous neural activities in brain and is widely used for brain disorder analysis.Previous studies propose to extract fMRI representations through diverse machine/deep learning methods for subsequent analysis. But the learned features typically lack biological interpretability, which limits their clinical utility. From the view of graph theory, the brain exhibits a remarkable modular structure in spontaneous brain functional networks, with each module comprised of functionally interconnected brain regions-of-interest (ROIs). However, most existing learning-based methods for fMRI analysis fail to adequately utilize such brain modularity prior. In this paper, we propose a Brain Modularity-constrained dynamic Representation learning (BMR) framework for interpretable fMRI analysis, consisting of three major components: (1) dynamic graph construction, (2) dynamic graph learning via a novel modularity-constrained graph neural network(MGNN), (3) prediction and biomarker detection for interpretable fMRI analysis. Especially, three core neurocognitive modules (i.e., salience network, central executive network, and default mode network) are explicitly incorporated into the MGNN, encouraging the nodes/ROIs within the same module to share similar representations. To further enhance discriminative ability of learned features, we also encourage the MGNN to preserve the network topology of input graphs via a graph topology reconstruction constraint. Experimental results on 534 subjects with rs-fMRI scans from two datasets validate the effectiveness of the proposed method. The identified discriminative brain ROIs and functional connectivities can be regarded as potential fMRI biomarkers to aid in clinical diagnosis.

Brain structural MRI has been widely used to assess the future progression of cognitive impairment (CI). Previous learning-based studies usually suffer from the issue of small-sized labeled training data, while there exist a huge amount of structural MRIs in large-scale public databases. Intuitively, brain anatomical structures derived from these public MRIs (even without task-specific label information) can be used to boost CI progression trajectory prediction. However, previous studies seldom take advantage of such brain anatomy prior. To this end, this paper proposes a brain anatomy prior modeling (BAPM) framework to forecast the clinical progression of cognitive impairment with small-sized target MRIs by exploring anatomical brain structures. Specifically, the BAPM consists of a pretext model and a downstream model, with a shared brain anatomy-guided encoder to model brain anatomy prior explicitly. Besides the encoder, the pretext model also contains two decoders for two auxiliary tasks (i.e., MRI reconstruction and brain tissue segmentation), while the downstream model relies on a predictor for classification. The brain anatomy-guided encoder is pre-trained with the pretext model on 9,344 auxiliary MRIs without diagnostic labels for anatomy prior modeling. With this encoder frozen, the downstream model is then fine-tuned on limited target MRIs for prediction. We validate the BAPM on two CI-related studies with T1-weighted MRIs from 448 subjects. Experimental results suggest the effectiveness of BAPM in (1) four CI progression prediction tasks, (2) MR image reconstruction, and (3) brain tissue segmentation, compared with several state-of-the-art methods.

Machine learning in medical imaging often faces a fundamental dilemma, namely, the small sample size problem. Many recent studies suggest using multi-domain data pooled from different acquisition sites/centers to improve statistical power. However, medical images from different sites cannot be easily shared to build large datasets for model training due to privacy protection reasons. As a promising solution, federated learning, which enables collaborative training of machine learning models based on data from different sites without cross-site data sharing, has attracted considerable attention recently. In this paper, we conduct a comprehensive survey of the recent development of federated learning methods in medical image analysis. In this survey, we first introduce the background knowledge of federated learning for dealing with privacy protection and collaborative learning issues in medical imaging. We then present a comprehensive review of recent advances in federated learning methods for medical image analysis. Specifically, existing methods are categorized based on three critical aspects of a federated learning system, including client end, server end, and communication techniques. In each category, we summarize the existing federated learning methods according to specific research problems in medical image analysis and also provide insights into the motivations of different approaches. In addition, we provide a review of existing benchmark medical imaging datasets and software platforms for current federated learning research. We also conduct an experimental study to empirically evaluate typical federated learning methods for medical image analysis. This survey can help to better understand the current research status, challenges, and potential research opportunities in this promising research field., Comment: 35 pages, 6 figures

Unsupervised domain adaptation (UDA) via deep learning has attracted appealing attention for tackling domain-shift problems caused by distribution discrepancy across different domains. Existing UDA approaches highly depend on the accessibility of source domain data, which is usually limited in practical scenarios due to privacy protection, data storage and transmission cost, and computation burden. To tackle this issue, many source-free unsupervised domain adaptation (SFUDA) methods have been proposed recently, which perform knowledge transfer from a pre-trained source model to unlabeled target domain with source data inaccessible. A comprehensive review of these works on SFUDA is of great significance. In this paper, we provide a timely and systematic literature review of existing SFUDA approaches from a technical perspective. Specifically, we categorize current SFUDA studies into two groups, i.e., white-box SFUDA and black-box SFUDA, and further divide them into finer subcategories based on different learning strategies they use. We also investigate the challenges of methods in each subcategory, discuss the advantages/disadvantages of white-box and black-box SFUDA methods, conclude the commonly used benchmark datasets, and summarize the popular techniques for improved generalizability of models learned without using source data. We finally discuss several promising future directions in this field., Comment: 19 pages, 10 figures

Late-life depression (LLD) is a highly prevalent mood disorder occurring in older adults and is frequently accompanied by cognitive impairment (CI). Studies have shown that LLD may increase the risk of Alzheimer's disease (AD). However, the heterogeneity of presentation of geriatric depression suggests that multiple biological mechanisms may underlie it. Current biological research on LLD progression incorporates machine learning that combines neuroimaging data with clinical observations. There are few studies on incident cognitive diagnostic outcomes in LLD based on structural MRI (sMRI). In this paper, we describe the development of a hybrid representation learning (HRL) framework for predicting cognitive diagnosis over 5 years based on T1-weighted sMRI data. Specifically, we first extract prediction-oriented MRI features via a deep neural network, and then integrate them with handcrafted MRI features via a Transformer encoder for cognitive diagnosis prediction. Two tasks are investigated in this work, including (1) identifying cognitively normal subjects with LLD and never-depressed older healthy subjects, and (2) identifying LLD subjects who developed CI (or even AD) and those who stayed cognitively normal over five years. To the best of our knowledge, this is among the first attempts to study the complex heterogeneous progression of LLD based on task-oriented and handcrafted MRI features. We validate the proposed HRL on 294 subjects with T1-weighted MRIs from two clinically harmonized studies. Experimental results suggest that the HRL outperforms several classical machine learning and state-of-the-art deep learning methods in LLD identification and prediction tasks.

Domain adaptation (DA) is an important technique for modern machine learning-based medical data analysis, which aims at reducing distribution differences between different medical datasets. A proper domain adaptation method can significantly enhance the statistical power by pooling data acquired from multiple sites/centers. To this end, we have developed the Domain Adaptation Toolbox for Medical data analysis (DomainATM) - an open-source software package designed for fast facilitation and easy customization of domain adaptation methods for medical data analysis. The DomainATM is implemented in MATLAB with a user-friendly graphical interface, and it consists of a collection of popular data adaptation algorithms that have been extensively applied to medical image analysis and computer vision. With DomainATM, researchers are able to facilitate fast feature-level and image-level adaptation, visualization and performance evaluation of different adaptation methods for medical data analysis. More importantly, the DomainATM enables the users to develop and test their own adaptation methods through scripting, greatly enhancing its utility and extensibility. An overview characteristic and usage of DomainATM is presented and illustrated with three example experiments, demonstrating its effectiveness, simplicity, and flexibility. The software, source code, and manual are available online., Comment: 10 pages, 13 figures

Subjective cognitive decline (SCD) is a preclinical stage of Alzheimer's disease (AD) which occurs even before mild cognitive impairment (MCI). Progressive SCD will convert to MCI with the potential of further evolving to AD. Therefore, early identification of progressive SCD with neuroimaging techniques (e.g., structural MRI) is of great clinical value for early intervention of AD. However, existing MRI-based machine/deep learning methods usually suffer the small-sample-size problem which poses a great challenge to related neuroimaging analysis. The central question we aim to tackle in this paper is how to leverage related domains (e.g., AD/NC) to assist the progression prediction of SCD. Meanwhile, we are concerned about which brain areas are more closely linked to the identification of progressive SCD. To this end, we propose an attention-guided autoencoder model for efficient cross-domain adaptation which facilitates the knowledge transfer from AD to SCD. The proposed model is composed of four key components: 1) a feature encoding module for learning shared subspace representations of different domains, 2) an attention module for automatically locating discriminative brain regions of interest defined in brain atlases, 3) a decoding module for reconstructing the original input, 4) a classification module for identification of brain diseases. Through joint training of these four modules, domain invariant features can be learned. Meanwhile, the brain disease related regions can be highlighted by the attention mechanism. Extensive experiments on the publicly available ADNI dataset and a private CLAS dataset have demonstrated the effectiveness of the proposed method. The proposed model is straightforward to train and test with only 5-10 seconds on CPUs and is suitable for medical tasks with small datasets., Comment: 10 pages, 12 figures