Self-supervised multimodal neuroimaging yields predictive representations for a spectrum of Alzheimer's phenotypes

Recent neuroimaging studies that focus on predicting brain disorders via modern machine learning approaches commonly include a single modality and rely on supervised over-parameterized models.However, a single modality provides only a limited view of the highly complex brain. Critically, supervised models in clinical settings lack accurate diagnostic labels for training. Coarse labels do not capture the long-tailed spectrum of brain disorder phenotypes, which leads to a loss of generalizability of the model that makes them less useful in diagnostic settings. This work presents a novel multi-scale coordinated framework for learning multiple representations from multimodal neuroimaging data. We propose a general taxonomy of informative inductive biases to capture unique and joint information in multimodal self-supervised fusion. The taxonomy forms a family of decoder-free models with reduced computational complexity and a propensity to capture multi-scale relationships between local and global representations of the multimodal inputs. We conduct a comprehensive evaluation of the taxonomy using functional and structural magnetic resonance imaging (MRI) data across a spectrum of Alzheimer's disease phenotypes and show that self-supervised models reveal disorder-relevant brain regions and multimodal links without access to the labels during pre-training. The proposed multimodal self-supervised learning yields representations with improved classification performance for both modalities. The concomitant rich and flexible unsupervised deep learning framework captures complex multimodal relationships and provides predictive performance that meets or exceeds that of a more narrow supervised classification analysis. We present elaborate quantitative evidence of how this framework can significantly advance our search for missing links in complex brain disorders.

Pipeline-Invariant Representation Learning for Neuroimaging

Deep learning has been widely applied in neuroimaging, including to predicting brain-phenotype relationships from magnetic resonance imaging (MRI) volumes. MRI data usually requires extensive preprocessing before it is ready for modeling, even via deep learning, in part due to its high dimensionality and heterogeneity. A growing array of MRI preprocessing pipelines have been developed each with its own strengths and limitations. Recent studies have shown that pipeline-related variation may lead to different scientific findings, even when using the identical data. Meanwhile, the machine learning community has emphasized the importance of shifting from model-centric to data-centric approaches given that data quality plays an essential role in deep learning applications. Motivated by this idea, we first evaluate how preprocessing pipeline selection can impact the downstream performance of a supervised learning model. We next propose two pipeline-invariant representation learning methodologies, MPSL and PXL, to improve consistency in classification performance and to capture similar neural network representations between pipeline pairs. Using 2000 human subjects from the UK Biobank dataset, we demonstrate that both models present unique advantages, in particular that MPSL can be used to improve out-of-sample generalization to new pipelines, while PXL can be used to improve predictive performance consistency and representational similarity within a closed pipeline set. These results suggest that our proposed models can be applied to overcome pipeline-related biases and to improve reproducibility in neuroimaging prediction tasks.

Tasting the cake: evaluating self-supervised generalization on out-of-distribution multimodal MRI data

Self-supervised learning has enabled significant improvements on natural image benchmarks. However, there is less work in the medical imaging domain in this area. The optimal models have not yet been determined among the various options. Moreover, little work has evaluated the current applicability limits of novel self-supervised methods. In this paper, we evaluate a range of current contrastive self-supervised methods on out-of-distribution generalization in order to evaluate their applicability to medical imaging. We show that self-supervised models are not as robust as expected based on their results in natural imaging benchmarks and can be outperformed by supervised learning with dropout. We also show that this behavior can be countered with extensive augmentation. Our results highlight the need for out-of-distribution generalization standards and benchmarks to adopt the self-supervised methods in the medical imaging community.

Taxonomy of multimodal self-supervised representation learning

Sensory input from multiple sources is crucial for robust and coherent human perception. Different sources contribute complementary explanatory factors and get combined based on factors they share. This system motivated the design of powerful unsupervised representation-learning algorithms. In this paper, we unify recent work on multimodal self-supervised learning under a single framework. Observing that most self-supervised methods optimize similarity metrics between a set of model components, we propose a taxonomy of all reasonable ways to organize this process. We empirically show on two versions of multimodal MNIST and a multimodal brain imaging dataset that (1) multimodal contrastive learning has significant benefits over its unimodal counterpart, (2) the specific composition of multiple contrastive objectives is critical to performance on a downstream task, (3) maximization of the similarity between representations has a regularizing effect on a neural network, which sometimes can lead to reduced downstream performance but still can reveal multimodal relations. Consequently, we outperform previous unsupervised encoder-decoder methods based on CCA or variational mixtures MMVAE on various datasets on linear evaluation protocol.

On self-supervised multi-modal representation learning: An application to Alzheimer's disease

Introspection of deep supervised predictive models trained on functional and structural brain imaging may uncover novel markers of Alzheimer's disease (AD). However, supervised training is prone to learning from spurious features (shortcut learning) impairing its value in the discovery process. Deep unsupervised and, recently, contrastive self-supervised approaches, not biased to classification, are better candidates for the task. Their multimodal options specifically offer additional regularization via modality interactions. In this paper, we introduce a way to exhaustively consider multimodal architectures for contrastive self-supervised fusion of fMRI and MRI of AD patients and controls. We show that this multimodal fusion results in representations that improve the results of the downstream classification for both modalities. We investigate the fused self-supervised features projected into the brain space and introduce a numerically stable way to do so.

Whole MILC: generalizing learned dynamics across tasks, datasets, and populations

Behavioral changes are the earliest signs of a mental disorder, but arguably, the dynamics of brain function gets affected even earlier. Subsequently, spatio-temporal structure of disorder-specific dynamics is crucial for early diagnosis and understanding the disorder mechanism. A common way of learning discriminatory features relies on training a classifier and evaluating feature importance. Classical classifiers, based on handcrafted features are quite powerful, but suffer the curse of dimensionality when applied to large input dimensions of spatio-temporal data. Deep learning algorithms could handle the problem and a model introspection could highlight discriminatory spatio-temporal regions but need way more samples to train. In this paper we present a novel self supervised training schema which reinforces whole sequence mutual information local to context (whole MILC). We pre-train the whole MILC model on unlabeled and unrelated healthy control data. We test our model on three different disorders (i) Schizophrenia (ii) Autism and (iii) Alzheimers and four different studies. Our algorithm outperforms existing self-supervised pre-training methods and provides competitive classification results to classical machine learning algorithms. Importantly, whole MILC enables attribution of subject diagnosis to specific spatio-temporal regions in the fMRI signal.

Transfer Learning of fMRI Dynamics

As a mental disorder progresses, it may affect brain structure, but brain function expressed in brain dynamics is affected much earlier. Capturing the moment when brain dynamics express the disorder is crucial for early diagnosis. The traditional approach to this problem via training classifiers either proceeds from handcrafted features or requires large datasets to combat the $m>>n$ problem when a high dimensional fMRI volume only has a single label that carries learning signal. Large datasets may not be available for a study of each disorder, or rare disorder types or sub-populations may not warrant for them. In this paper, we demonstrate a self-supervised pre-training method that enables us to pre-train directly on fMRI dynamics of healthy control subjects and transfer the learning to much smaller datasets of schizophrenia. Not only we enable classification of disorder directly based on fMRI dynamics in small data but also significantly speed up the learning when possible. This is encouraging evidence of informative transfer learning across datasets and diagnostic categories.

Prediction of Progression to Alzheimer's disease with Deep InfoMax

Arguably, unsupervised learning plays a crucial role in the majority of algorithms for processing brain imaging. A recently introduced unsupervised approach Deep InfoMax (DIM) is a promising tool for exploring brain structure in a flexible non-linear way. In this paper, we investigate the use of variants of DIM in a setting of progression to Alzheimer's disease in comparison with supervised AlexNet and ResNet inspired convolutional neural networks. As a benchmark, we use a classification task between four groups: patients with stable, and progressive mild cognitive impairment (MCI), with Alzheimer's disease, and healthy controls. Our dataset is comprised of 828 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our experiments highlight encouraging evidence of the high potential utility of DIM in future neuroimaging studies.

Learning deep representations by mutual information estimation and maximization

In this work, we perform unsupervised learning of representations by maximizing mutual information between an input and the output of a deep neural network encoder. Importantly, we show that structure matters: incorporating knowledge about locality of the input to the objective can greatly influence a representation's suitability for downstream tasks. We further control characteristics of the representation by matching to a prior distribution adversarially. Our method, which we call Deep InfoMax (DIM), outperforms a number of popular unsupervised learning methods and competes with fully-supervised learning on several classification tasks. DIM opens new avenues for unsupervised learning of representations and is an important step towards flexible formulations of representation-learning objectives for specific end-goals.

Almost instant brain atlas segmentation for large-scale studies

Large scale studies of group differences in healthy controls and patients and screenings for early stage disease prevention programs require processing and analysis of extensive multisubject datasets. Complexity of the task increases even further when segmenting structural MRI of the brain into an atlas with more than 50 regions. Current automatic approaches are time-consuming and hardly scalable; they often involve many error prone intermediate steps and don't utilize other available modalities. To alleviate these problems, we propose a feedforward fully convolutional neural network trained on the output produced by the state of the art models. Incredible speed due to available powerful GPUs neural network makes this analysis much easier and faster (from $>10$ hours to a minute). The proposed model is more than two orders of magnitudes faster than the state of the art and yet as accurate. We have evaluated the network's performance by comparing it with the state of the art in the task of differentiating region volumes of healthy controls and patients with schizophrenia on a dataset with 311 subjects. This comparison provides a strong evidence that speed did not harm the accuracy. The overall quality may also be increased by utilizing multi-modal datasets (not an easy task for other models) by simple adding more modalities as an input. Our model will be useful in large-scale studies as well as in clinical care solutions, where it can significantly reduce delay between the patient screening and the result.