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Purpose: To propose a domain-conditioned and temporal-guided diffusion modeling method, termed dynamic Diffusion Modeling (dDiMo), for accelerated dynamic MRI reconstruction, enabling diffusion process to characterize spatiotemporal information for time-resolved multi-coil Cartesian and non-Cartesian data.

Methods: The dDiMo framework integrates temporal information from time-resolved dimensions, allowing for the concurrent capture of intra-frame spatial features and inter-frame temporal dynamics in diffusion modeling. It employs additional spatiotemporal ($x$-$t$) and self-consistent frequency-temporal ($k$-$t$) priors to guide the diffusion process. This approach ensures precise temporal alignment and enhances the recovery of fine image details. To facilitate a smooth diffusion process, the nonlinear conjugate gradient algorithm is utilized during the reverse diffusion steps. The proposed model was tested on two types of MRI data: Cartesian-acquired multi-coil cardiac MRI and Golden-Angle-Radial-acquired multi-coil free-breathing lung MRI, across various undersampling rates.

Results: dDiMo achieved high-quality reconstructions at various acceleration factors, demonstrating improved temporal alignment and structural recovery compared to other competitive reconstruction methods, both qualitatively and quantitatively. This proposed diffusion framework exhibited robust performance in handling both Cartesian and non-Cartesian acquisitions, effectively reconstructing dynamic datasets in cardiac and lung MRI under different imaging conditions.

Conclusion: This study introduces a novel diffusion modeling method for dynamic MRI reconstruction.

Medical imaging systems are commonly assessed and optimized by the use of objective measures of image quality (IQ). The performance of the ideal observer (IO) acting on imaging measurements has long been advocated as a figure-of-merit to guide the optimization of imaging systems. For computed imaging systems, the performance of the IO acting on imaging measurements also sets an upper bound on task-performance that no image reconstruction method can transcend. As such, estimation of IO performance can provide valuable guidance when designing under-sampled data-acquisition techniques by enabling the identification of designs that will not permit the reconstruction of diagnostically inappropriate images for a specified task - no matter how advanced the reconstruction method is or how plausible the reconstructed images appear. The need for such analysis is urgent because of the substantial increase of medical device submissions on deep learning-based image reconstruction methods and the fact that they may produce clean images disguising the potential loss of diagnostic information when data is aggressively under-sampled. Recently, convolutional neural network (CNN) approximated IOs (CNN-IOs) was investigated for estimating the performance of data space IOs to establish task-based performance bounds for image reconstruction, under an X-ray computed tomographic (CT) context. In this work, the application of such data space CNN-IO analysis to multi-coil magnetic resonance imaging (MRI) systems has been explored. This study utilized stylized multi-coil sensitivity encoding (SENSE) MRI systems and deep-generated stochastic brain models to demonstrate the approach. Signal-known-statistically and background-known-statistically (SKS/BKS) binary signal detection tasks were selected to study the impact of different acceleration factors on the data space IO performance.

Animals survive in dynamic environments changing at arbitrary timescales, but such data distribution shifts are a challenge to neural networks. To adapt to change, neural systems may change a large number of parameters, which is a slow process involving forgetting past information. In contrast, animals leverage distribution changes to segment their stream of experience into tasks and associate them with internal task abstractions. Animals can then respond flexibly by selecting the appropriate task abstraction. However, how such flexible task abstractions may arise in neural systems remains unknown. Here, we analyze a linear gated network where the weights and gates are jointly optimized via gradient descent, but with neuron-like constraints on the gates including a faster timescale, nonnegativity, and bounded activity. We observe that the weights self-organize into modules specialized for tasks or sub-tasks encountered, while the gates layer forms unique representations that switch the appropriate weight modules (task abstractions). We analytically reduce the learning dynamics to an effective eigenspace, revealing a virtuous cycle: fast adapting gates drive weight specialization by protecting previous knowledge, while weight specialization in turn increases the update rate of the gating layer. Task switching in the gating layer accelerates as a function of curriculum block size and task training, mirroring key findings in cognitive neuroscience. We show that the discovered task abstractions support generalization through both task and subtask composition, and we extend our findings to a non-linear network switching between two tasks. Overall, our work offers a theory of cognitive flexibility in animals as arising from joint gradient descent on synaptic and neural gating in a neural network architecture.

Accurate forecasting of contagious illnesses has become increasingly important to public health policymaking, and better prediction could prevent the loss of millions of lives. To better prepare for future pandemics, it is essential to improve forecasting methods and capabilities. In this work, we propose a new infectious disease forecasting model based on physics-informed neural networks (PINNs), an emerging area of scientific machine learning. The proposed PINN model incorporates dynamical systems representations of disease transmission into the loss function, thereby assimilating epidemiological theory and data using neural networks (NNs). Our approach is designed to prevent model overfitting, which often occurs when training deep learning models with observation data alone. In addition, we employ an additional sub-network to account for mobility, vaccination, and other covariates that influence the transmission rate, a key parameter in the compartment model. To demonstrate the capability of the proposed model, we examine the performance of the model using state-level COVID-19 data in California. Our simulation results show that predictions of PINN model on the number of cases, deaths, and hospitalizations are consistent with existing benchmarks. In particular, the PINN model outperforms the basic NN model and naive baseline forecast. We also show that the performance of the PINN model is comparable to a sophisticated Gaussian infection state space with time dependence (GISST) forecasting model that integrates the compartment model with a data observation model and a regression model for inferring parameters in the compartment model. Nonetheless, the PINN model offers a simpler structure and is easier to implement. In summary, our results show that the proposed forecaster could potentially serve as a new computational tool to enhance the current capacity of infectious disease forecasting.

Decades after their initial observation in prion-infected brain tissues, the identities of virus-like dense particles, varicose tubules, and oval bodies containing parallel bands and fibrils have remained elusive. Our recent work revealed that a phenotype of dilation of the endoplasmic reticulum (ER), most notable for the perinuclear space (PNS), contributes to spongiform degeneration. To assess the significance of this phenotype for the etiology of prion diseases, we explored whether it can be functionally linked to other neuropathological hallmarks observed in these diseases, as this would indicate it to be a central event. Having surveyed the neuropathological record and other distant literature niches, we propose a model in which pathogenic forms of the prion protein poison raft domains, including essential Na⁺, K⁺-ATPases (NKAs) embedded within them, thereby triggering an ER-centered cellular rescue program coordinated by the unfolded protein response (UPR). The execution of this program stalls general protein synthesis, causing the deterioration of synaptic spines. As the disease progresses, cells selectively increase sterol biosynthesis, along with ribosome and ER biogenesis. These adaptive rescue attempts cause morphological changes to the ER which manifest as ER dilation or ER hypertrophy in a manner that is influenced by Ca²⁺ influx into the cell. The nuclear-to-cytoplasmic transport of mRNAs and tRNAs interrupts in late stage disease, thereby depriving ribosomes of supplies and inducing them to aggregate into a paracrystalline form. In support of this model, we share previously reported data, whose features are consistent with the interpretation that 1) the phenotype of ER dilation is observed in major prion diseases, 2) varicose tubules and oval bodies represent ER hypertrophy, and 3) virus-like dense particles are paracrystalline aggregates of inactive ribosomes.

Stability in recurrent neural models poses a significant challenge, particularly in developing biologically plausible neurodynamical models that can be seamlessly trained. Traditional cortical circuit models are notoriously difficult to train due to expansive nonlinearities in the dynamical system, leading to an optimization problem with nonlinear stability constraints that are difficult to impose. Conversely, recurrent neural networks (RNNs) excel in tasks involving sequential data but lack biological plausibility and interpretability. In this work, we address these challenges by linking dynamic divisive normalization (DN) to the stability of "oscillatory recurrent gated neural integrator circuits" (ORGaNICs), a biologically plausible recurrent cortical circuit model that dynamically achieves DN and that has been shown to simulate a wide range of neurophysiological phenomena. By using the indirect method of Lyapunov, we prove the remarkable property of unconditional local stability for an arbitrary-dimensional ORGaNICs circuit when the recurrent weight matrix is the identity. We thus connect ORGaNICs to a system of coupled damped harmonic oscillators, which enables us to derive the circuit's energy function, providing a normative principle of what the circuit, and individual neurons, aim to accomplish. Further, for a generic recurrent weight matrix, we prove the stability of the 2D model and demonstrate empirically that stability holds in higher dimensions. Finally, we show that ORGaNICs can be trained by backpropagation through time without gradient clipping/scaling, thanks to its intrinsic stability property and adaptive time constants, which address the problems of exploding, vanishing, and oscillating gradients. By evaluating the model's performance on RNN benchmarks, we find that ORGaNICs outperform alternative neurodynamical models on static image classification tasks and perform comparably to LSTMs on sequential tasks.

Motivation: Powerful generative AI models of protein-ligand structure have recently been proposed, but few of these methods support both flexible protein-ligand docking and affinity estimation. Of those that do, none can directly model multiple binding ligands concurrently or have been rigorously benchmarked on pharmacologically relevant drug targets, hindering their widespread adoption in drug discovery efforts.

Results: In this work, we propose FlowDock, the first deep geometric generative model based on conditional flow matching that learns to directly map unbound (apo) structures to their bound (holo) counterparts for an arbitrary number of binding ligands. Furthermore, FlowDock provides predicted structural confidence scores and binding affinity values with each of its generated protein-ligand complex structures, enabling fast virtual screening of new (multi-ligand) drug targets. For the well-known PoseBusters Benchmark dataset, FlowDock outperforms single-sequence AlphaFold 3 with a 51% blind docking success rate using unbound (apo) protein input structures and without any information derived from multiple sequence alignments, and for the challenging new DockGen-E dataset, FlowDock outperforms single-sequence AlphaFold 3 and matches single-sequence Chai-1 for binding pocket generalization. Additionally, in the ligand category of the 16th community-wide Critical Assessment of Techniques for Structure Prediction (CASP16), FlowDock ranked among the top-5 methods for pharmacological binding affinity estimation across 140 protein-ligand complexes, demonstrating the efficacy of its learned representations in virtual screening.

Availability: Source code, data, and pre-trained models are available at https://github.com/BioinfoMachineLearning/FlowDock.

Recent advances in neural recording technology allow simultaneously recording action potentials from hundreds to thousands of neurons in awake, behaving animals. However, characterizing spike patterns in the resulting data, and linking these patterns to behaviour, remains a challenging task. The lack of a rigorous mathematical language for variable numbers of events (spikes) emitted by multiple agents (neurons) is an important limiting factor. We introduce a new mathematical operation to decompose complex spike patterns into a set of simple, structured elements. This creates a mathematical language that allows comparing spike patterns across trials, detecting sub-patterns, and making links to behaviour via a clear distance measure. We first demonstrate the method using Neuropixel recordings from macaque motor cortex. We then apply the method to dual Utah array recordings from macaque prefrontal cortex, where this technique reveals previously unseen structure that can predict both memory-guided decisions and errors in a virtual-reality working memory task. These results demonstrate that this technique provides a powerful new approach to understand structure in the spike times of neural populations, at a scale that will continue to grow more and more rapidly in upcoming years.

Purpose: Deformable image registration (DIR) is an enabling technology in many diagnostic and therapeutic tasks. Despite this, DIR algorithms have limited clinical use, largely due to a lack of benchmark datasets for quality assurance during development. DIRs of intra-patient abdominal CTs are among the most challenging registration scenarios due to significant organ deformations and inconsistent image content. To support future algorithm development, here we introduce our first-of-its-kind abdominal CT DIR benchmark dataset, comprising large numbers of highly accurate landmark pairs on matching blood vessel bifurcations.

Acquisition and validation methods: Abdominal CT image pairs of 30 patients were acquired from several publicly available repositories as well as the authors' institution with IRB approval. The two CTs of each pair were originally acquired for the same patient but on different days. An image processing workflow was developed and applied to each CT image pair: 1) Abdominal organs were segmented with a deep learning model, and image intensity within organ masks was overwritten. 2) Matching image patches were manually identified between two CTs of each image pair. 3) Vessel bifurcation landmarks were labeled on one image of each image patch pair. 4) Image patches were deformably registered, and landmarks were projected onto the second image 5) Landmark pair locations were refined manually or with an automated process. This workflow resulted in 1895 total landmark pairs, or 63 per case on average. Estimates of the landmark pair accuracy using digital phantoms were 0.7mm +/- 1.2 mm.

Data format and usage notes: The data is published in Zenodo at https://doi.org/10.5281/zenodo.14362785. Instructions for use can be found at https://github.com/deshanyang/Abdominal-DIR-QA.

Potential applications: This dataset is a first-of-its-kind for abdominal DIR validation. The number, accuracy, and distribution of landmark pairs will allow for robust validation of DIR algorithms with precision beyond what is currently available.