Vision-language models have demonstrated impressive capabilities in generating 2D images under various conditions; however the impressive performance of these models in 2D is largely enabled by extensive, readily available pretrained foundation models. Critically, comparable pretrained foundation models do not exist for 3D, significantly limiting progress in this domain. As a result, the potential of vision-language models to produce high-resolution 3D counterfactual medical images conditioned solely on natural language descriptions remains completely unexplored. Addressing this gap would enable powerful clinical and research applications, such as personalized counterfactual explanations, simulation of disease progression scenarios, and enhanced medical training by visualizing hypothetical medical conditions in realistic detail. Our work takes a meaningful step toward addressing this challenge by introducing a framework capable of generating high-resolution 3D counterfactual medical images of synthesized patients guided by free-form language prompts. We adapt state-of-the-art 3D diffusion models with enhancements from Simple Diffusion and incorporate augmented conditioning to improve text alignment and image quality. To our knowledge, this represents the first demonstration of a language-guided native-3D diffusion model applied specifically to neurological imaging data, where faithful three-dimensional modeling is essential to represent the brain's three-dimensional structure. Through results on two distinct neurological MRI datasets, our framework successfully simulates varying counterfactual lesion loads in Multiple Sclerosis (MS), and cognitive states in Alzheimer's disease, generating high-quality images while preserving subject fidelity in synthetically generated medical images. Our results lay the groundwork for prompt-driven disease progression analysis within 3D medical imaging.

Rapid progress has been made in instruction-learning for image editing with natural-language instruction, as exemplified by InstructPix2Pix. In biomedicine, such methods can be applied to counterfactual image generation, which helps differentiate causal structure from spurious correlation and facilitate robust image interpretation for disease progression modeling. However, generic image-editing models are ill-suited for the biomedical domain, and counterfactual biomedical image generation is largely underexplored. In this paper, we present BiomedJourney, a novel method for counterfactual biomedical image generation by instruction-learning from multimodal patient journeys. Given a patient with two biomedical images taken at different time points, we use GPT-4 to process the corresponding imaging reports and generate a natural language description of disease progression. The resulting triples (prior image, progression description, new image) are then used to train a latent diffusion model for counterfactual biomedical image generation. Given the relative scarcity of image time series data, we introduce a two-stage curriculum that first pretrains the denoising network using the much more abundant single image-report pairs (with dummy prior image), and then continues training using the counterfactual triples. Experiments using the standard MIMIC-CXR dataset demonstrate the promise of our method. In a comprehensive battery of tests on counterfactual medical image generation, BiomedJourney substantially outperforms prior state-of-the-art methods in instruction image editing and medical image generation such as InstructPix2Pix and RoentGen. To facilitate future study in counterfactual medical generation, we plan to release our instruction-learning code and pretrained models.