Solving the where problem and quantifying geometric variation in neuroanatomy using generative diffeomorphic mapping

A current focus in neuroscience is to map neuronal cell types in whole vertebrate brains using different imaging modalities. Mapping modern molecular and anatomical datasets into a common atlas includes challenges that existing workflows do not adequately address: multimodal signals, missing data or non reference signals, and quantification of individual variation. Our solution implements a generative model describing the likelihood of data given a sequence of transforms of an atlas, and a maximum a posteriori estimation framework. Our approach allows composition of mappings across chains of datasets rather than only pairs, and computes metrics for geometric quantification. We study a range of datasets (in/ex-vivo MRI, STP and fMOST, 2D serial histology, snRNAseq prepared tissue), quantifying cell density and geometric fluctuations across covariates, and reveal that individual variation is often greater than differences due to tissue processing techniques. We provide open source code, dataset standards, and a web interface. This establishes a quantitative workflow for unifying multi-modal whole-brain images in an atlas framework, validated using mouse datasets, enabling large scale integration of datasets essential to modern neuroscience.