Advancing brain network models to reconcile functional neuroimaging and clinical research

Functional magnetic resonance imaging (fMRI) captures information on brain function beyond the anatomical alterations that are traditionally visually examined by neuroradiologists. However, the fMRI signals are complex in addition to being noisy, so fMRI still faces limitations for clinical applications. Here we review methods that have been proposed as potential solutions so far, namely statistical, biophysical and decoding models, with their strengths and weaknesses. We especially evaluate the ability of these models to directly predict clinical variables from their parameters (predictability) and to extract clinically relevant information regarding biological mechanisms and relevant features for classification and prediction (interpretability). We then provide guidelines for useful applications and pitfalls of such fMRI-based models in a clinical research context, looking beyond the current state of the art. In particular, we argue that the clinical relevance of fMRI calls for a new generation of models for fMRI data, which combine the strengths of both biophysical and decoding models. This leads to reliable and biologically meaningful model parameters, which thus fulfills the need for simultaneous interpretability and predictability. In our view, this synergy is fundamental for the discovery of new pharmacological and interventional targets, as well as the use of models as biomarkers in neurology and psychiatry.