Multimodal connectomic signatures of functional rigidity identify bipolar disorder at the individual level

Bipolar Disorder (BD) is characterized by severe emotional instability. While traditionally viewed through the lens of anatomical dysconnectivity, it remains unclear how the brain's anatomical scaffold abnormally constrains its functional dynamics to produce such volatile mood states.

We investigated the multi-modal connectome in 41 BD patients and 40 healthy controls (N=81). A high-fidelity pipeline was employed to robustly reconstruct structural networks. We then applied Graph Signal Processing (GSP) and functional gradient analysis to resting-state fMRI data to quantify structure-function alignment and hierarchical network dynamics.

Network-based statistics revealed no NBS-detected macroscale structural disruptions in BD. However, GSP analysis uncovered a profound pathological shift toward "functional rigidity". BD patients exhibited significantly elevated structure-function alignment (hyper-coupling), indicating that functional dynamics are excessively restricted by the underlying anatomical backbone. Furthermore, a multimodal connectomic model demonstrated good performance in distinguishing BD from healthy controls at the individual level (accuracy=74.1%, AUC=0.888, sensitivity=70.7%, specificity=77.5%, permutation p=0.001). SHAP analysis localized the dominant predictors to the prefrontal-limbic emotion-regulation circuit.

BD is characterized by profound "functional rigidity" rather than sheer anatomical degradation. This excessive structure-function tethering may constitute a candidate inter-episode connectomic signature with preliminary individual-level discrimination potential, offering new insights into the connectomic basis of inter-episode functional dysregulation in BD and motivating prospective validation in independent longitudinal cohorts.