Neurobehavioral mechanisms of fear and anxiety in multiple sclerosis

BACKGROUND: Anxiety is a common yet often underdiagnosed and undertreated comorbidity in multiple sclerosis (MS). While altered fear processing is a hallmark of anxiety in other populations, its neurobehavioral mechanisms in MS remain poorly understood. This study investigates the extent to which neurobehavioral mechanisms of fear generalization contribute to anxiety in MS. METHODS: We recruited 18 persons with MS (PwMS) and anxiety, 36 PwMS without anxiety, and 23 healthy persons (HPs). Participants completed a functional MRI (fMRI) fear generalization task to assess fear processing and diffusion-weighted MRI for graph-based structural connectome analyses. RESULTS: Consistent with findings in non-MS anxiety populations, PwMS with anxiety exhibit fear overgeneralization, perceiving non-threating stimuli as threatening. A machine learning model trained on HPs in a multivariate pattern analysis (MVPA) cross-decoding approach accurately predicts behavioral fear generalization in both MS groups using whole-brain fMRI fear response patterns. Regional fMRI prediction and graph-based structural connectivity analyses reveal that fear response activity and structural network integrity of partially overlapping areas, such as hippocampus (for fear stimulus comparison) and anterior insula (for fear excitation), are crucial for MS fear generalization. Reduced network integrity in such regions is a direct indicator of MS anxiety. CONCLUSIONS: Our findings demonstrate that MS anxiety is substantially characterized by fear overgeneralization. The fact that a machine learning model trained to associate fMRI fear response patterns with fear ratings in HPs predicts fear ratings from fMRI data across MS groups using an MVPA cross-decoding approach suggests that generic fear processing mechanisms substantially contribute to anxiety in MS.