Health-related quality of life (HRQoL) is an essential complementary parameter in the assessment of disease burden and treatment outcome in multiple sclerosis (MS) and can be affected by neuropsychiatric symptoms, which in turn are sensitive to psychological stress. However, until now, the impact of neurobiological stress and relaxation on HRQoL in MS has not been investigated. We thus evaluated whether the activity of neural networks triggered by mild psychological stress (elicited in an fMRI task comprising mental arithmetic with feedback) or by stress termination (i.e., relaxation) at baseline (T0) predicts HRQoL variations occurring between T0 and a follow-up visit (T1) in 28 patients using a robust regression and permutation testing. The median delay between T0 and T1 was 902 (range: 363-1,169) days. We assessed HRQoL based on the Hamburg Quality of Life Questionnaire in MS (HAQUAMS) and accounted for the impact of established HRQoL predictors and the cognitive performance of the participants. Relaxation-triggered activity of a widespread neural network predicted future variations in overall HRQoL (t = 3.68, p(family-wise error [FWE])-corrected = 0.008). Complementary analyses showed that relaxation-triggered activity of the same network at baseline was associated with variations in the HAQUAMS mood subscale on an alpha(FWE) = 0.1 level (t = 3.37, p(FWE) = 0.087). Finally, stress-induced activity of a prefronto-limbic network predicted future variations in the HAQUAMS lower limb mobility subscale (t = -3.62, p(FWE) = 0.020). Functional neural network measures of psychological stress and relaxation contain prognostic information for future HRQoL evolution in MS independent of clinical predictors.
