Neural stress processing, glucocorticoid functioning, and body mass in lean to obese persons with multiple sclerosis

Abstract

Background and Objectives: Obesity aggravates disease severity in multiple sclerosis (MS). Altered neural processing of food motivation and cognitive control, and the sensitivity of these processes to stress have been recognized as key obesity mechanisms but never been investigated in MS. Methods: In this cross-sectional observational study, we evaluated the link between body mass and neural, endocrine and immunological stress parameters in persons with MS (PwMS). We conducted an Arterial-Spin-Labeling MRI task comprising a rest and stress stage (mental arithmetic plus evaluative feedback) in 57 PwMS (37 female, 46.4 +/- 10.6 years) covering the full spectrum of the Body Mass Index (BMI (kg/m2); 6 obese, 19 over-, 28 normal-, 4 underweight). We tested whether BMI in MS links to (i) functional connectivity (FC) between stress-reactive brain regions (showing activity differences for stress vs. rest) computed separately for the task's rest and stress stage, (ii) T cell glucocorticoid sensitivity and (iii) salivary cortisol secretion. Results: BMI correlated positively with MS relapse rate (t = 3.23, p = 0.003 = pFamily-Wise-Error (FWE)-corrected = 0.012, and f2 = 0.22) and rest stage FC between right anterior insula and supramarginal gyrus (t = 4.02, p = 2.5 x 10-4 = pFWE = 0.034, f2 = 0.51) and negatively with stress stage FC between right superior parietal lobule and cerebellum exterior (t = -3.67, p = 3.3 x 10-4 = pFWE = 0.045, f2 = 0.30). Further, BMI was negatively associated with the expression of the co-chaperone FKBP4 on CD8+ T cells (t = -2.96, p = 0.003 = pFWE = 0.024, f2 = 0.13) and positively with that of FKBP5 (t = 1.83, p = 0.003 = pFWE = 0.024, f2 = 0.38). Conclusion: Our study shows that higher BMI in MS is linked to increased FC between key food motivation and stimulus salience regions and to reduced FC between regions critically involved in cognitive control and generation of stressful states. We further report on correlations between BMI and co-chaperones modulating immune system stress responsivity. Taken together, these results demonstrate that BMI in MS is tied to stress processing across different biological systems.