Prospective clinical studies support a link between psychological stress and multiple sclerosis (MS) disease severity, and peripheral stress systems are frequently dysregulated in MS patients. However, the exact link between neurobiological stress systems and MS symptoms is unknown. To evaluate the link between neural stress responses and disease parameters, we used an arterial-spin-labeling functional MRI stress paradigm in 36 MS patients and 21 healthy controls. Specifically, we measured brain activity during a mental arithmetic paradigm with performance-adaptive task frequency and performance feedback and related this activity to disease parameters. Across all participants, stress increased heart rate, perceived stress, and neural activity in the visual, cerebellar and insular cortex areas compared with a resting condition. None of these responses was related to cognitive load (task frequency). Consistently, although performance and cognitive load were lower in patients than in controls, stress responses did not differ between groups. Insula activity elevated during stress compared with rest was negatively linked to impairment of pyramidal and cerebral functions in patients. Cerebellar activation was related negatively to gray matter (GM) atrophy (i.e., positively to GM volume) in patients. Interestingly, this link was also observed in overlapping areas in controls. Cognitive load did not contribute to these associations. The results show that our task induced psychological stress independent of cognitive load. Moreover, stress-induced brain activity reflects clinical disability in MS. Finally, the link between stress-induced activity and GM volume in patients and controls in overlapping areas suggests that this link cannot be caused by the disease alone.multiple sclerosis | psychological stress | functional magnetic resonance imaging | clinical disability | brain atrophy M ultiple sclerosis (MS) is an autoimmune disease of the central nervous system leading to demyelination, axonal damage. and neuronal degeneration (1). In addition to sensorimotor symptoms, stress-related syndromes such as depression and anxiety disorders are among the most frequent comorbidities in MS (2).A role for psychological stress in the pathobiology of MS was hypothesized as early as the 19th century when Charcot first described the disease, and a link between stress and the risk of MS relapse is now supported by numerous prospective clinical studies (e.g., 3). Moreover, MS patients frequently exhibit dysregulated psychobiological stress systems, and these systems interact with the key neurologic characteristics. Neuroendocrine studies revealed a link between MS and altered regulation of both stress systems, the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) (4). Specifically, pharmacological challenge tests have shown that glucocorticoid responsivity is elevated in MS patients (5) and that impaired HPA axis feedback control is linked to brain atrophy (6) and subsequent deterioration of clinical di...

Lower 25(OH)D3 levels already in the earliest phase of disease and in clinically hardly affected patients suggest that low 25(OH)D3 levels are rather a risk factor for than a consequence of MS. Nevertheless, because bioavailable vitamin D levels did not differ between the two groups, the mechanism underlying the association of 25(OH)D3 and MS does not appear to be related to reduced bioavailability of vitamin D.

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) have a similar clinical phenotype but represent distinct diseases, requiring different therapies. MicroRNAs (miRNAs) are short non-coding RNAs whose expression profiles can serve as diagnostic biomarkers and which may be involved in the pathophysiology of neuroinflammatory diseases. Here, we analyzed miRNA profiles in serum and whole blood of patients with NMOSD and clinically isolated syndrome (CIS)/relapsing-remitting MS (RRMS) as well as healthy controls by next-generation sequencing (NGS).MethodsMiRNA expression profiles were determined by NGS in sera of patients with aquaporin-4 antibody-positive NMOSD (n = 20), CIS/RRMS (n = 20), and healthy controls (n = 20) and in whole blood of patients with NMOSD (n = 11), CIS/RRMS (n = 60), and healthy controls (n = 43). Differentially expressed miRNAs were calculated by analysis of variance and t tests. All significance values were corrected for multiple testing. Selected miRNAs were validated in whole blood of patients with NMOSD (n = 18) and CIS/RRMS (n = 19) by quantitative real-time polymerase chain reaction (qRT-PCR).ResultsNone of 261 miRNAs detected in serum but 178 of 416 miRNAs detected in whole blood showed significantly different expression levels among the three groups. Pairwise comparisons revealed 115 (NMOSD vs. CIS/RRMS), 141 (NMOSD vs. healthy controls), and 44 (CIS/RRMS vs. healthy controls) miRNAs in whole blood with significantly different expression levels. qRT-PCR confirmed different expression levels in whole blood of patients with NMOSD and CIS/RRMS for 9 out of 10 exemplarily chosen miRNAs. In silico enrichment analysis demonstrated an accumulation of altered miRNAs in NMOSD in particular in CD15+ cells (i.e., neutrophils and eosinophils).ConclusionsThis study identifies a set of miRNAs in whole blood, which may have the potential to discriminate NMOSD from CIS/RRMS and healthy controls. In contrast, miRNA profiles in serum do not appear to be promising diagnostic biomarkers for NMOSD. Enrichment of altered miRNAs in CD15+ neutrophils and eosinophils, which were previously implicated in the pathophysiology of NMOSD, suggests that miRNAs could be involved in the regulation of these cells in NMOSD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0418-1) contains supplementary material, which is available to authorized users.

We identified dysregulated activity linked to impairment in specific cognitive stages of reward-related DM. The link of brain activity and impaired DM in areas with MS-induced GM loss suggests that this deficit might be tightly coupled to MS neuropathology.