Understanding the mechanisms of fatigue in multiple sclerosis: linking interoception, metacognition and white matter dysconnectivity

One of the most prominent symptoms in multiple sclerosis(MS) is pathological fatigue, often described by sufferers as one of the most debilitating symptoms, affecting quality of life and employment. However, the mechanisms of both, physical and cognitive fatigue in multiple sclerosis remain elusive. Here we use behavioural tasks and quantitative MRI to investigate the neural correlates of interoception (the ability to sense internal bodily signals) and metacognition (the ability of the brain to assess its own performance), in modulating cognitive fatigue. Assuming that structural damage caused by MS pathology might impair the neural pathways subtending interoception and/or metacognition, we considered three alternative hypotheses to explain fatigue as a consequence of, respectively: 1) reduced interoceptive accuracy, 2) reduced interoceptive insight, or 3) reduced global metacognition. We then explored associations between these behavioural measures and white matter microstructure, assessed by diffusion and magnetization transfer MRI. Seventy-one relapsing-remitting MS patients participated in this cross-sectional study (mean age 43), 62% female. Patient outcomes relevant for fatigue were measured, including disability, disease duration, depression, anxiety, sleepiness, cognitive function, MS disease modifying treatment and quality of life. Interoceptive and metacognitive parameters were measured using heartbeat tracking and discrimination tasks, and metacognitive visual and memory tasks. MRI was performed in 69 participants, including diffusion tensor MRI, neurite orientation dispersion and density imaging and quantitative magnetization transfer. Associations between interoception and metacognition and the odds of high cognitive fatigue were tested by unconditional binomial logistic regression. The odds of cognitive fatigue were higher in the people with low interoceptive insight (p=0.03), while no significant relationships were found between MS fatigue and other interoceptive or metacognitive parameters, suggesting a specific impairment in interoceptive metacognition, rather than interoception generally, or metacognition generally. Diffusion MRI-derived fractional anisotropy and neurite density index showed significant (p<0.05) negative associations with cognitive fatigue in a widespread bilateral white matter network. Moreover, there was a significant (p<0.05) interaction between cognitive fatigue and interoceptive insight, suggesting that the poorer the white matter structure, the lower the interoceptive insight, and the worse the fatigue. 3 The results point towards metacognitive impairment confined to the interoceptive domain, in relapsing-remitting patients with cognitive fatigue. The neural basis of this impairment is supported by a widespread white matter network in which loss of neurite density plays a role. Key words: Multiple Sclerosis, cognitive fatigue, white matter, interoceptive insight, diffusion MRI Abbreviations: ASE=Allostatic self-efficacy; BICAMS = The Brief International Cognitive Assessment for MS; DMT = disease-modifying treatment; DT = diffusion tensor; EDSS = Expanded Disability Status Scale; ESS = Epworth Sleepiness Scale; FA = fractional anisotropy; FAMS = Functional Assessment in Multiple Sclerosis; FSL = FMRIB Software Library; FSS = fatigue Severity Scale; HADS-A = Hospital Anxiety and Depression Scale – Anxiety sub-domain; HADS-D = Hospital Anxiety and Depression Scale – Depression subdomain; HDT = heartbeat discrimination task; HTT = Heartbeat Tracking Task; ISO = isotropic compartment volume fraction; MD = mean diffusivity; MFIS = Modified Fatigue Impact Scale; MFIS-Tot = total MFIS; MFIS-Cog = cognitive MFIS; MFIS-phys = physical MFIS; MFISSoc = psychosocial MFIS; MRI = magnetic resonance imaging; MS = multiple sclerosis; MT = magnetization transfer; NDI = neurite density; NODDI = neurite orientation dispersion and density imaging; ODI = orientation dispersion; Q-Q = quantile-quantile; RRMS= relapsingremitting multiple sclerosis; TBSS = Tract-Based Spatial Statistics; TFCE = threshold-free cluster enhancement; VAS = visual analogue scale</p

Copper tolerance and genetic diversity of Porcellionides sexfasciatus (Isopoda) in a highly contaminted mine habitat.

Organisms inhabiting metal-contaminated areas may develop metal tolerance, with either phenotypic adjustments or genetic changes (adaptation) or with both. In the present study, three populations of the terrestrial isopod Porcellionides sexfasciatus, collected at an abandoned mine area, were compared to assess the effects of metal contamination on tolerance to lethal and sublethal levels of copper, through comparison of survival, avoidance, and feeding. The effects of metal contamination on genetic diversity were considered using random amplified polymorphic DNA (RAPD) markers. No evidence of increased metal tolerance of the population inhabiting the contaminated site was found. There was no correlation between metal exposure and within-population genetic variance, but the three populations were clearly separated from each other. In conclusion, the populations of P. sexfasciatus in the mine landscape live rather isolated from each other and show no differential tolerance to Cu or indications of genetic erosion. Their phenotypic plasticity provides a means to survive despite exposure to extremely high metal concentrations in the soil. © 2013 SETAC

Studies of the relativistic electron source and related phenomena in Petawatt Laser matter interactions

The interaction of laser radiation with solid targets at 1 petawatt power and intensity up to 3x10{sup 20} Wcm{sup -2} has been studied with emphasis on relativistic electrons and high energy ions. Secondary effects including Bremsstrahlung radiation, nuclear interactions and heating have been characterized. A collimated beam of protons with up to 55 MeV energy is emitted normal to the rear surface of thin targets and its characteristics and origin are discussed. The significance of the data for radiography, fast ignition and proton beam applications is summarized