Tumor Necrosis Factor Receptor SF10A (TNFRSF10A) SNPs Correlate With Corticosteroid Response in Duchenne Muscular Dystrophy

Background Duchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment. Methods and Findings We enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had maintained the ability to walk after 15 years of age and low responders (LR) for those who had lost ambulation before the age of 10 despite corticosteroid therapy. Based on interactome mapping, we prioritized 205 genes and sequenced them in 21 DMD patients (discovery cohort or DiC = 21). We identified 43 SNPs that discriminate between HR and LR. Discriminant Analysis of Principal Components (DAPC) prioritized 2 response-associated SNPs in theTNFRSF10Agene. Validation of this genotype was done in two additional larger cohorts composed of 46 DMD patients on corticosteroid therapy (validation cohorts or VaC1), and 150 non ambulant DMD patients and never treated with corticosteroids (VaC2). SNP analysis in all validation cohorts (N= 207) showed that the CT haplotype is significantly associated with HR DMDs confirming the discovery results. Conclusion We have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker

Gender Differences in Sleep Deprivation Effects on Risk and Inequality Aversion: Evidence from an Economic Experiment

Excessive working hours—even at night—are becoming increasingly common in our modern 24/7 society. The prefrontal cortex (PFC) is particularly vulnerable to the effects of sleep loss and, consequently, the specific behaviors subserved by the functional integrity of the PFC, such as risk-taking and pro-social behavior, may be affected significantly. This paper seeks to assess the effects of one night of sleep deprivation on subjects’ risk and social preferences, which are probably the most explored behavioral domains in the tradition of Experimental Economics. This novel cross-over study employs thirty-two university students (gender-balanced) participating to 2 counterbalanced laboratory sessions in which they perform standard risk and social preference elicitation protocols. One session was after one night of undisturbed sleep at home, and the other was after one night of sleep deprivation in the laboratory. Sleep deprivation causes increased sleepiness and decreased alertness in all subjects. After sleep loss males make riskier decisions compared to the rested condition, while females do the opposite. Females likewise show decreased inequity aversion after sleep deprivation. As for the relationship between cognitive ability and economic decisions, sleep deprived individuals with higher cognitive reflection show lower risk aversion and more altruistic behavior. These results show that one night of sleep deprivation alters economic behavior in a gender-sensitive way. Females’ reaction to sleep deprivation, characterized by reduced risky choices and increased egoism compared to males, may be related to intrinsic psychological gender differences, such as in the way men and women weigh up probabilities in their decision-making, and/or to the different neurofunctional substrate of their decision-making.The authors acknowledge financial support from the Spanish Ministry of Economic Competititveness (ECO2012-34928), Italian Ministry of University and Research MIUR (PRIN 20103S5RN3_002), Generalitat Valenciana (Research Projects Gruposo3/086), the Instituto Valenciano de Investigaciones Económicas (IVIE), and the Ministero della Salute (RF-2009-1528677)

The Key of the Maze: the role of mental imagery and cognitive flexibility in navigational planning

Spatial navigation planning ability relies on both mental imagery and cognitive flexibility. Considering the importance of planning ability in everyday life, several neuropsychological tests are used in clinical practice for its assessment, although some of these are not aimed at assessing the strategies of navigational planning. The Porteus Maze Test (PMT) and the Key Search Task (KST) require to plan a strategy in a maze and in an imagined space, respectively. To the best of our knowledge, although these two tests share some features, the relationship between them has never been explored. The purpose of the present study was to investigate, for the first time, the relationship between the PMT and the KST performances in 38 healthy subjects in order to understand the implications of this association for the assessment of spatial navigation ability. Subjects were subdivided in bad or good navigation planners on the basis of the their KST score. The results of the study have revealed a significant difference (t = 2.35; p = 0.03) in the number of errors made at the PMT by bad navigational planners (0.78±0.28) and good navigational planners (0.10±0.06). The first group (bad navigational planners) made more errors at the PMT than the good navigational planners (who made less errors at the PMT). This provides evidence of the possibility to use the KST and the PMT in a combined way as a new tool for the assessment of spatial navigational planning ability. Furthermore, this finding highlights the importance of mental imagery and cognitive flexibility in spatial navigation, suggesting that these functions could be the link between a good planning ability and a successful spatial navigation. In conclusion, this study suggests that an efficient navigation would not be possible without a good navigational planning ability

Does ventrolateral prefrontal cortex help in searching for the lost key? Evidence from an fNIRS study

The Key Search Task (KST) is a neuropsychological test that requires strategies for searching a lost key in an imaginary field. This request may involve different cognitive processes as mental imagery and navigation planning. This study was aimed at investigating, by a twenty-channel functional near-infrared spectroscopy (fNIRS) system, the hemodynamic response (i.e., oxygenated-hemoglobin (O2Hb) and deoxygenated-hemoglobin (HHb) changes) of the prefrontal cortex in navigation planning. A right ventrolateral prefrontal cortex (rVLPFC) activation during the KST was hypothesized. Thirty-eight volunteers performed the KST and a Control Task (CT), the latter requiring the volunteers to mark the X letter. An activation (i.e., increase/decrease in O2Hb/ HHb) of: 1) rVLPFC during the KST execution, and 2) bilateral dorsolateral prefrontal cortex (DLPFC) during the CT execution was found. The present study provides a contribution in localizing the rVLPFC as the critically active region, within the frontal lobes, that was found maximally activated during mental navigation in the mind’s eye of healthy participants while performing the KST. Considering the contribution of rVLPFC in spatial navigation, its activation suggests that the KST could be adopted in the clinical routine for investigating navigation planning. Compared to other neuroimaging techniques, fNIRS (with its relatively low physical constraints) contributes to better clarifying the role of rVLPFC in some aspects of human navigation. Therefore, the combined use of the fNIRS and the KST could be considered as an innovative and valid tool to evaluate fundamental functions for everyday life, such as spatial navigation planning

Regression analysis.

<p>Notes: <i>standard errors in parentheses;</i></p><p><i>* p< 0</i>.<i>10</i>,</p><p><i>** p< 0</i>.<i>05</i>,</p><p><i>*** p< 0</i>.<i>01;</i></p><p><i>Estimates have been performed with Stata 13</i>.</p><p>^<i>1</i></p><p></p><p></p><p></p><p></p><p></p><p><i><mi>χ</mi></i></p><i><mo>-</mo><p></p><p></p><p><mo>(</mo><mn>1</mn><mo>)</mo></p><p><mn>2</mn></p><p></p><p></p><p></p></i><i>is an Lr test on the null hypothesis of no difference between the pooled estimator and the panel one</i>.<p></p><p>Regression analysis.</p

A novel semi-immersive virtual reality visuo-motor task activates ventrolateral prefrontal cortex: A functional near-infrared spectroscopy study

Objective. In the last few years, the interest in applying virtual reality systems for neurorehabilitation is increasing. Their compatibility with neuroimaging techniques, such as functional near-infrared spectroscopy (fNIRS), allows for the investigation of brain reorganization with multimodal stimulation and real-time control of the changes occurring in brain activity. The present study was aimed at testing a novel semi-immersive visuo-motor task (VMT), which has the features of being adopted in the field of neurorehabilitation of the upper limb motor function. Approach. A virtual environment was simulated through a threedimensional hand-sensing device (the LEAP Motion Controller), and the concomitant VMTrelated prefrontal cortex (PFC) response was monitored non-invasively by fNIRS. Upon the VMT, performed at three different levels of difficulty, it was hypothesized that the PFC would be activated with an expected greater level of activation in the ventrolateral PFC (VLPFC), given its involvement in the motor action planning and in the allocation of the attentional resources to generate goals from current contexts. Twenty-one subjects were asked to move their right hand/ forearm with the purpose of guiding a virtual sphere over a virtual path. A twenty-channel fNIRS system was employed for measuring changes in PFC oxygenated\u2013deoxygenated hemoglobin (O2Hb/HHb, respectively). Main results. A VLPFC O2Hb increase and a concomitant HHb decrease were observed during the VMT performance, without any difference in relation to the task difficulty. Significance. The present study has revealed a particular involvement of the VLPFC in the execution of the novel proposed semi-immersive VMT adoptable in the neurorehabilitation field