MiR-449a antagonizes EMT through IL-6-mediated trans-signaling in laryngeal squamous cancer.

MicroRNAs (miRNAs) are involved in post-transcriptional gene expression regulation and in mechanisms of cancer growth and metastases. In this light, miRNAs could be promising therapeutic targets and biomarkers in clinical practice. Therefore, we investigated if specific miRNAs and their target genes contribute to laryngeal squamous cell carcinoma (LSCC) development. We found a significant decrease of miR-449a in LSCC patients with nodal metastases (63.3%) compared with patients without nodal involvement (44%). The AmpliSeq Transcriptome of HNO-210 miR-449a-transfected cell lines allowed the identification of IL6-R as a potential target. Moreover, the downregulation of IL6-R and the phosphorylation reduction of the downstream signaling effectors, suggested the inhibition of the IL-6 trans-signaling pathway. These biochemical effects were paralleled by a significant inhibition of invasion and migration in vitro and in vivo, supporting an involvement of epithelial-mesenchymal transition. These findings indicate that miR-449a contributes to suppress the metastasization of LSCC by the IL-6 trans-signaling block and affects sensitivity to external stimuli that mimic pro-inflammatory conditions.

Bayesian interpretation of the prefrontal P2 ERP component based on stimulus/response mapping uncertainty.

The brain can be seen as a predictive system continuously computing prior information to guess posterior probabilities minimizing sources of uncertainty. To test this Bayesian view of the brain, event-related potentials (ERP) methods have been used focusing on the well-known P3 component, traditionally associated with decision-making processes and sources of uncertainty regarding target probability. Another ERP component linked with decision-making is the prefrontal P2 (pP2) component, which has never been considered within the Bayesian framework. To test which source of uncertainty could be associated with the pP2, uncertainty induced by target probability and stimulus-response (S/R) mapping were modulated in three visuomotor tasks. Results showed that the pP2 had the largest amplitude in the task with the largest uncertainty regarding the S/R mapping and degraded as the S/R mapping became more predictable. The P3 was maximal in the tasks with larger uncertainty regarding the target probability. While we confirmed the P3 association with target probability, we extended our knowledge on the pP2 associating it with S/R mapping uncertainty. This component, which has been previously localized within the anterior insular cortex, may minimize S/R mapping uncertainty allowing response-related evidence accumulation and comparing current events with internal representations to extract action-related probabilities.

Cortical dynamics in visual areas induced by the first use of multifocal contact lenses in presbyopes.

A common non-spectacle strategy to correct presbyopia is to provide simultaneous images with multifocal optical designs. Understanding the neuroadaptation mechanisms behind multifocal devices usage would have important clinical implications, such as predicting whether patients will be able to tolerate multifocal optics. The aim of this study was to evaluate the brain correlates during the initial wear of multifocal contact lenses (CLs) using high-density visual evoked potential (VEP) measures. Fifteen presbyopes (mean age 51.8 ±â€¯2.6 years) who had previously not used multifocal CLs were enrolled. VEP measures were achieved while participants looked at arrays of 0.5 logMAR Sloan letters in three different optical conditions arranged with CLs: monofocal condition with the optical power appropriate for the distance viewing; multifocal correction with medium addition; and multifocal correction with low addition. An ANOVA for repeated measures showed that the amplitude of the C1 and N1 components significantly dropped with both multifocal low and medium addition CL conditions compared to monofocal CLs. The P1 and P2 components showed opposite behavior with an increase in amplitudes for multifocal compared to monofocal conditions. VEP data indicated that multifocal presbyopia corrections produce a loss of feedforward activity in the primary visual cortex that is compensated by extra feedback activity in extrastriate areas only, in both early and late visual processing.

A Nonpharmacologic Treatment for Anxiety in Older Adults Based on Cognitive-Motor Training With Response-Generated Feedback.

OBJECTIVES: Simultaneous combinations of cognitive and physical exercises (cognitive-motor dual-task training [CMDT]) are more effective than physical and cognitive training alone in counteracting the decline of older adults and promoting physical and psychological well-being. The CMDT can be particularly effective in improving cognitive and functional abilities. Here, we validated an innovative nonpharmacologic intervention for anxiety and general well-being in older people by combining CMDT and response-generated feedback (RGF) principles. As outcomes, anxiety, cognitive functions, and functional mobility were evaluated. In addition, electroencephalographic methods were employed to investigate the neural basis of the possible intervention effects. METHODS: Thirty older adults were divided into an experimental group trained using a CMDT + RGF protocol and a control group using the CMDT only. The CMDT + RGF consisted of the simultaneous execution of whole-body exercises, cognitive tasks that were realized using interactive devices, and continuous feedback on every response. RESULTS: Results showed decreased anxiety and increased response speed in the experimental group, and both groups improved their functional ability and response accuracy after the intervention. According to electroencephalographic results, both groups showed an increase in the bilateral prefrontal cortex anticipatory activity, but the experimental group also showed a further increase in the left prefrontal cortex and in the premotor areas anticipatory functions. DISCUSSION: This study confirms the effectiveness of the proposed intervention on anxiety by adopting a nonpharmacology treatment that could affect public and individual health costs by proposing an alternative approach to expensive medications and psychotherapy and could significantly improve older adults' quality of life.

Effect of anticipatory multisensory integration on sensory-motor performance.

Multisensory integration (MSI) is a phenomenon that occurs in sensory areas after the presentation of multimodal stimuli. Nowadays, little is known about the anticipatory top-down processes taking place in the preparation stage of processing before the stimulus onset. Considering that the top-down modulation of modality-specific inputs might affect the MSI process, this study attempts to understand whether the direct modulation of the MSI process, beyond the well-known sensory effects, may lead to additional changes in multisensory processing also in non-sensory areas (i.e., those related to task preparation and anticipation). To this aim, event-related potentials (ERPs) were analyzed both before and after auditory and visual unisensory and multisensory stimuli during a discriminative response task (Go/No-go type). Results showed that MSI did not affect motor preparation in premotor areas, while cognitive preparation in the prefrontal cortex was increased and correlated with response accuracy. Early post-stimulus ERP activities were also affected by MSI and correlated with response time. Collectively, the present results point to the plasticity accommodating nature of the MSI processes, which are not limited to perception and extend to anticipatory cognitive preparation for task execution. Further, the enhanced cognitive control emerging during MSI is discussed in the context of Bayesian accounts of augmented predictive processing related to increased perceptual uncertainty.

Motor-cognitive exercise with variability of practice and feedback improves functional ability and cognition in older individuals.

BACKGROUND: Motor-cognitive dual-task training seems the most favorable form of exercise for functional and cognitive improvements in older individuals.  The optimal exercise regime is still uncertain, and the potential benefits of qualitative parameters of exercise prescription such as feedback provision and practice variability are mostly unknown. AIMS: To verify the effects of a motor-cognitive dual-task training with feedback provision and variability of practice for improving functional ability and cognition in older individuals. METHODS: Thirty individuals (3 men) aged over 65 years were tested on walking speed, static and dynamic balance, lower limb strength, and cognition before and after a 5-week motor-cognitive intervention. Training consisted of twice weekly, 30 min gross-motor coordination exercises with variable practice conditions combined with stimulus-response cognitive tasks generated by an interactive device. Participants were divided into an experimental group and a control group, respectively receiving and nonreceiving feedback during training. A 2 × 2 ANOVA was used to verify the effects of training. RESULTS: Both groups improved static and dynamic balance (p < 0.05), walking speeds (p < 0.05), lower limb strength (p < 0.05) and cognitive functions with greater gains observed in the experimental group (p < 0.01). DISCUSSION: Variability of practice applied to motor-cognitive dual-task training is effective for improving, in only 5 weeks, functional ability and cognitive processing in older individuals. These changes were possibly afforded through motor and cognitive enhancement induced by exercise complexity. Provision of feedback seems to particularly benefit cognitive functions. CONCLUSIONS: Brief motor-cognitive dual-task training using practice variability and feedback seems effective for counteracting the age-related cognitive and functional decline.

Specific effect of a cognitive-motor dual-task training on sport performance and brain processing associated with decision-making in semi-elite basketball players.

OBJECTIVES: In this study, we aimed at evaluating the effects of cognitive-motor dual-task training (CMDT) on sport-specific athletic performance and cognitive functions of semi-elite basketball players. Further, we investigated the CMDT effects on reactive brain processing by employing event-related potential (ERP) analysis. DESIGN: A randomized controlled trial was conducted including 52 young semi-elite basketball players (28 females mean age 16.3 ± 1.1 years) who were randomly assigned into an experimental (Exp) group executing the CMDT and a control (Con) group performing standard motor training. METHOD: Athletes' sport-specific performance was evaluated with dribbling tests before and after a five-week training. Cognitive performance was assessed by measuring speed and accuracy in a discrimination response task. Brain activity associated with sensory processing, selective attention, and decision-making was measured through the P1, N1, and P3 components. The CMDT consisted of simultaneous execution of dribbling exercises and cognitive tasks which were realized using interactive devices located around the athlete on the basket court. Data were submitted to a mixed analysis of variance. RESULTS: Both groups showed some improvements from pre-to post-tests, but the Exp group improved basket-specific performance by 13% more than the Con group; in addition, the cognitive performance also improved more in the Exp group (25.8% in accuracy and 5.4% response speed). According to the EEG results, training did not affect sensory processing and attentional processing which were equally increased after both kinds of training; however, decision-making processes were specifically affected by the experimental training. CONCLUSIONS: This study confirmed the effectiveness of the proposed CMDT protocol on both sport-specific and cognitive performance of basketball players and showed that the neural basis of these benefits may be mediated by more intense decisional processing allowing faster connection between sensory encoding and response execution.

Testing a Multicomponent Training Designed to Improve Sprint, Agility and Decision-Making in Elite Basketball Players.

This study tested if, in elite basketball players' training, the integration of a cognitive component within a multi-component training (MCT) could be more effective than an MCT with motor components only to improve both physical and cognitive skills. To this purpose, we designed an MCT focussed on sprint and agility incorporating a cognitive-motor dual-task training (CMDT) focussed on decision-making speed. Specific tests on sprint, agility and decision-making, and event-related potential (ERP) during the latter test were evaluated before and after the intervention. Thirty elite basketball players were recruited and divided into an experimental group executing CMDT integrated into the MCT and a control group performing the motor MCT (without cognitive components). The MCT with CMDT session was performed by four athletes simultaneously that executed different circuits. One circuit was the CMDT which was realized using interactive devices. Results on physical performance showed that only the experimental group improved in sprint and agility and also shortened response time in the decision-making test. At the neural level, the experimental group only shows an increase in the P3 ERP component, which has been associated with a series of post-perceptual cognitive functions, including decision-making. In conclusion, CMDT implemented within an MCT, likely stimulating more than physical training cortical plasticity, could be more effective than a motor MCT alone in improving the physical and cognitive skills of elite basketball players in five weeks only.

Sex Differences in Cognitive-Motor Dual-Task Training Effects and in Brain Processing of Semi-Elite Basketball Players.

In the current study, we aimed at evaluating the possible sex differences in cognitive-motor dual-task training (CMDT) effects on the sport and cognitive performance of semi-elite basketball athletes. Moreover, we investigated the CMDT effects on proactive brain processing using event-related potential (ERP) analysis. Fifty-two young basketball athletes (age 16.3 years) were randomly assigned into an experimental (Exp) group performing the CMDT, and a control (Con) group executing standard motor training. Before and after a 5-week training intervention, participants' motor performance was evaluated using dribbling tests. Cognitive performance was assessed by measuring response time and accuracy in a discrimination response task (DRT). Brain activity related to motor and cognitive preparation was measured through the Bereitschaftspotential (BP) and the prefrontal negativity (pN) ERP components. The CMDT involved the simultaneous execution of dribbling exercises and cognitive tasks which were realized using interactive technologies on the court. Results showed that both groups had some enhancements from pre- to post-tests, but only the Exp group enhanced in the dribbling exercise. In the DRT after the CMDT, females performed faster than males in the Exp group. All groups, except for the Con group of males, performed the DRT more accurately after the training. According to the ERP results, in the Exp group of males and in Exp and Con group of females, we found an increase in pN amplitude (associated with better accuracy); in the Exp group of females and in Exp and Con group of males, we found an increase in BP (associated with better response time). In conclusion, the present study endorsed the efficacy of the proposed CMDT protocol on both the sport and cognitive performance of semi-elite basketball players and showed that the neural basis of these benefits may be interpreted as sex-related compensatory effects.

Modality predictability modulation confirms the sensorial readiness function of the pre-stimulus activity in sensory brain areas.

The auditory Positivity (aP) and the visual Negativity (vN) are recently discovered modality-specific event-related potential (ERP) components associated with sensory readiness, which seems promising to study anticipatory perception and attention. However, a crucial aspect of these waves remains to be determined since it is still unclear if these components are indeed related to sensory readiness or represent the result of stimulus predictably. Indeed, earlier studies found these components in tasks where stimuli were repeatedly presented uniquely in the same sensory modality. To disentangle this issue, we used an experimental design consisting of three passive tasks: a unimodal auditory condition, a unimodal visual condition, and an intermodal condition in which the visual and auditory stimuli were unpredictably alternated. Then, we compared the amplitudes of the aP and vN in the three conditions and performed correlation analyses between pre-stimulus and post-stimulus components. Crucially, results showed that in the intermodal condition the components still occur, but their amplitudes are decreased compared to unimodal condition, providing evidence that they are only partially dependent on the task and that expectancy might modulate them. This result is in line with the "modality-shift effect" costs phenomenon which can occur also for passive tasks even before stimulus presentation. In addition, the amplitude of the post-stimulus components correlated with pre-stimulus ERP. Collectively, the present study confirms that the aP and the vN reflect sensory readiness processes that "boost" post-stimulus auditory N1 and visual P1 components.

The Dominance of Anticipatory Prefrontal Activity in Uncued Sensory-Motor Tasks.

Anticipatory event-related potentials (ERPs) precede upcoming events such as stimuli or actions. These ERPs are usually obtained in cued sensory-motor tasks employing a warning stimulus that precedes a probe stimulus as in the contingent negative variation (CNV) paradigms. The CNV wave has been widely studied, from clinical to brain-computer interface (BCI) applications, and has been shown to emerge in medial frontoparietal areas, localized in the cingulate and supplementary motor areas. Several dated studies also suggest the existence of a prefrontal CNV, although this component was not confirmed by later studies due to the contamination of ocular artifacts. Another lesser-known anticipatory ERP is the prefrontal negativity (pN) that precedes the uncued probe stimuli in discriminative response tasks and has been localized in the inferior frontal gyrus. This study aimed to characterize the pN by comparing it with the CNV in cued and uncued tasks and test if the pN could be associated with event preparation, temporal preparation, or both. To achieve these aims, high-density electroencephalographic recording and advanced ERP analysis controlling for ocular activity were obtained in 25 volunteers who performed 4 different visuomotor tasks. Our results showed that the pN amplitude was largest in the condition requiring both time and event preparation, medium in the condition requiring event preparation only, and smallest in the condition requiring temporal preparation only. We concluded that the prefrontal CNV could be associated with the pN, and this activity emerges in complex tasks requiring the anticipation of both the category and timing of the upcoming stimulus. The proposed method can be useful in BCI studies investigating the endogenous neural signatures triggered by different sensorimotor paradigms.

Special Issue: Neural Bases of Cognitive Processing.

The main aim of Cognitive Neuroscience is investigating how brain functions lead to mental processes and behavior [...].

Neural Basis of Anticipatory Multisensory Integration.

The brain is able to gather different sensory information to enhance salient event perception, thus yielding a unified perceptual experience of multisensory events. Multisensory integration has been widely studied, and the literature supports the hypothesis that it can occur across various stages of stimulus processing, including both bottom-up and top-down control. However, evidence on anticipatory multisensory integration occurring in the fore period preceding the presentation of the expected stimulus in passive tasks, is missing. By means of event-related potentials (ERPs), it has been recently proposed that visual and auditory unimodal stimulations are preceded by sensory-specific readiness activities. Accordingly, in the present study, we tested the occurrence of multisensory integration in the endogenous anticipatory phase of sensory processing, combining visual and auditory stimuli during unimodal and multimodal passive ERP paradigms. Results showed that the modality-specific pre-stimulus ERP components (i.e., the auditory positivity -aP- and the visual negativity -vN-) started earlier and were larger in the multimodal stimulation compared with the sum of the ERPs elicited by the unimodal stimulations. The same amplitude effect was also present for the early auditory N1 and visual P1 components. This anticipatory multisensory effect seems to influence stimulus processing, boosting the magnitude of early stimulus processing. This paves the way for new perspectives on the neural basis of multisensory integration.

Effects of a Cognitive-Motor Training on Anticipatory Brain Functions and Sport Performance in Semi-Elite Basketball Players.

The aim of this research was to test the possible effects of cognitive-motor training (CMT) on athletes' sport performance and cognitive functions. Namely, specific athletic tests, brain processes associated with anticipatory event-related potential (ERP) components and behavioral performance during a cognitive discrimination response task were evaluated pre- and post-training. Twenty-four young semi-professional basketball players were recruited for the study and randomly divided into an experimental (Exp) group executing the CMT training and a control (Con) group performing standard motor training. The CMT training protocol included exercises in which participants performed cognitive tasks during dribbling exercises using interactive devices which emitted visual and auditory stimuli, in which athletes' responses were recorded. Results showed that following training, only the Exp group improved in all sport-specific tests (17%) and more than the Con group (88% vs. 60%) in response accuracy during the cognitive test. At brain level, post-training anticipatory cognitive processes associated with proactive inhibition and top-down attention in the prefrontal cortex were earlier and heightened in the Exp group. Our findings confirm previous studies on clear improved efficacy of CMT training protocols on sport performance and cognition compared to training based on motor exercises only, but extend the literature in showing that these effects might be explained by enhanced anticipatory brain processing in the prefrontal cortex. The present study also suggests that in order to achieve specific athletic goals, the brain adapts cognitive functions by means of neuroplasticity processes.

New Myocardial Deformation by 2D Multi-layer Speckle-Tracking Analysis in Healthy Patients: Normal Reference Values and Their Physiologic Determinants.

There are limited data regarding intrinsic changes of the left (LV) and right ventricular (RV) deformation assessed layer-by-layer. We designed a prospective multi-centric study, using a new multi-layer 2D-speckle-tracking-echo (MSTE). We investigated the impact of different physiologic parameters on layer-specific LV/RV myocardial deformation and synchrony, in a large group of healty subjects. 151 subjects were feasible for MSTE, divided in 4 groups: <40 yrs, 41 to 50 yrs, 51 to 60, and >61 yrs. We found a significant higher LV dyssynchrony index with age. In all groups, an endo-epicardial gradient was present in longitudinal LV/RV and circumferential deformation, with higher values in endocardial layer (p<0.001). There were no differences in deformation with age in all layers. We provided normal reference values for a new index of LV dyssynchrony, and also for RV longitudinal, LV circumferential and longitudinal layer-specific deformation, which can be further used when assessing subclinical dysfunction in myocardial diseases.

Cardiovascular Dysfunction in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic neurological condition, characterized by recurrent episodes of inflammation and demyelination of the central nervous system called relapsing-remitting episodes, and continuous axonal degeneration that leads to irreversible progressive invalidity. Patients with multiple sclerosis present a higher mortality rate compared to the general population, and the excess of mortality may be explained by the increased cardiovascular risk and occurrence of cardiovascular disease. However, the exact pathways to cardiovascular dysfunction are not yet completely elucidated. This review focuses on the most important mechanisms of cardiovascular dysfunction in MS, such as the cardiomyocite structure alteration, the cardiovascular autonomous nervous system dysfunction, physical invalidity, oxidative stress and endothelial dysfunction, as well as the impact of cardiovascular risk factors in MS. The latest evidence about therapeutic approaches for MS, such as immunomodulatory treatment, vitamin D supplementation and statins are also discussed. There is little knowledge about the cardiovascular dysfunction in MS, and further research is required to improve the understanding of these complex mechanisms.

Early detection of epirubicin-induced cardiotoxicity in patients with breast cancer.

BACKGROUND: Epirubicin is a cytotoxic drug, widely used in patients with breast cancer, but its application is limited by its cardiotoxicity. Assessment of left ventricular (LV) ejection fraction (EF) is performed to demonstrate cardiac dysfunction. Because normal EF can mask LV impairment, the aim of this study was to evaluate whether deformation and rotation assessed using speckle-tracking echocardiography represent better markers of early epirubicin-induced cardiotoxicity. METHODS: Forty women with breast cancer (mean age, 51 ± 8 years), scheduled to be treated with epirubicin-based chemotherapy, were prospectively enrolled. All patients underwent conventional echocardiography, tissue velocity imaging, and speckle-tracking echocardiography to evaluate LV geometry and EF, S', deformation (longitudinal, circumferential, and radial strain and strain rate), and rotation. Patients were reevaluated after the third and sixth cycles of epirubicin (mean cumulative dose, 268 ± 22 g/m(2)). RESULTS: After the sixth cycle of treatment, 14 patients (35%) had developed epirubicin-induced cardiotoxicity (a decrease in EF of ≥10% to an EF of <55%; group I), and 26 patients (65%) did not fulfill the criteria for cardiotoxicity (group II). In the entire study population, after the third cycle of epirubicin, there were reductions in diastolic and longitudinal function, but patients in group I had significantly lower S', longitudinal strain, and longitudinal strain rate than those in group II. Although after the third cycle of treatment, radial and circumferential deformation and rotation remained unchanged, these parameters showed significant reductions after the sixth cycle of epirubicin. A decrease in longitudinal strain after the third cycle of epirubicin was the best independent and accurate predictor of cardiotoxicity after the completion of treatment. CONCLUSIONS: Assessment of myocardial longitudinal deformation detects subclinical LV dysfunction and can predict further changes in EF and therefore can be used to monitor epirubicin-induced cardiotoxicity.

Benefit vs. Risk of a Permanent Inferior Vena Cava Filter in Pulmonary Embolism with Anticoagulation Contraindication.

ABSTRACT: Cases of pulmonary embolism (PE) with contraindication of anticoagulation have low incidence. Under these circumstances the placement of an inferior vena cava (IVC) filter may be life-saving. Paradoxically, the presence of the filter imposes anticoagulation itself, due to the risk of filter thrombosis, promoting stasis and increasing the risk of filter related deep venous thrombosis (DVT) and PE recurrence by means of a substantial collateral venous return that bypasses the IVC filter (1,2). We present the case of a woman with DVT, complicated with high risk PE. After thrombolysis with alteplase the patient develops retroperitoneal hematoma originating from undiagnosed renal angiomyolipoma. Therefore long term anticoagulation is considered contraindicated and an IVC filter is installed. Shortly after hospital release the patient presents occlusion of the IVC filter with DVT recurrence. The initiation of low molecular weight heparin and afterwards of acenocumarol has a favorable outcome, and after six months of follow up the patient is completely recovered.