Sonno e funzioni cognitive: ruolo della microstruttura del sonno NREM

STUDY OBJECTIVE: Cyclic Alternating Pattern (CAP) is a fluctuation of the arousal level during NREM sleep and consists of the alternation between two phases: phase A (divided into three subtypes A1, A2, and A3) and phase B. A1 is thought to be generated by the frontal cortex and is characterized by the presence of K complexes or delta bursts; additionally, CAP A1 seems to have a role in the involvement of sleep slow wave activity in cognitive processing. Our hypothesis was that an overall CAP rate would have a negative influence on cognitive performance due to excessive fluctuation of the arousal level during NREM sleep. However, we also predicted that CAP A1 would be positively correlated with cognitive functions, especially those related to frontal lobe functioning. For this reason, the objective of our study was to correlate objective sleep parameters with cognitive behavioral measures in normal healthy adults. METHODS: 8 subjects (4 males; 4 females; mean age 27.75 years, range 2334) were recruited for this study. Two nocturnal polysomnography (night 2 and 3 = N2 and N3) were carried out after a night of adaptation. A series of neuropsychological tests were performed by the subjects in the morning and afternoon of the second day (D2am; D2pm) and in the morning of the third day (D3am). Raw scores from the neuropsychological tests were used as dependent variables in the statistical analysis of the results. RESULTS: We computed a series of partial correlations between sleep microstructure parameters (CAP, A1, A2 and A3 rate) and a number of indices of cognitive functioning. CAP rate was positively correlated with visuospatial working memory (Corsi block test), Trial Making Test Part A (planning and motor sequencing) and the retention of words from the Hopkins Verbal Learning Test (HVLT). Conversely, CAP was negatively correlated with visuospatial fluency (Ruff Figure Fluency Test). CAP A1 were correlated with many of the tests of neuropsychological functioning, such as verbal fluency (as measured by the COWAT), working memory (as measured by the Digit Span – Backward test), and both delay recall and retention of the words from the HVLT. The same parameters were found to be negatively correlated with CAP A2 subtypes. CAP 3 were negatively correlated with the Trial Making Test Parts A and B. DISCUSSION: To our knowledge this is the first study indicating a role of CAP A1 and A2 on behavioral cognitive performance of healthy adults. The results suggest that high rate of CAP A1 might be related to an improvement whereas high rate of CAP A2 to a decline of cognitive functions. Further studies need to be done to better determine the role of the overall CAP rate and CAP A3 on cognitive behavioral performances.

Cyclic alternating pattern in sleep and its relationship to creativity

Background/Objectives: Sleep has been shown to enhance creativity, but the reason for this enhancement is not entirely known. There are several different physiological states associated with sleep. In addition to rapid (REM) and non-rapid eye movement (NREM) sleep, NREM sleep can be broken down into Stages (1-4) that are characterized by the degree of EEG slow wave activity. In addition, during NREM sleep there are transient but cyclic alternating patterns (CAP) of EEG activity and these CAPs can also be divided into three subtypes (A1-A3) according to speed of the EEG waves. Differences in CAP ratios have been previously linked to cognitive performances. The purpose of this study was to learn the relationship CAP activity during sleep and creativity. Methods: The participants were 8 healthy young adults (4 women), who underwent 3 consecutive nights of polysomnographic recording and took the Abbreviated Torrance Test for Adults (ATTA) on the 2 and 3rd mornings after the recordings. Results: There were positive correlations between Stage 1 of NREM sleep and some measures of creativity such as fluency (R= .797; p=.029) and flexibility ( R=.43; p=.002), between Stage 4 of Non-REM sleep and originality (R= .779; p=.034) and a global measure of figural creativity (R= .758; p=.040). There was also a negative correlation between REM sleep and originality (R= -.827; p= .042) . During NREM sleep the CAP rate, which in young people is primarily the A1 subtype, also correlated with originality (R= .765; p =.038). Conclusions: NREM sleep is associated with low levels of cortical arousal and low cortical arousal may enhance the ability of people to access to the remote associations that are critical for creative innovations. In addition, A1 CAP activity reflects frontal activity and the frontal lobes are important for divergent thinking, also a critical aspect of creativity.

Influenza dell'Omeostasi Idrico-Elettrolitica sul Ciclo Veglia-Sonno

During the wake sleep (W-S) cycle in mammals, the alternation of the different states, wake, NREM sleep (NREMS) and REM sleep (REMS), is associated not only with electroencephalographic or behavioural changes, but also with modifications in the physiological regulations of the organism. The most evident change is the existence of a suspension of the somatic and autonomic thermoregulatory responses during REMS. Since thermoregulation is prevalently controlled by the Preoptic Area-Anterior Hypothalamus (PO-AH), its suspension during REM sleep has been taken as a sign of an impairment of the hypothalamic integrative activity that could explain the modifications in physiological regulation observed in this sleep stage. The recent finding from our laboratory that the secretion of the antidiuretic hormone arginine-vasopressin (AVP) in response to a central osmotic stimulation is quantitatively the same throughout the different stages of the W-S cycle, has shown that hypothalamic osmoregulation is not suspended during REMS. In order to clarify the extent of the hypothalamic involvement in the regulation of the W-S cycle, we have studied the effects of three days of water deprivation and of two days of recovery during which animals were allowed a free access to water, on the architecture of the W-S cycle. The condition of water deprivation represents a severe challenge involving neuroendocrine and autonomic hypothalamic regulations. In contradiction with thermoregulatory studies, in which it has been clearly demonstrated that a thermal challenge selectively reduces REMS occurrence, the results of this study show that REMS occurrence is mildly reduced only in the third day of water deprivation. The most striking effects produced by water deprivation appear to concern NREMS, which shows a selective and significant reduction in its slow EEG activity (delta-power) but not in its duration. The recovery period is mainly characterized by a disruption of the normal circadian rhythm of REMS occurrence and by a rebound of the delta power in NREMS. Thus, an autonomic challenge different from those related to thermoregulation and an endocrine challenge as the continuous secretion of AVP show to exert different effects on the stages of the wake-sleep cycle. Also, this study demonstrates that the impairment of the hypothalamic integrative activity thought to characterize the occurrence of REMS only involves thermoregulatory structures.

“Nanoglial interfaces: nanostructured materials, interfaces and devices to unveil the role of astrocytes in brain function and dysfunction”

The role of non-neuronal brain cells, called astrocytes, is emerging as crucial in brain function and dysfunction, encompassing the neurocentric concept that was envisioning glia as passive components. Ion and water channels and calcium signalling, expressed in functional micro and nano domains, underpin astrocytes’ homeostatic function, synaptic transmission, neurovascular coupling acting either locally and globally. In this respect, a major issue arises on the mechanism through which astrocytes can control processes across scales. Finally, astrocytes can sense and react to extracellular stimuli such as chemical, physical, mechanical, electrical, photonic ones at the nanoscale. Given their emerging importance and their sensing properties, my PhD research program had the general goal to validate nanomaterials, interfaces and devices approaches that were developed ad-hoc to study astrocytes. The results achieved are reported in the form of collection of papers. Specifically, we demonstrated that i) electrospun nanofibers made of polycaprolactone and polyaniline conductive composites can shape primary astrocytes’ morphology, without affecting their function ii) gold coated silicon nanowires devices enable extracellular recording of unprecedented slow wave in primary differentiated astrocytes iii) colloidal hydrotalcites films allow to get insight in cell volume regulation process in differentiated astrocytes and to describe novel cytoskeletal actin dynamics iv) gold nanoclusters represent nanoprobe to trigger astrocytes structure and function v) nanopillars of photoexcitable organic polymer are potential tool to achieve nanoscale photostimulation of astrocytes. The results were achieved by a multidisciplinary team working with national and international collaborators that are listed and acknowledged in the text. Collectively, the results showed that astrocytes represent a novel opportunity and target for Nanoscience, and that Nanoglial interface might help to unveil clues on brain function or represent novel therapeutic approach to treat brain dysfunctions.

Numerical simulations of magma chamber dynamics at Campi Flegrei, and associated seismicity, deformation and gravity changes

Understanding the complex relationships between quantities measured by volcanic monitoring network and shallow magma processes is a crucial headway for the comprehension of volcanic processes and a more realistic evaluation of the associated hazard. This question is very relevant at Campi Flegrei, a volcanic quiescent caldera immediately north-west of Napoli (Italy). The system activity shows a high fumarole release and periodic ground slow movement (bradyseism) with high seismicity. This activity, with the high people density and the presence of military and industrial buildings, makes Campi Flegrei one of the areas with higher volcanic hazard in the world. In such a context my thesis has been focused on magma dynamics due to the refilling of shallow magma chambers, and on the geophysical signals detectable by seismic, deformative and gravimetric monitoring networks that are associated with this phenomenologies. Indeed, the refilling of magma chambers is a process frequently occurring just before a volcanic eruption; therefore, the faculty of identifying this dynamics by means of recorded signal analysis is important to evaluate the short term volcanic hazard. The space-time evolution of dynamics due to injection of new magma in the magma chamber has been studied performing numerical simulations with, and implementing additional features in, the code GALES (Longo et al., 2006), recently developed and still on the upgrade at the Istituto Nazionale di Geofisica e Vulcanologia in Pisa (Italy). GALES is a finite element code based on a physico-mathematical two dimensional, transient model able to treat fluids as multiphase homogeneous mixtures, compressible to incompressible. The fundamental equations of mass, momentum and energy balance are discretised both in time and space using the Galerkin Least-Squares and discontinuity-capturing stabilisation technique. The physical properties of the mixture are computed as a function of local conditions of magma composition, pressure and temperature.The model features enable to study a broad range of phenomenologies characterizing pre and sin-eruptive magma dynamics in a wide domain from the volcanic crater to deep magma feeding zones. The study of displacement field associated with the simulated fluid dynamics has been carried out with a numerical code developed by the Geophysical group at the University College Dublin (O’Brien and Bean, 2004b), with whom we started a very profitable collaboration. In this code, the seismic wave propagation in heterogeneous media with free surface (e.g. the Earth’s surface) is simulated using a discrete elastic lattice where particle interactions are controlled by the Hooke’s law. This method allows to consider medium heterogeneities and complex topography. The initial and boundary conditions for the simulations have been defined within a coordinate project (INGV-DPC 2004-06 V3_2 “Research on active volcanoes, precursors, scenarios, hazard and risk - Campi Flegrei”), to which this thesis contributes, and many researchers experienced on Campi Flegrei in volcanological, seismic, petrological, geochemical fields, etc. collaborate. Numerical simulations of magma and rock dynamis have been coupled as described in the thesis. The first part of the thesis consists of a parametric study aimed at understanding the eect of the presence in magma of carbon dioxide in magma in the convection dynamics. Indeed, the presence of this volatile was relevant in many Campi Flegrei eruptions, including some eruptions commonly considered as reference for a future activity of this volcano. A set of simulations considering an elliptical magma chamber, compositionally uniform, refilled from below by a magma with volatile content equal or dierent from that of the resident magma has been performed. To do this, a multicomponent non-ideal magma saturation model (Papale et al., 2006) that considers the simultaneous presence of CO2 and H2O, has been implemented in GALES. Results show that the presence of CO2 in the incoming magma increases its buoyancy force promoting convection ad mixing. The simulated dynamics produce pressure transients with frequency and amplitude in the sensitivity range of modern geophysical monitoring networks such as the one installed at Campi Flegrei . In the second part, simulations more related with the Campi Flegrei volcanic system have been performed. The simulated system has been defined on the basis of conditions consistent with the bulk of knowledge of Campi Flegrei and in particular of the Agnano-Monte Spina eruption (4100 B.P.), commonly considered as reference for a future high intensity eruption in this area. The magmatic system has been modelled as a long dyke refilling a small shallow magma chamber; magmas with trachytic and phonolitic composition and variable volatile content of H2O and CO2 have been considered. The simulations have been carried out changing the condition of magma injection, the system configuration (magma chamber geometry, dyke size) and the resident and refilling magma composition and volatile content, in order to study the influence of these factors on the simulated dynamics. Simulation results allow to follow each step of the gas-rich magma ascent in the denser magma, highlighting the details of magma convection and mixing. In particular, the presence of more CO2 in the deep magma results in more ecient and faster dynamics. Through this simulations the variation of the gravimetric field has been determined. Afterward, the space-time distribution of stress resulting from numerical simulations have been used as boundary conditions for the simulations of the displacement field imposed by the magmatic dynamics on rocks. The properties of the simulated domain (rock density, P and S wave velocities) have been based on data from literature on active and passive tomographic experiments, obtained through a collaboration with A. Zollo at the Dept. of Physics of the Federici II Univeristy in Napoli. The elasto-dynamics simulations allow to determine the variations of the space-time distribution of deformation and the seismic signal associated with the studied magmatic dynamics. In particular, results show that these dynamics induce deformations similar to those measured at Campi Flegrei and seismic signals with energies concentrated on the typical frequency bands observed in volcanic areas. The present work shows that an approach based on the solution of equations describing the physics of processes within a magmatic fluid and the surrounding rock system is able to recognise and describe the relationships between geophysical signals detectable on the surface and deep magma dynamics. Therefore, the results suggest that the combined study of geophysical data and informations from numerical simulations can allow in a near future a more ecient evaluation of the short term volcanic hazard.

Sulforaphane as a multifunctional neuroprotective molecule to prevent and slow down the progression of Alzheimer’s disease

Oxidative stress has been implicated in the pathogenesis of a number of diseases including neurodegenerative disorders, cancer, ischemia, etc. Alzheimer’s disease (AD) is histopathologically characterized by the presence of extracellular senile plaque (SP), predominantly consisting of fibrillar amyloid-peptide (Aβ), intracellular neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau protein, and cell loss in the selected regions of the brain. However, the pathogenesis of AD remains largely unknown, but a number of hypothesis were proposed for AD mechanisms, which include: the amyloid cascade, excitotoxicity, oxidative stress and inflammation hypothesis, and all of them are based, to some extent on the role of A. Accumulated evidence indicates that the increased levels of ROS may act as important mediators of synaptic loss and eventually promote formation of neurofibrillary tangles and senile plaques. Therefore a vicious circle between ROS and Aaccumulation may accelerate progression of AD. For these reasons, growing attention has focused on oxidative mechanism of Atoxicity as well as the search for novel neuroprotective agents. A strategy to prevent the oxidative stress in neurons may be the use of chemopreventive agents as inducers of antioxidant and phase 2 enzymes. Sulforaphane (SF), derived from corresponding glucoraphanin, glucosinolate found in abundance in cruciferous vegetables, has recently gained attention as a potential neuroprotective compound inducer of antioxidant phase 2 enzymes. Consistent with this evidence, the study is aimed at identifying the SF ability to prevent and counteract the oxidative damage inducted by oligomers of Aβ (1-42) in terms of impairment in the intracellular redox state and cellular death in differentiated human neuroblastoma and microglia primary cultures. In addition we will evaluated the mechanism underlying the SF neuroprotection activity.

Analysis of the Slow Food movement impact on the farmers and rural areas’ sustainable development

The evaluation of the farmers’ communities’ approach to the Slow Food vision, their perception of the Slow Food role in supporting their activity and their appreciation and expectations from participating in the event of Mother Earth were studied. The Unified Theory of Acceptance and Use of Technology (UTAUT) model was adopted in an agro-food sector context. A survey was conducted, 120 questionnaires from farmers attending the Mother Earth in Turin in 2010 were collected. The descriptive statistical analysis showed that both Slow Food membership and participation to Mother Earth Meeting were much appreciated for the support provided to their business and the contribution to a more sustainable and fair development. A positive social, environmental and psychological impact on farmers also resulted. Results showed also an interesting perspective on the possible universality of the Slow Food and Mother Earth values. Farmers declared that Slow Food is supporting them by preserving the biodiversity and orienting them to the use of local resources and reducing the chemical inputs. Many farmers mentioned the language/culture and administration/bureaucratic issues as an obstacle to be a member in the movement and to participate to the event. Participation to Mother Earth gives an opportunity to exchange information with other farmers’ communities and to participate to seminars and debates, helpful for their business development. The absolute majority of positive answers associated to the farmers’ willingness to relate to Slow Food and participate to the next Mother Earth editions negatively influenced the UTAUT model results. A factor analysis showed that the variables associated to the UTAUT model constructs Performance Expectancy and Effort Expectancy were consistent, able to explain the construct variability, and their measurement reliable. Their inclusion in a simplest Technology Acceptance Model could be considered in future researches.

Hydrodynamic induced by an array of wave energy converters. Experimental and numerical analysis

The thesis analyses the hydrodynamic induced by an array of Wave energy Converters (WECs), under an experimental and numerical point of view. WECs can be considered an innovative solution able to contribute to the green energy supply and –at the same time– to protect the rear coastal area under marine spatial planning considerations. This research activity essentially rises due to this combined concept. The WEC under exam is a floating device belonging to the Wave Activated Bodies (WAB) class. Experimental data were performed at Aalborg University in different scales and layouts, and the performance of the models was analysed under a variety of irregular wave attacks. The numerical simulations performed with the codes MIKE 21 BW and ANSYS-AQWA. Experimental results were also used to calibrate the numerical parameters and/or to directly been compared to numerical results, in order to extend the experimental database. Results of the research activity are summarized in terms of device performance and guidelines for a future wave farm installation. The device length should be “tuned” based on the local climate conditions. The wave transmission behind the devices is pretty high, suggesting that the tested layout should be considered as a module of a wave farm installation. Indications on the minimum inter-distance among the devices are provided. Furthermore, a CALM mooring system leads to lower wave transmission and also larger power production than a spread mooring. The two numerical codes have different potentialities. The hydrodynamics around single and multiple devices is obtained with MIKE 21 BW, while wave loads and motions for a single moored device are derived from ANSYS-AQWA. Combining the experimental and numerical it is suggested –for both coastal protection and energy production– to adopt a staggered layout, which will maximise the devices density and minimize the marine space required for the installation.

Optimization of the power electronics system associated with ocean wave electric generators

The present thesis is focused on wave energy, which is a particular kind of ocean energy, and is based on the activity carried out during the EU project SEA TITAN. The main scope of this work is the design of a power electronic section for an innovative wave energy extraction system based on a switched-reluctance machine. In the first chapter, the general features of marine wave energy harvesting are treated. The concept of Wave Energy Converter (WEC) is introduced as well as the mathematical description of the waves, their characterization and measurement, the WEC classification, the operating principles and the standardization framework. Also, detailed considerations on the environmental impact are presented. The SEA TITAN project is briefly described. The second chapter is dedicated to the technical issues of the SEA TITAN project, such as the operating principle, the performance optimization carried out in the project, the main innovations as well as interesting demonstrations on the behavior of the generator and its control. In the third chapter, the power electronics converters of SEA TITAN are described, and the design choices, procedures and calculations are shown, with a further insight into the application given by analyzing the MATLAB Simulink model of the system and its control scheme. Experimental tests are reported in the fourth chapter, with graphs and illustrations of the power electronic apparatus interfaced with the real machine. Finally, the conclusion in the fifth chapter offers a global overview of the project and opens further development pathways.

Chemo-physical and biological mechanisms behind the anticancer activity of plasma activated Ringer's Lactate solution for the treatment of peritoneal carcinosis from primitive epithelial ovarian/tubular tumor

Cancer research and development of targeting agents in this field is based on robust studies using preclinical models. The failure rate of standardized treatment approaches for several solid tumors has led to the urgent need to fine-tune more sophisticated and faithful preclinical models able to recapitulate the features of in vivo human tumors, with the final aim to shed light on new potential therapeutic targets. Epithelial Ovarian Cancer (EOC) serous histotype (HGSOC) is one of the most lethal diseases in women due to its high aggressiveness (75% of patients diagnosed at FIGO III-IV state) and poor prognosis (less of 50% in 5 years), whose therapy often fails as chemoresistance sets in. This thesis aimed at using the novel perfusion-based bioreactor U-CUP that provides direct perfusion throughout the tumor tissue seeking to obtain an EOC 3D ex vivo model able to recapitulate the features of the original tumor including the tumor microenvironment and maintaining its cellular heterogeneity. Moreover, we optimized this approach so that it can be successfully applied to slow-frozen tumoral tissues, further extending the usefulness of this tool. We also investigated the effectiveness of Plasma Activated Ringer’s Lactate solution (PA-RL) against Epithelial Ovarian Cancer (EOC) serous histotype in both 2D and 3D cultures using ex-vivo specimens from HGSOC patients. We propose PA-RL as a novel therapy with local intraperitoneal administration, which could act on primary or metastatic ovarian tumors inducing a specific cancer cell death with reduced damage on the surrounding healthy tissues.

Effect of pulsed electromagnetic fields (pemfs) on muscle activity, tissue oxygenation and vo2 during exercise.

PEMF are a medical and non-invasive therapy successfully used for clinical treatments of bone disease, due to the piezoelectric effect that improve bone mass and density, by the stimulation of osteoblastogenesis, with modulation of calcium storages and mineral metabolism. PEMF enhance tissue oxygenation, microcirculation and angiogenesis, in rats and cells erythrocytes, in cells-free assay. Such responses could be caused by a modulation of nitric oxide signal and interaction between PEMF and Ca2+/NO/cGMP/PKG signal. PEMF improve blood flow velocity of smallest vein without changing their diameter. PEMF therapy helpful in patients with diabetes, due to increased microcirculation trough enhance capillary blood velocity and diameter. We investigated the influence of stimulation on muscular activity, tissue oxygenation and pulmonary VO2, during exercise, on different intensity, as heavy or moderate, different subjects, as a athlete or sedentary, and different sport activity, as a cycling or weightlifting. In athletes, we observed a tendency for a greater change and a faster kinetic of HHb concentration. PEMF increased the velocity and the quantity of muscle O2 available, leading to accelerate the HHb kinetics. Stimulation induced a bulk muscle O2 availability and a greater muscle O2 extraction, leading to a reduced time delay of the HHb slow component. Stimulation increased the amplitude of muscle activity under different conditions, likely caused by the effect of PEMF on contraction mechanism of muscular fibers, by the change of membrane permeability and Ca2+ channel conduction. In athletes, we observed an increase of overall activity during warm-up. In sedentary people, stimulation increased the magnitude of muscle activity during moderate constant-load exercise and warm-up. In athletes and weightlifters, stimulation caused an increase of blood lactate concentration during exercise, confirming a possible influence of stimulation on muscle activity and on glycolytic metabolism of type-II muscular fibers.