Singular Spectrum Analysis and Adaptive Filtering: A Novel Approach for Assessing the Functional Connectivity in fMRI Resting State Experiments

Functional Magnetic Resonance Imaging (fMRI) is used to investigate brain functional connectivity at rest after filtering out non-neuronal components related to cardiac and respiratory processes and to the instrumental noise of MRI scanner. These components are generally removed at their fundamental frequencies through band-pass filtering of the Blood-Oxygen-Level-Dependent (BOLD) signal (low-frequency band – LFB: 0.01–0.10 Hz) while General Linear Model (GLM) is usually employed to suppress slow variations of physiological noise in the LFB, using a signal template derived from non-neuronal regions (e.g. brain ventricles). However, these sources of noise exhibit a non-stationary nature due to the intrinsic time variability of physiological activities or to the nonlinear characteristics of MRI scanner drifts: at present, the standard procedure (band-pass filtering and GLM) does not take into account these noise properties in the processing of BOLD signal. This thesis proposes the joint usage of two methods (Singular Spectrum Analysis – SSA – and adaptive filtering) that takes advantage of their statistical and time flexibility features, respectively. Indeed SSA is a nonparametric technique capable of extracting amplitude and phase modulated components against a null hypothesis of autocorrelated noise, while the adaptive filter removes the noise correlated to a reference signal, exploiting its non-stationary properties. The novel procedure (SSA and adaptive filtering) was applied to eight resting state recordings and compared to the standard procedure. The functional connectivity between homologous contralateral regions was then estimated in the LFB using a multivariate correlation index (the RV coefficient) and assessed on preselected grey (GM) and white matter (WM) regions of interest (ROIs). A corrected version of the RV coefficient for the number of voxels was developed and used to compare the functional connectivity estimates obtained by the standard procedure (using all available voxels) and from the novel procedure based on the voxel time courses with significant SSA components in the LFB (active voxels). The adaptive filtering showed a greater reduction of noise compared to GLM (average signal variance decrease in all ROIs: −43.9% vs. −10.1%), using a non-stationary noise template obtained from brain ventricles signals in the LFB. The functional connectivity quantified by the RV coefficient and estimated on the active voxels identified by SSA showed a higher contrast between GM and WM regions with respect to the standard procedure (35% vs. 28%). These results suggest that SSA and adaptive filtering may be a feasible procedure for properly removing the physiological noise in the LFB of BOLD signal and for highlighting resting state functional networks

Physiological Cybernetics: An Old-Novel Approach for Students in Biomedical Systems

Wiener in a seminal book (Wiener, 1948) associated the ancient Greek word ‘κυβερνητικος’ to the control of physiological systems. “Thus, as far back as four years ago, the group of scientists about Dr. Rosenblueth and myself had already become aware of the essential unity of the set of problems centering about communication, control and statistical mechanics, whether in the machine or in the living tissue. [...] We have decided to call the entire field [...] by the name Cybernetics, which we form from the Greek κυβερνητης or steersman. In choosing this term, we wish to recognize that the first significant paper on feed-back mechanisms is an article on governors, which was published by Clerk Maxwell in 1868 and that governor is derived from a Latin corruption of κυβερνητης. We also wish to refer to the fact that the steering engines of a ship are indeed one of the earliest and best developed forms of feed-back mechanisms.” The increasing knowledge in each sector of science led to a huge diversification of scientific research, especially in a borderline sector like cybernetics applied to physiological systems. A first problem to solve was the following: let’s suppose that two groups, one with a control engineering experience and the other one with a medical background (e.g., physicians), decide to cooperate, because they strongly believe that a joined research could be useful for developing mathematical and statistical models. Usually physicians do not have enough time to study and apply advanced modelling. Wiener approached the communication between scientists belonging to different disciplines: “If a physiologist, who knows no mathematics, works together with a mathematician, who knows no physiology, the one will be unable to state his problem in terms that the other can manipulate, and the second will be unable to put the answers in any form that the first can understand. [...] The mathematician need not have the skill to conduct a physiological experiment, but he must have the skill to understand one, to criticize one, and to suggest one. The physiologist need not be able to prove a certain mathematical theorem, but he must be able to grasp its physiological significance and to tell the mathematician for what he should look.” A correct interaction in terms of a clear communication and reciprocal comprehension of the objectives of the research activity between groups with different competences is a crucial aspect in any interdisciplinary research. In 2003 at the University of Pisa it was decided to introduce a new course for undergraduate students in biomedical engineering, based on the Wiener ‘utopia’, in order to teach a novel discipline useful for helping biomedical students to communicate and cooperate effectively with physicians. We named this new course as Physiological Cybernetics, remembering the old Wiener definition. The organization of this course was a difficult task, and it required to gain experience in order to integrate so different disciplines and to produce a common language between students in biomedical engineer and physicians. At a first glance this attempt seemed to be too ambitious, because the different approaches of biomedical engineers with respect to physicians seemed incompatible and even the languages of the two groups were so different to remember the Babel tower… A great deal of effort and attention was required to produce appealing and stimulating lectures, but after many years we can affirm that this challenge is successful, especially for the enthusiastic answers of the students: their number was increasing year after year (about seventy students per year are now attending the course). A strict and trusted cooperation between different groups of physicians is growing up and several groups of physicians belonging to different medical fields are going to join us for new interactions. The aim of this chapter is to describe how the approach to physiological cybernetics has led to integrate academic lessons with research activities. To be more specific, the basic idea of Physiological Cybernetics was to search for models able to emulate physiological systems based on the feedback theory and/or the system theory. In fact, recently, the widespread use of friendly software packages for modelling, along with the development of powerful identification and control techniques has led to a renewed interest in control (Khoo, 2011; Hoppensteadt & Peskin, 2002; Cobelli & Carson, 2008) and identification (Westwick & Kearney, 2003) of physiological systems. Unfortunately physiological systems are intrinsically time variant and highly non linear. Moreover, an effective balance of the model complexity is a difficult task: low order models are usually too simple to be useful, on the other hand high order models are too complex for simulation purposes and they have too many unknown parameters to be identified. Each model selected for investigation was studied by a group of biomedical students supervised by physicians. Each model required several iterations and reformulations, due to the continuous adjustment of the research objectives, changing their final horizon, because of the gap between experimental data and theoretical models, so that the answers to the doubts and questions were continuously moving with the obtained partial results. A final goal of the research was to apply a mathematical framework for helping medical diagnostic techniques and for testing new therapeutic protocols. The procedure of model extraction followed two main pathways: the first one (pathway A) led to a formulation of a mathematical model usually based on differential equations and on an as deep as possible insight into physiological mechanisms (Marmarelis, 2004; Ottesen et al., 2004; Edelstein-Keshet, 2005; Jones et al., 2009) via a physical description of the system. The second one (pathway B) was founded on a model description based on a black-box and data-driven identification (Westwick & Kearney, 2003; Cobelli & Carson, 2008), usually leaving to stochastic models with a parametric or non-parametric structure (Ljung, 1987), depending on the a-priori knowledge of constitutive laws governing the observed system. In this paper we will describe two examples of research activity based on the Physiological Cybernetics, both of them addressed to produce a biomedical framework for predicting the effects of therapeutic actions, but following the two different pathways. The first example follows a statistical non parametric approach, the second one a mathematical model based on differential equations

Static sensitivity of whole-room indirect calorimeters

Whole-room indirect calorimeters (WRIC) are accurate tools to precisely measure energy metabolism in humans via calculation of oxygen consumption and carbon dioxide production. Yet, overall accuracy of metabolic measurements relies on the validity of the theoretical model for gas exchange inside the WRIC volume in addition to experimental and environmental conditions that contribute to the uncertainty of WRIC outcome variables. The aim of this study was to quantitatively study the static sensitivity of a WRIC operated in a push configuration and located at the laboratories of the University Hospital of Pisa with the goal to identify the experimental conditions required to reach the best degree of accuracy for outcome metabolic measurements. Herein we demonstrate that achieving a fractional concentration of carbon dioxide inside the WRIC>0.2% at the steady state conditions allows to obtain a relative uncertainty <5% for the outcome metabolic measurement

Sensitivity Analysis of Whole-Room Indirect Calorimeters at the Steady-state Condition

Whole-Room Indirect Calorimeters (WRIC) are accurate tools to precisely measure energy metabolism in humans via calculation of oxygen consumption and carbon dioxide production. Yet, overall accuracy of metabolic measurements relies on the validity of the dynamic model for gas exchange inside the calorimeter volume in addition to experimental and environmental conditions that contribute to the uncertainty of WRIC outcome variables. The aim of this work is to formally study the sensitivity of a WRIC system operated in a push configuration at the steady-state condition to identify the optimal experimental conditions to obtain the best degree of accuracy for outcome metabolic measurements. The results of our sensitivity analysis are then validated with measurements obtained during propane combustion tests performed at the WRIC located at the University Hospital of Pisa. Our results demonstrate that achieving a fractional concentration of carbon dioxide inside the calorimeter >0.2% leads to relative uncertainty <5% for the outcome metabolic measurements when assuming an accuracy class of 1% for gas analyzer instruments

Liver enlargement predicts obstructive sleep apnea–hypopnea syndrome in morbidly obese women

Obstructive sleep apnea–hypopnea syndrome (OSAHS) is frequently present in patients with severe obesity, but its prevalence especially in women is not well defined. OSAHS and non-alcoholic fatty liver disease are common conditions, frequently associated in patients with central obesity and metabolic syndrome and are both the result of the accumulation of ectopic fat mass. Identifying predictors of risk of OSAHS may be useful to select the subjects requiring instrumental sleep evaluation. In this cross-sectional study, we have investigated the potential role of hepatic left lobe volume (HLLV) in predicting the presence of OSAHS. OSAHS was quantified by the apnea/hypopnea index (AHI) and oxygen desaturation index in a cardiorespiratory inpatient sleep study of 97 obese women [age: 47 ± 11 years body mass index (BMI): 50 ± 8 kg/m2]. OSAHS was diagnosed when AHI was ≥5. HLLV, subcutaneous and intra-abdominal fat were measured by ultrasound. After adjustment for age and BMI, both HLLV and neck circumference (NC) were independent predictors of AHI. OSAHS was found in 72% of patients; HLLV ≥ 370 cm3 was a predictor of OSAHS with a sensitivity of 66%, a specificity of 70%, a positive and negative predictive values of 85 and 44%, respectively (AUC = 0.67, p < 0.005). A multivariate logistic model was used including age, BMI, NC, and HLLV (the only independent predictors of AHI in a multiple linear regression analyses), and a cut off value for the predicted probability of OSAHS equal to 0.7 provided the best diagnostic results (AUC = 0.79, p < 0.005) in terms of sensitivity (76%), specificity (89%), negative and positive predictive values (59 and 95%, respectively). All patients with severe OSAHS were identified by this prediction model. In conclusion, HLLV, an established index of visceral adiposity, represents an anthropometric parameter closely associated with OSAHS in severely obese women

FGF21 is a Hormonal Mediator of the Human "Thrifty" Metabolic Phenotype

Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change after low-protein overfeeding in rodent models. The change in EE after low-protein overfeeding diet is a predictor of weight change in humans and a feature of the "thrifty" metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 hours of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by 3-fold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after six months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain

Role of Thyroglobulin, Neck Ultrasound, Thyroglobulin Antibodies Trend and Diagnostic Whole Body Scan in the Management of Differentiated Thyroid Cancer Patients with Persistent Thyroglobulin Antibodies

Background: During the follow-up of differentiated thyroid cancer patients, the presence of thyroglobulin antibodies makes thyroglobulin measurements unreliable. For this reason, thyroglobulin antibodies measurement and the evaluation of their titer trend are also recommended. Objective: We aimed to identify the best method among stimulated thyroglobulin, thyroglobulin antibodies titer trend, neck ultrasound and diagnostic whole body scan for detecting the presence of disease in a group of differentiated thyroid cancer patients with thyroglobulin antibodies. Patients and methods: We retrospectively reviewed the data of 212 consecutive differentiated thyroid cancer patients with thyroglobulin antibodies referred to us between 2005 and 2007 for performing a diagnostic whole body scan. All patients were evaluated during the first two years after the initial treatment. Results: Diagnostic whole body scan sensitivity and specificity in detecting persistent diseases were 70% and 72%, respectively. Diagnostic whole body scan alone had the best positive and negative predictive values (93% and 32%, respectively). A low sensitivity and specificity (56% and 10%, respectively) for increasing or stable thyroglobulin antibodies titer trends were also identified. A good compromise between sensitivity and specificity was obtained when diagnostic whole body scan, stimulated thyroglobulin and neck ultrasound were combined without considering thyroglobulin antibodies trend evaluations (82% and 45%, respectively). Conclusions: Diagnostic whole body scan plays an important role in detecting persistent disease in differentiated thyroid cancer patients with thyroglobulin antibodies, both alone and in association with other methods. However, its low negative predictive value suggests that when a suspicious persistent disease is present, the use of other imaging methods, such as computed tomography scan or FDG-positron emission computed tomography, is recommended. Finally, from this study, it appears that the thyroglobulin antibodies titer trend does not add any useful information about the disease status in the first two years after initial treatment

Ophthalmologic evaluation of severely obese patients undergoing bariatric surgery: A pilot, monocentric, prospective, open-label study

PURPOSE: The aim of this study was to investigate the pathogenic role of obesity on blinding eye diseases in a population of severely obese patients with no history of eye diseases, and to verify whether weight loss induced by bariatric surgery may have a protective effect. METHODS: This was a pilot, monocentric, prospective, and open label study conducted at the University Hospital of Pisa. Fifty-seven severely obese patients with a mean body mass index value of 44.1 ± 6 kg/m2 were consecutively recruited and received a complete ophthalmological evaluation and optical coherence tomography. Twenty-nine patients who underwent gastric bypass were evaluated also 3 months, and 1 year after surgery. RESULTS: At baseline, blood pressure value were directly and significantly related to intraocular pressure values (p&lt;0.05, R = 0.35). Blood pressure values were also significantly and inversely related to retinal nerve fiber layer thickness, particularly in the temporal sector (RE p&lt;0.05 r-0.30; LE p&lt;0.01, R = -0.43). Moreover, minimum foveal thickness values were significantly and inversely associated with body mass index (RE p&lt;0.02, R = -0.40; LE p&lt;0.02, R = -0.30). A significant reduction of body mass index (p&lt;0.05) and a significant (p&lt;0.05) improvement of blood pressure was observed three months and one year after gastric bypass, which were significantly associated with an increase in retinal nerve fiber layer thickness and minimum foveal thickness values in both eyes (p&lt;0.05). CONCLUSIONS: The results of this study suggest that obese patients may have a greater susceptibility to develop glaucomatous optic nerve head damage and age-related macular degeneration. Moreover, weight reduction and improvement of comorbidities obtained by bariatric surgery may be effective in preventing eye disease development by improving retinal nerve fiber layer and foveal thickness

Sweat Rate Monitoring During Maximal Exercise in Healthy Soccer Players: A Close Relationship with Anaerobic Threshold

Purpose: Sweating is a homeostatic phenomenon regulated by both thermal and non-thermal factors during exercise. There are no evidences whether anaerobic metabolism induced during isotonic maximal exercise can modify sweating rate. Aim of the study was to investigate the relationship between sweating and the anaerobic threshold (AT). Methods: The sweat rate in thirteen soccer players was measured by a sensor providing a continuous monitoring of sweating, whereas the anaerobic threshold was assessed with ergospirometry during maximal isotonic stress test. During stress test, cardio respiratory, metabolic and galvanic skin response (GSR) were also monitored. Results: At AT, stroke volume, heart rate and systolic blood pressure significantly increased (p<0.001), as well as GSR (p=0.04). Sweat rate abruptly increased at AT compared with rest (p<0.001). AT-to-rest changes in sweating rate were associated with concomitant changes in VO2 max (r=0.82, p<0.001), heart rate (r=0.73, p=0.04) and GSR (r=0.79, p=0.001). Conclusion: We suggest that aerobic-to-anaerobic switch is associated with a sudden increase in sweating likely induced by sympathetic activation. Considering the role of hydration in preserving the health status and optimizing the physical performance, we believe that this finding may have relevant practical implication in particular in soccer, which is characterized by an alternation of aerobic and anaerobic phases