Nonlinear and factorization methods for the non-invasive investigation of the central nervous system

This thesis focuses on the functional study of the Central Nervous System (CNS) with non-invasive techniques. Two different aspects are investigated: nonlinear aspects of the cerebrovascular system, and the muscle synergies model for motor control strategies. The main objective is to propose novel protocols, post-processing procedures or indices to enhance the analysis of cerebrovascular system and human motion analysis with noninvasive devices or wearable sensors in clinics and rehabilitation. We investigated cerebrovascular system with Near-infrared Spectroscopy (NIRS), a technique measuring blood oxygenation at the level of microcirculation, whose modification reflects cerebrovascular response to neuronal activation. NIRS signal was analyzed with nonlinear methods, because some physiological systems, such as neurovascular coupling, are characterized by nonlinearity. We adopted Empirical Mode Decomposition (EMD) to decompose signal into a finite number of simple functions, called Intrinsic Mode Functions (IMF). For each IMF, we computed entropy-based features to characterize signal complexity and variability. Nonlinear features of the cerebrovascular response were employed to characterize two treatments. Firstly, we administered a psychotherapy called eye movement desensitization and reprocessing (EMDR) to two groups of patients. The first group performed therapy with eye movements, the second without. NIRS analysis with EMD and entropy-based features revealed a different cerebrovascular pattern between the two groups, that may indicate the efficacy of the psychotherapy when administered with eye movements. Secondly, we administered ozone autohemotherapy to two groups of subjects: a control group of healthy subjects and a group of patients suffering by multiple sclerosis (MS). We monitored the microcirculation with NIRS from oxygen-ozone injection up 1.5 hours after therapy, and 24 hours after therapy. We observed that, after 1.5 hours after the ozonetherapy, oxygenation levels improved in both groups, that may indicate that ozonetherapy reduced oxidative stress level in MS patients. Furthermore, we observed that, after ozonetherapy, autoregulation improved in both groups, and that the beneficial effects of ozonetherapy persisted up to 24 hours after the treatment in MS patients. Due to the complexity of musculoskeletal system, CNS adopts strategies to efficiently control the execution of motor tasks. A model of motor control are muscle synergies, defined as functional groups of muscles recruited by a unique central command. Human locomotion was the object of investigation, due to its importance for daily life and the cyclicity of the movement. Firstly, by exploiting features provided from statistical gait analysis, we investigated consistency of muscle synergies. We demonstrated that synergies are highly repeatable within-subjects, reinforcing the hypothesis of modular control in motor performance. Secondly, in locomotion, we distinguish principal from secondary activations of electromyography. Principal activations are necessary for the generation of the movement. Secondary activations generate supplement movements, for instance slight balance correction. We investigated the difference in the motor control strategies underlying muscle synergies of principal (PS) and secondary (SS) activations. We found that PS are constituted by a few modules with many muscles each, whereas SS are described by more modules than PS with one or two muscles each. Furthermore, amplitude of activation signals of PS is higher than SS. Finally, muscle synergies were adopted to investigate the efficacy of rehabilitation of stiffed-leg walking in lower back pain (LBP). We recruited a group of patients suffering from non-specific LBP stiffening the leg at initial contact. Muscle synergies during gait were extracted before and after rehabilitation. Our results showed that muscles recruitment and consistency of synergies improved after the treatment, showing that the rehabilitation may affect motor control strategies

Evaluation of muscle synergies stability in human locomotion: A comparison between normal and fast walking speed

Motor control strategies can be described by muscle synergies, a model of functional muscle recruitment to perform a movement. However, stability of muscle synergies during locomotion has not yet been investigated. The objective of this work was the evaluation of the stability of muscle synergies while walking at normal (NS) and fast (FS) speed. Each walking condition was tested during a prolonged session lasting 5 minutes on five healthy subjects. After data processing with statistical gait analysis, 168±29 valid strides in NS and 181±48 in FS were obtained. They were aggregated in subgroups, with 10 strides each. Muscle synergies were extracted for all subgroups with non-negative matrix factorization. On the average, 6 synergies were suitable to reconstruct the original electromyographic signal. They were functionally correlated to the activities of propulsion, trunk stability, limb deceleration at the end of swing, forefoot control, and limb stiffening for initial contact stability. To compare muscle synergy stability over time, a similarity measurement was carried out. This showed that from 1 to 3 synergies were unstable in NS. As for the FS condition, only one subject showed unstable synergies, corresponding to the hip stabilizing synergy

The speed of reinfusion affects the vascular system during ozone major autohemotherapy

Ozone major autohemotherapy (O-MAHT) is a way of ozonetherapy administration consisting of drawing patient’s venous blood, mixing with oxygen/ozone, and reinfusing it into the vein. Some ozone therapists reported side effects during the O-MAHT, but the origin has not been described yet. We investigated the effect of blood drawing velocity during O-MAHT to see its effects on the vascular system and symptomatology. We administered O-MAHT to 11 subjects, and we interleaved fast and slow reinfusions. We monitored cerebral macrocirculation with transcranial Doppler (TCD) and tissue microcirculation with near-infrared spectroscopy (NIRS). Annoying symptoms appeared just during the fast reinfusion periods. NIRS and TCD parameters revealed vasoconstriction during fast reinfusion and improved metabolism during slow reinfusion. Overall, our investigation well discriminated fast from slow reinfusion velocity

Clinical Features to Predict the Use of a sEMG Wearable Device (REMO®) for Hand Motor Training of Stroke Patients: A Cross-Sectional Cohort Study

After stroke, upper limb motor impairment is one of the most common consequences that compromises the level of the autonomy of patients. In a neurorehabilitation setting, the implementation of wearable sensors provides new possibilities for enhancing hand motor recovery. In our study, we tested an innovative wearable (REMO®) that detected the residual surface-electromyography of forearm muscles to control a rehabilitative PC interface. The aim of this study was to define the clinical features of stroke survivors able to perform ten, five, or no hand movements for rehabilitation training. 117 stroke patients were tested: 65% of patients were able to control ten movements, 19% of patients could control nine to one movement, and 16% could control no movements. Results indicated that mild upper limb motor impairment (Fugl-Meyer Upper Extremity 18 points) predicted the control of ten movements and no flexor carpi muscle spasticity predicted the control of five movements. Finally, severe impairment of upper limb motor function (Fugl-Meyer Upper Extremity > 10 points) combined with no pain and no restrictions of upper limb joints predicted the control of at least one movement. In conclusion, the residual motor function, pain and joints restriction, and spasticity at the upper limb are the most important clinical features to use for a wearable REMO® for hand rehabilitation training

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data

Background: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real-world setting.Methods: The analysed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 17 Italian centres. The primary endpoint of the study was progression-free survival (PFS), whereas secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model.Results: From February 2022 to November 2022, 145 patients were enrolled. After a median follow-up of 8.5 months (95% CI: 7.9-13.6), the median PFS was 8.9 months (95% CI: 7.4-11.7). Median OS was 12.9 months (95% CI: 10.9-12.9). The investigator-assessed confirmed ORR was 34.5%, and the disease control rate was 87.6%. Any grade adverse events (AEs) occurred in 137 patients (94.5%). Grades 3-4 AEs occurred in 51 patients (35.2%). The rate of immune-mediated AEs (imAEs) was 22.7%. Grades 3-4 imAEs occurred in 2.1% of the patients. In univariate analysis, non-viral aetiology, ECOG PS >0 and NLR >= 3 correlated with shorter PFS.Conclusion: The results reported in this first real-world analysis mostly confirmed the results achieved in the TOPAZ-1 trial in terms of PFS, ORR and safety

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research