The purpose of this clinical trial is to investigate on different types of patients the effects of 10 sessions of whole-body cryostimulation (WBC): 1) in patients with obesity (BMI > 30), we want to investigate whether WBC increases thermogenesis, basal metabolic rate (BMR), respiratory quotient (which indirectly provides an estimate of energy substrate oxidation), reduces chronic inflammatory status, fatigue and pain, and improves functional abilities and general physical and psychological capacities; 2) in patients diagnosed with fibromyalgia and/or osteoarthrytis, we want to investigate the reduction of pain, inflammatory status, increase in functional capacity and general physical and psychological abilities, and improvement in mood; 3) in neurological patients diagnosed with Parkinson's disease, Multiple Sclerosis, and Disimmune Polyneuropathies, the effects of WBC on pain, fatigue, and sleep quality are to be investigated; 4) in normal/overweight (BMI<30 kg/m2) subjects, the effects of WBC on all parameters described previously for the other protocols are to be investigated. Specifically, for all enrolled subjects, we want to assess blood catecholamine levels, investigate the effects of sympathetic response on body composition, blood pressure, heart rate, lipid profile, and physical performance. Three hundred patients admitted for a rehabilitation program (diet + physiotherapy + exercise) will be non-randomly assigned to either a group following the program (R) or a group additionally receiving ten 2-3 minute WBC sessions at -110°C over two weeks (RWBC).

Introduction: Istituto Auxologico Italiano (IAI) has as its institutional mission the study, treatment and rehabilitation of patients with obesity and neurological disorders as well as translational research from bench to bedside to improve these care pathways. The validation of innovative therapeutic modalities of proven efficacy on these patients, potentially scalable to the health care system, is a signature activity of the Institute's Current Research program. IAI in Piancavallo admits 3300 rehabilitation patients with comorbid obesity, including fibromyalgia, and 480 with neurological conditions each year. Pain, chronic fatigue, poor sleep quality, inflammatory status, thymic tone deflection, and obesity have a negative impact on rehabilitation treatment. Whole-body Cryostimulation (WBC) represents an innovative method that induces increased thermogenesis by promoting weight loss, reduced inflammation and oxidative stress with therapeutic effect on fatigue, pain, thymic tone and sleep (Polish Cryomedical Society, Polish Society for Rheumatology). Exposure to cryogenic temperatures would cause activation of the sympathetic system and thus an increase in catecholamine levels, which would stimulate excess adipose tissue to convert from white, metabolically inert tissue to brown, i.e., metabolically active adipose tissue. In fact, it has been previously reported that repeated exposure to WBC reduces inflammation and oxidation, improving immunity, antioxidant activity, and insulin sensitivity, and increasing the percentage of brown adipose tissue (BAT) volume and fatty acid utilization by decreasing the percentage of adipose tissue. This would be reflected in increased tolerance to rehabilitation treatment, improved neuro-cognitive performance and psychological state. The metabolic effect of repeated cold exposure with WBC (browning of adipose tissue and increased thermogenesis) would allow, within multidisciplinary rehabilitation pathways, a better weight loss goal for functional recovery and disease progression in patients with obesity. Since the changes demonstrated at the molecular level after WBC are similar to those induced by exercise, WBC treatment would represent a potential alternative to exercise that is often poorly tolerated in patients with complicated metabolic diseases and disabling neurological conditions and thus a complementary innovative nonpharmacological rehabilitation strategy within a rehabilitation pathway.

Participants: Using a consecutive sampling technique, the investigators will recruit patients for a comprehensive, multidisciplinary rehabilitation program for obesity. Patients of both sex, age 18-65 years with BMI > 35 kg/m2 will be selected and consecutively evaluated for inclusion in the protocol. Exclusion criteria are: severe psychiatric conditions, acute respiratory disease, acute cardiovascular disease, unstable hypertension, cold intolerance, claustrophobia, pregnancy, recent modification of usual drug treatment, previous treatment with WBC, weight loss in the last 3 months, and body temperature greater than 37.5°C. All patients will perform a multidisciplinary rehabilitation program (diet + exercise and physiotherapy).

Study design: Patients will be assigned to either a "rehabilitation + WBC" (RWBC) or "rehabilitation" intervention (R) group in a consecutive, non-randomized manner until the total sample for each group is reached (15 subjects per group).

Anthropometric values, body composition, plasma catecholamine concentration, demographic and hematological analyses, muscle strength and functional values of both groups will be assessed at admission (PRE-T0) and at discharge (POST-T10), two weeks later, for both groups within the hospital facility. They will undergo 10 sessions of WBC over two weeks (1 treatment per day, Monday through Friday, before exercise classes and physical therapy). Skin temperatures will be recorded immediately before and after each WBC exposure. Description of the WBC session: Study participants will be exposed to extremely cold, dry air at -110°C for 2-3 minutes in a cryochamber (Artic, CryoScience, Rome. The first WBC session will last 1 minute at -110°C to familiarize the patient with the cryochamber temperature, while all subsequent treatments will last 2 minutes. The patient's skin surface temperature at the neck, quadriceps, popliteal fossa, and calf will be measured before and after each treatment. The operator supervising the procedure will be in constant visual and vocal contact with the subjects. For safety reasons, the systolic and diastolic blood pressure of each participant will be measured before and after treatment.

Rehabilitation program: The multidisciplinary rehabilitation program will consist of individual nutritional intervention, psychological support, and supervised physical activity throughout hospitalization. All patients will receive a balanced hypocaloric Mediterranean diet with 18-20 % proteins, 27-30 % fats (of which < 8% saturated fat) and 50-55 % carbohydrates (< 15% simple sugars), and 30 g of fibers from fresh vegetables. The diet plan will be organized by the hospital dietitian into three meals: breakfast, lunch, and dinner, with an energy distribution of 20 %, 40 % and 40 %, respectively. Two daily 60-minute physiotherapy sessions consisting of personalized progressive aerobic training, postural control exercises and progressive strengthening exercises were performed under the supervision of a physiotherapist. The first aerobic session performed in the morning after WBC consists of walking at a self-selected cadence. The second session performed in the afternoon consists of arm-cranking at an intensity of 65% of HRmax according to the Karvonen equation ((220 - age) × 0.65).

Measurements. Demographic and clinical characteristics: Baseline demographic and clinical characteristics will be collected at the time of admission and will include age, sex, weight, height and body mass index (BMI).

Body Composition: Body composition will be assessed in the morning in a quiet room at a temperature of 22-25 °C using bioimpedentiometry (BIA) analyzes with the patient in a supine position with lower limbs slightly apart and empty bladder. Whole-body resistance (Rz) and reactance (Xc) will be measured by trained operators and these parameters will be assessed (in Kg and %): fat mass (FM), free fat mass (FFM), muscle mass (MM), appendicular skeletal muscle mass (ASMM).

Skin temperatures: The patient's skin surface temperature (°C) in at the neck,quadriceps, popliteal fossa, and calf will be measured before and after each WBC treatment.

Blood collection and Hematological/Biochemical analyses: Blood samples will be taken in the morning after overnight fasting conditions to determine plasma catecholamine levels (epinephrine, norepinephrine, dopamine, cortisol); red blood cell count (RBC), white blood cell count (WBC), platelet count (PLT), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), and mean platelet volume (MPV), complete blood count derived inflammatory biomarkers (NLR, dNLR, SII, AISI), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), TNF-α, cholesterol, HDL, LDL, glucose, insulin.

Performance-based physical functioning: to measure aerobic endurance, we will use the six-minute walk test (6MWT), performed indoors, along a 30-m, flat, undisturbed hospital corridor, with the length scored every 5 m. Chest pain, severe dyspnea, physical exhaustion, muscle cramps, sudden gait instability or other signs of severe distress are additional criteria for stopping the test. The Timed Up and Go test (TUG) test will be used to assess balance and functional mobility. The participant is asked to stand up from a standard chair, walk for 3 minutes, turn around, return to the chair, and sit down. The score corresponds to the time (seconds) taken to perform the test. Isometric strength will be assessed with the hand grip test using the American Society of Hand Therapists (ASHT) protocol as a reference.

Condition specific questionnaires will be administered to assess:

General health: Short-form health survey-36 (SF-36) and World Health Organization Well-being index (WHO5); pain: visual analogue scale (VAS), pain numeric rating scale (PNRS), brief pain inventory (BPI), central sensitization index (CSI), Promis global health scale, the Quantitative Analgesic Questionnaire (QAQ); fatigue: fatigue severity scale (FSS); sleep: Pittsburgh sleep quality index (PSQI), Promis sleep disturbance short form, Epworth Sleepiness Scale; Fibromyalgia Impact Questionnaire (FIQ) for the evaluation of fibromyalgia; Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) for the evaluation for patients with osteoarthritis; psychological weel-being, mood and depression: Psychological General Well-Being Index (PGWBI); State-Trait Anxiety Inventory (STAI); Depression, Anxiety and Stress Scale - 21 Items (DASS-21); Beck's Depression Inventory (BDI); Fear of movement: Tampa Scale of Kinesiophobia (TSK-I); Intestinal function: Wexner score; obesity-related disability: Test of Obesity-Related Disability (SIO Obesity-Related Disability Test, TSD-OC).

Statistical analysis: A sample of 15 obese adult individuals (BMI>35 Kg/m2, age 18-65 years, both sexes) will be considered for each of the two groups, for a total of 30 individuals. Since there is no a priori data on this and it is a pilot study, the sample size was chosen based on the literature, which suggests considering a minimum number of 12 subjects for pilot studies.

To avoid confounding by BMI and age, patients will be matched for BMI and age to ensure an equal distribution between the groups of the variables believed to be confounding. Patients will not be blinded to study condition assignment.

Inclusion Criteria:

• both sexes
• age 18-65 yrs
• BMI > 35 kg/m2

Exclusion Criteria:

• severe psychiatric conditions
• acute respiratory disease
• acute cardiovascular disease
• unstable hypertension
• cold intolerance
• claustrophobia
• pregnancy
• recent modification of usual drug treatment
• previous treatment with WBC
• weight loss in the last 3 months
• body temperature greater than 37.5°C.