Effects of Feet Mechanical Stimulation on Cardiovascular Autonomic Profile and Inflammation in Parkinson's Disease

Study Overview
=================
Brief Summary
-----------------
In the present study, investigators test the hypothesis that a controlled mechanical pressure applied on specific sites of both fore-feet (ES) can reduce the inflammatory state and arterial blood pressure in patients with Parkinson's Disease by increasing the overall parasympathetic activity and reducing vascular sympathetic modulation.

Detailed Description
-----------------
Neuroinflammation may contribute to the cascade of events leading to neuronal loss in Parkinson's disease (PD) thus facilitating motor and autonomic impairment. A link between autonomic function and chronic and acute inflammation has been previously described. Specifically, active inflammatory state was associated with an overall increased sympathetic tone, whereas the parasympathetic cholinergic activation seemed to promote a decrease of inflammatory compounds in inflamed tissues. In addition, a functional link between peripheral sensory afferents and autonomic control has been reported. In a recent study it was observed that in PD patients a somatosensory activation by mechanical stimulation of specific sites of the fore-foot (effective stimulus, ES), improved gait, increased cardiac vagal modulation and decreased vascular sympathetic activity at rest. This latter effect was associated with a decline in arterial blood pressure values. The present study is aimed at: Addressing the magnitude of the inflammatory state in PD patients. Testing the hypothesis that a change in the autonomic profile of PD patients induced by ES, consistent with cardiovascular increased parasympathetic and decreased sympathetic activities, may promote an overall reduction of the PD inflammatory state.

Official Title
-----------------
Effects of Feet Mechanical Stimulation on the Inflammatory State and Cardiovascular Autonomic Profile in Patients With Parkinson's Disease

Conditions
-----------------
Parkinson's Disease, Autonomic Neuropathy, Inflammation, Hypertension

Intervention / Treatment
-----------------
* Device: Foot Mechanical Stimulation (Gondola®, CE marking n° 0476)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Idiopathic PD characterized by a moderate/important motor impairment (Hoehn&Yhar scale 2-4) PD will be diagnosed according to the United Kingdom (UK) Parkinson's Disease Society Brain Bank criteria, (or on the basis of clinical criteria, Dopamine Transporter (DAT)- scan and/or MRI). Exclusion Criteria: Dysautonomias and other neurodegenerative diseases History/familiarity with seizures Atrial fibrillation and other relevant cardiac rhythm disturbances Chronic inflammatory diseases and chronic use on anti-inflammatory drugs Diabetes Other neurological or psychiatric diseases Pacemakers or other electronic implants inserted into the body Coronary disorders, elevated intracranial blood pressure Assumption of drugs facilitating seizures, psychiatric drugs, alcohol abuse

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Foot Mechanical Stimulation<br>Intervention: Foot Mechanical Stimulation (FMS) will be performed on enrolled patients every 72 hours (total 5 stimulation sessions) by a pressure-controlled mechanical stimulator (Gondola®, European Community (CE) marking n° 0476) . The sites of the stimulation will be the tip of the hallux and the lower big toe first metatarsal joint plantar surface. The FMS procedure consists in the application of the patient's calibrated pressure for 6 seconds, over the selected sites. Each of the 2 cutaneous sites of both feet will be mechanically stimulated. The procedure will be automatically repeated for 4 times in every subject so that the overall time of stimulation will be approximately 2 minutes. | Device: Foot Mechanical Stimulation (Gondola®, CE marking n° 0476)<br>* The feet mechanical stimulation will be performed by Gondola (Gondola®, CE marking n° 0476).<br>* Other names: Pressure-controlled mechanical stimulator (Gondola®);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes of Pentraxin 3 (PTX3) plasma levels induced by feet mechanical stimulation. | PTX3 as an index of systemic inflammatory profile will be assessed by a developed and optimized ELISA and expressed by ng/ml. | Blood samples will be collected at Baseline, and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of Interleukine-6 (IL-6), plasma levels induced by feet mechanical stimulation. | IL-6 will be tested by commercially available ELISA and immunoturbidimetric assays and expressed by ng/ml. | Blood samples will be collected at Baseline, and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of Tumor Necrosis Factor (TNF) plasma levels induced by feet mechanical stimulation. | TNF will be tested by commercially available ELISA and immunoturbidimetric assays and expressed by ng/ml. | Blood samples will be collected at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of C Reactive Protein (CRP) plasma levels induced by feet mechanical stimulation. | CRP will be tested by commercially available ELISA and immunoturbidimetric assays and expressed by mg/dl. | Blood samples will be collected at Baseline, and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of Heart Rate (HR) values in supine position induced by feet mechanical stimulation. | Mean value of 15 minute-ECG continuous recording in supine position will be used. | HR will be assessed in beats/min at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of Blood Pressure (BP) values in supine position induced by feet mechanical stimulation. | Mean value of 5 measures obtained every 3 minutes by an Automatic-cycling non-invasive blood pressure monitor in supine position will be used. | BP will be assessed in mmHg at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of the index of cardiac vagal modulation (HFRR, High Frequency oscillatory component of R-R interval (RR) variability at  0.25Hz) in supine position induced by feet mechanical stimulation. | HFRR will be obtained by the spectral analysis of R-R interval spontaneous variability in supine position. | HFRR will be assessed in msec2 at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of the index of cardiac sympathetic modulation (LFRR, Low Frequency oscillatory component of R-R interval variability at  0.10 Hz) in supine position induced by feet mechanical stimulation. | LFRR will be obtained by the spectral analysis of R-R interval spontaneous variability in supine position. | LFRR will be assessed in msec2 at baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of the index of cardiac sympatho-vagal modulation (LF/HF)RR in supine position induced by feet mechanical stimulation. | LF/HF is the ratio between LFRR index of cardiac sympathetic modulation and HFRR index of the cardiac vagal modulation obtained by the spectral analysis of R-R interval spontaneous variability. | LF/HF (unit-less value) will be assessed at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of the index of sympathetic modulation to the vessels (LFSAP) in supine position induced by by feet mechanical stimulation. | LFSAP will be quantified by spectral analysis of systolic arterial pressure variability obtained by beat by beat blood pressure non-invasive continuous recording in supine position. | LFSAP will be assessed in mmHg2 at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of plasma Norepinephrine (NE) in supine position induced by feet mechanical stimulation. | Plasma NE will be quantified by High Performance Liquid Chromatography (HPLC) with electrochemical detection (ED) from blood samples collected in supine position | Plasma NE will be assessed in ng/L at baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of plasma Epinephrine (E) in supine position induced by feet mechanical stimulation. | Plasma E will be quantified by High Performance Liquid Chromatography (HPLC) and electrochemical detection (ED) from blood samples collected in supine position | Plasma E will be quantified in ng/L at baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of Heart Rate (HR beats/min) values during 75°head-up tilt induced by feet mechanical stimulation. | The mean value of 15 minute-ECG continuous recording during 75°head-up tilt will be used. | HR will be assessed in beats/min at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of Blood Pressure (BP) values during 75°head-up tilt induced by feet mechanical stimulation. | The mean value of 5 measures obtained every 3 minutes by an automatic-cycling non-invasive blood pressure monitor during 75°head-up tilt will be used. | BP will be assessed in mmHg at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of the index of cardiac vagal modulation (HFRR, High Frequency oscillatory component of R-R interval variability at  0.25Hz) during 75°head-up tilt induced by feet mechanical stimulation. | HFRR will be obtained by the spectral analysis of R-R interval spontaneous variability during 75°head-up tilt. | HFRR will be assessed in (msec2) at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of the index of cardiac sympathetic modulation (LFRR, Low Frequency oscillatory component of R-R interval variability at  0.10 Hz) during 75° head-up tilt induced by feet mechanical stimulation. | LFRR will be obtained by the spectral analysis of R-R interval spontaneous variability during 75° head-up tilt. | LFRR will be assessed in msec2 at baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of the index of cardiac sympatho-vagal modulation (LF/HF)RR during 75°head-up tilt induced by feet mechanical stimulation. | LF/HF will be quantified as a ratio between LFRR index of cardiac sympathetic modulation and HFRR index of the cardiac vagal modulation obtained by the spectral analysis of R-R interval spontaneous variability during 75°head-up tilt. | LF/HF (unit-less value) will be assessed at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of the index of sympathetic modulation to the vessels (LFSAP , mmHg2) during 75°head-up tilt induced by feet mechanical stimulation. | LFSAP expressed will be quantified by spectral analysis of systolic arterial pressure variability obtained by beat by beat blood pressure non-invasive continuous recording during 75°head-up tilt. | LFSAP will be assessed in mmHg2 at Baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of plasma Norepinephrine (NE) during 75°head-up tilt induced by feet mechanical stimulation. | Plasma NE will be evaluated by High Performance Liquid Chromatography (HPLC) with electrochemical detection (ED) from blood samples collected after 5 minutes of 75°head-up tilt. | Plasma NE will be quantified in ng/L at baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 
| Changes of plasmatic Epinephrine (E) during 75°head-up tilt induced by feet mechanical stimulation. | Plasma E will be evaluated by High Performance Liquid Chromatography (HPLC) and electrochemical detection (ED) from blood samples collected after 5 minutes lasting 75°head-up tilt. | Plasma E will be quantified in ng/L at baseline and 16 days from baseline (after 5 feet mechanical stimulation sessions). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Unified Parkinson's Disease Rating Scale (UDPRS) induced by feet mechanical stimulation. | UDPRS will be performed by neurologist | UDPRS will be done at baseline and 16 days from baseline, after 5 feet mechanical stimulation sessions | 
| Changes in Timed Up and Go induced by feet mechanical stimulation. | Timed Up and Go test will be performed before and after the feet mechanical stimulations at baseline,72 hours and 16 days from baseline (i.e. after 5 stimulations) | Timed Up and Go will be evaluated at Baseline, 72 hours and 16 days from baseline after 5 feet stimulation sessions | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Inflammation, Foot mechanical stimulation, Autonomic nervous system, Parkinson's disease, Spectral analysis, Heart rate variability, Blood pressure variability