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

Overview

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.

Full Title of Study: “Effects of Feet Mechanical Stimulation on the Inflammatory State and Cardiovascular Autonomic Profile in Patients With Parkinson’s Disease”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Supportive Care
    • Masking: None (Open Label)
  • Study Primary Completion Date: August 2016

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.

Interventions

  • Device: Foot Mechanical Stimulation (Gondola®, CE marking n° 0476)
    • The feet mechanical stimulation will be performed by Gondola (Gondola®, CE marking n° 0476).

Arms, Groups and Cohorts

  • Experimental: Foot Mechanical Stimulation
    • 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.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

  • Changes in Unified Parkinson’s Disease Rating Scale (UDPRS) induced by feet mechanical stimulation.
    • Time Frame: UDPRS will be done at baseline and 16 days from baseline, after 5 feet mechanical stimulation sessions
    • UDPRS will be performed by neurologist
  • Changes in Timed Up and Go induced by feet mechanical stimulation.
    • Time Frame: Timed Up and Go will be evaluated at Baseline, 72 hours and 16 days from baseline after 5 feet stimulation sessions
    • 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)

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 50 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Istituto Clinico Humanitas
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Raffaello Furlan, MD, Study Director, Humanitas Research Hospital, University of Milan
    • Raffaello Furlan, MD, Study Chair, Humanitas Rsearch Hospital, University of Milan
    • Franca Barbic, MD, Principal Investigator, Humanitas Research Hospital; Humanitas University, Rozzano (MI)

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