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Trial registered on ANZCTR

Registration number

ACTRN12618000819224

Ethics application status

Approved

Date submitted

9/05/2018

Date registered

14/05/2018

Date last updated

14/05/2018

Type of registration

Retrospectively registered

Titles & IDs

Public title

Effects of mechanical vibration on tremor in Essential Tremor patients

Scientific title

Assessment of tremor evolution in 18 Essential Tremor patients when mechanical afferent stimulation is applied.

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Essential Tremor

Condition category

Condition code

Neurological

Other neurological disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

- Brief name.
Effects of mechanical afferent stimulation on tremor in Essential Tremor patients

- Materials.
In order to apply mechanical afferent stimuli and assess the ongoing tremor in patients, a device was designed and built which is able to deliver vibratory stimuli with different frequencies to the forearm and the hand and simultaneously record the movement of the wrist. Vibratory stimuli were delivered using piezoelectric actuators (model QP-10W, for the fingertips; PPA-4011 for the hand; PPA-1022 for the forearm; all from Mide Technology, US), which were controlled at 5 kHz through piezoelectric haptic drivers (DRV8662, Texas Instruments, US) via a data acquisition card (DAQ) (NI USB 6003, National Instrument, US) connected to a consumer laptop. The amplitude of the mechanical vibration was left constant during the experiment, and set to the maximum. Wrist movement was monitored at 100 Hz using inertial sensors (TechMCS, Technaid, SP).

- Procedures
The experiments are performed in the arm most affected by tremor, which is identified by a neurologist at the beginning of the experimental session. During the experiments, patients are comfortably seated in front of a desk. Piezoelectric actuators were located over the fingertips, the hand and the forearm, the areas where Pacinian corpuscle density is higher (Bruce Goldstein, 2010). To measure wrist movement, inertial sensors are strapped to the dorsal side of the hand and forearm. Patients perform a standard postural task, while their proximal arm rests on a purposely-built support which not constrain hand or forearm movements. The support decreases muscle fatigue and ensures repeatability across trials. During the trials, patients are instructed to hold the arm, forearm and hand outstretched against gravity, to trigger their tremor.
The experimental protocol consists of four 4-min trials in which different stimulation strategies are applied. These trials are interleaved with 10 min long resting periods. The experimental session lasts for ~90 minutes.
1. Stimulation at 50 Hz: vibration was delivered at 50 Hz, a frequency which should minimally recruit Pacinian corpuscles.
2. Stimulation at 250 Hz stimulation: vibration was delivered at 250 Hz, a frequency which should maximally recruit Pacinian corpuscles.
3. Increasing stimulation frequency: vibration was delivered in 50 Hz steps (increasingly, from 50Hz to 450Hz); each frequency was applied during 13.33 s. This trial was designed to test the frequency-dependency of the stimulation.
4. Random stimulation frequency: vibration was delivered at the same frequencies as during the IncreasingFreq trials, but their order was randomized; each frequency was again applied during 13.33 seconds. This trial was designed any potential adaptation to the stimulation from the frequency-dependent effects.
These trials are divided into four 60 s epochs: during the first epoch (Pre-stim) the patient’s basal tremor is assessed; during epochs 2 and 3 (Stim1 and Stim2), we apply vibratory stimuli as defined by the corresponding strategy; during the last epoch (Post-stim), the tremor is assessed to detect potential after-effects.

- Intervention providers
A neurologist and an engineer are present during the trials. The first is responsible of assessing the basal tremor of the patient and evaluating his/her state while the stimulation is applied. The engineer is responsible of managing the device and recording the data.
Both researchers monitor fidelity to the intervention by direct supervision.

- Modes of delivery
The protocol is provided to one participant at a time. Each patient completes the protocol once.

- Location
Hospital Universitario 12 de Octubre (Madrid, Spain)

- Tailoring and modifications
The protocol remains unaltered across applications. The only adaptation to patients is the choice of the arm most affected by tremor.

Intervention code [1]

Treatment: Devices

Comparator / control treatment

The patients act as their own control. The amplitude of the basal tremor is assessed during 240 seconds, 10 minutes prior to trial 1. In addition, previously to each application of afferent stimulation, 60 seconds of the ongoing tremor is also measured.

Control group

Active

Outcomes

Primary outcome [1]

Tremor amplitude is measured using Inertial Sensors (sample frequency of 100Hz).

Timepoint [1]

This outcome is assessed continuously throughout the 4-min that each trial lasts.

Secondary outcome [1]

No secondary outcomes are measured

Timepoint [1]

Not applicable

Eligibility

Key inclusion criteria

Patients that had been diagnosed as having Essential Tremor

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1) Having a pacemaker implanted
2) Having a deep brain stimulator implanted
3) Previous history of epilepsy
4) Head trauma
5) Stroke

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Who is / are masked / blinded?

Intervention assignment

Crossover

Other design features

Phase

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

1/04/2014

Date of last participant enrolment

Anticipated

Actual

1/06/2017

Date of last data collection

Anticipated

Actual

30/06/2017

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

Spain

State/province [1]

Madrid

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Spanish Ministry of Economy, Industry and Competitiveness

Address [1]

Pº. de la Castellana, 162. 28046-Madrid.

Country [1]

Spain

Primary sponsor type

Government body

Name

Centre for Automation and Robotics, Spanish National Research Council

Address

Ctra. M300 Campo Real, Km 0,200
Arganda del Rey - 28500 Madrid

Country

Spain

Secondary sponsor category [1]

Hospital

Name [1]

University Hospital 12 de Octubre

Address [1]

Avda. de Córdoba, s/n. 28041. Madrid

Country [1]

Spain

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Local Ethical Committee of the “Hospital Universitario 12 de Octubre”

Ethics committee address [1]

Avda. de Córdoba, s/n. 28041. Madrid

Ethics committee country [1]

Spain

Date submitted for ethics approval [1]

Approval date [1]

25/02/2014

Ethics approval number [1]

NºCEIC: 14/041

Summary

Brief summary

Background and study aims
Essential tremor (ET) is one of the most prevalent movement disorders in adults, affecting approximately 5% of people over age 65. ET manifests as a bilateral, largely symmetric postural or kinetic tremor involving the hands and forearms, and is often accompanied by head tremor. Importantly, even though as many as 75% of ET patients report significant disability, tremor is only effectively managed in 50% of all patients. Therefore, there is an important need to develop new treatments for ET.  
Tremor in ET is thought to originate because of the projection of pathological oscillations in cerebello-thalamo-cortical pathways to the motoneurons innervating the affected muscles (Helmich et al., 2013), although its exact mechanisms remain elusive. A classic hypothesis proposes that the inferior olivary nucleus is the ultimate cause of tremor in ET, due to abnormal oscillations in the olivo-cerebellar pathways that are transmitted to thalamo-cortical circuits(Deuschl and Elble, 2000).
Mechanoreceptors, including Pacinian and Meissner corpuscles, are sensitive to vibratory stimuli. Sensory responses from both types of receptors are projected to the ipsilateral cuneate nucleus(Douglas et al., 1978), which has important projections to the thalamus and the inferior olivary nucleus (Douglas et al., 1978; Geborek et al., 2012), and therefore may provide a pathway to modulate the circuits that mediate tremor in ET. For example, direct stimulation of the cuneate nucleus has inhibitory effects on cerebellar activity in decerebrated cats(Geborek et al., 2012). 
Our hypothesis is that vibration would recruit Pacinian corpuscles and thus modulate the abnormal activity in tremor-related pathways, which would in turn reduce the tremor.

Who can participate?
Patients aged over 18, males and females, who have been diagnosed as having Essential Tremor.

What does the study involve?
All the participants complete five 4-min trials. During the first, we measure the tremor amplitude without stimulating the patients. Trials 2-5 comprised a 1-min epoch during which we do not apply any stimulation, followed by a 2-min epoch in which we apply different kinds of stimulation strategies, which vary in the frequency of the vibration applied; trials end with a 1-min epoch in which we only measure the evolution of the tremor.

What are the possible benefits and risks of participating?
Participants may reduce their tremor amplitude when we apply the vibratory stimulation. There is no side effects of the experiment.

Where is the study run from?
Hospital Universitario 12 de Octubre (Madrid, Spain)

When is the study starting and how long is it expected to run for?
February 2016 to June 2017

Who is funding the study?
Ministry of Economy and Competitiveness (Spain)

Who is the main contact?
Dr Eduardo Racon
e.rocon@csic.es

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Eduardo Rocon

Address

Centre for Automation and Robotics.
Ctra. Campo Real Km 0,2. 28500.
Arganda del Rey. Madrid.

Country

Spain

Phone

+34 91 8711900

Fax

e.rocon@csic.es

Contact person for public queries

Name

Eduardo Rocon

Address

Centre for Automation and Robotics.
Ctra. Campo Real Km 0,2. 28500.
Arganda del Rey. Madrid.

Country

Spain

Phone

+34 91 8711900

Fax

e.rocon@csic.es

Contact person for scientific queries

Name

Julio Lora

Address

Centre for Automation and Robotics.
Ctra. Campo Real Km 0,2. 28500.
Arganda del Rey. Madrid.

Country

Spain

Phone

+34 91 8711900

Fax

julio.lora@csic.es

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

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Documents added automatically

No additional documents have been identified.

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