Sensory-specific Peripheral Stimulation for Tremor Management

Sponsor

Shirley Ryan AbilityLab (Other)

Overall Status

Recruiting

CT.gov ID

NCT04501133

Collaborator

Northwestern University (Other)

100

Enrollment

Location

Arms

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to understand the neurophysiological mechanisms of peripheral electrical stimulation (PES) in modulating supraspinal tremorogenic input to motoneurons. For this purpose, the investigators will use transcutaneous PES, high-density electromyography (HD-EMG), transcranial magnetic stimulation (TMS), electroencephalography (EEG), magnetic resonance imaging (MRI), and neuromusculoskeletal modelling. This study will be carried out in both healthy participants and patients with essential tremor (ET) and Parkinson's disease (PD).

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease Essential Tremor	Device: Peripheral electrical stimulation Device: Single pulse TMS	N/A

Detailed Description

In Experiment A, the investigators will recruit healthy participants without motor disorders and medications influencing brain function (n = 25). The investigators will characterize inhibition of wrist flexors/wrist extensors and first dorsal interossei (FDI) and abductor pollicis brevis (APB) muscles with PES, and also use TMS to stimulate the corresponding areas in the brain and see if the movement can be reduced through PES. HD-EMG will be used to collect data and identify associated motor unit spike trains. Motor-evoked potentials (MEPs) will be recorded with EMG when TMS is targeted to the primary motor cortex. Resting state functional magnetic imaging resonance (rs-fMRI) and high-angular resolution diffusion imaging (HARDI) tractography of the brain will be recorded.

In Experiment B, the investigators will recruit patients with essential tremor (ET) and/or Parkinson's disease (PD) (n = 25 for each pathology). The investigators will repeat the same characterization of inhibition of wrist flexors/wrist extensors and PDI/APB with PES and also use TMS to stimulate corresponding areas in the brain. Additionally, the investigators will test PES conditions as a tremor reduction strategy at the wrist level. The investigators will also test PES conditions at the elbow and shoulder joints as a tremor reduction strategy. Finally, the investigators will observe and characterize the long-term effects (lasting 24h, 48h, and 7 days post stimulation) of PES via coherence between HD-EMG and EEG at the tremor frequency.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

The purpose of this study is to understand how motor activation can be reduced. For this purpose, it will be examined how some muscles of the arm respond to electric and magnetic stimulation. The effects of the electric and/or magnetic stimulation will be recorded non-invasively with HD-EMG.The purpose of this study is to understand how motor activation can be reduced. For this purpose, it will be examined how some muscles of the arm respond to electric and magnetic stimulation. The effects of the electric and/or magnetic stimulation will be recorded non-invasively with HD-EMG.

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Sensory-specific Peripheral Stimulation for Tremor Management

Actual Study Start Date :

Sep 1, 2020

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Healthy Participants Healthy participants without motor disorders and medications influencing brain functions will be scanned with MRI and undergo PES and/or single pulse TMS during several visits, each with different stimulation patterns, while HD-EMG is recorded.	Device: Peripheral electrical stimulation Electrical stimulation will be delivered to forearm muscles with an electrical stimulator (Digitimer Ltd., Hertfordshire, UK) so that they generate forces opposed to those arising from the tremorgenic input. Device: Single pulse TMS Single-pulse TMS (spTMS) will be delivered with a TMS stimulator (MagPro X100 w/ MagOption, MagVenture, Farum, Denmark) and a figure-of-eight TMS coil. An MRI-based TMS navigation system will be used to navigate the TMS coil (Localite, St Augustin, Germany).
Experimental: Patients Participants with Parkinson's Disease or essential tremor will be scanned with MRI and undergo PES and/or single pulse TMS during several visits, each with different stimulation patterns, while HD-EMG and EEG are recorded.	Device: Peripheral electrical stimulation Electrical stimulation will be delivered to forearm muscles with an electrical stimulator (Digitimer Ltd., Hertfordshire, UK) so that they generate forces opposed to those arising from the tremorgenic input. Device: Single pulse TMS Single-pulse TMS (spTMS) will be delivered with a TMS stimulator (MagPro X100 w/ MagOption, MagVenture, Farum, Denmark) and a figure-of-eight TMS coil. An MRI-based TMS navigation system will be used to navigate the TMS coil (Localite, St Augustin, Germany).

Arm

Intervention/Treatment

Experimental: Healthy Participants

Healthy participants without motor disorders and medications influencing brain functions will be scanned with MRI and undergo PES and/or single pulse TMS during several visits, each with different stimulation patterns, while HD-EMG is recorded.

Device: Peripheral electrical stimulation

Electrical stimulation will be delivered to forearm muscles with an electrical stimulator (Digitimer Ltd., Hertfordshire, UK) so that they generate forces opposed to those arising from the tremorgenic input.

Device: Single pulse TMS

Single-pulse TMS (spTMS) will be delivered with a TMS stimulator (MagPro X100 w/ MagOption, MagVenture, Farum, Denmark) and a figure-of-eight TMS coil. An MRI-based TMS navigation system will be used to navigate the TMS coil (Localite, St Augustin, Germany).

Experimental: Patients

Participants with Parkinson's Disease or essential tremor will be scanned with MRI and undergo PES and/or single pulse TMS during several visits, each with different stimulation patterns, while HD-EMG and EEG are recorded.

Device: Peripheral electrical stimulation

Device: Single pulse TMS

Outcome Measures

Primary Outcome Measures

Changes in Amount of Motor Inhibition [Experiment A: Short-term: before vs. during and at 1 minute after PES. Experiment B: Short-term: before vs. during and at 1 minute after PES. Long-term: persistence of changes at post 24 hours, post 48 hours, and post 1 week after PES.]
HD-EMG will be recorded with a 64-channel device (EMG-Quattrocento; 400-channel EMG amplifier, OT Bioelettronica, Italy). The HD-EMG data will be recorded at the wrist level before, during and after muscle contractions. All data will be analyzed offline. Changes in the amount of inhibition will be assessed. The amount of inhibition is calculated as the mean discharge rate across trials and normalized as a percentage of the baseline (100%). To assess the short-term effects, HD-EMG data will be collected before (baseline), during and 1 minute (Post) after PES. Changes in amount of motor inhibition will be measured by comparing the amount of inhibition before (baseline), during and 1 minute after PES (Post). To assess long-term effects, HD-EMG data will be collected at post 24h, post 48h, and post 1 week after PES. The amount of inhibition at 24h, 48h, and 1 week after PES will be compared with the baseline amount of inhibition (before PES).
Changes in motor evoked potentials (MEPs) [Experiment A: Short-term: before vs. during and at 5 minutes after PES. Experiment B: Short-term: before vs. during and at 5 minutes after PES. Long-term: persistence of changes at post 24 hours, post 48 hours, and post 1 week after PES.]
To assess the effects of electrical stimulation in motor inhibition, single-pulse TMS will be administered to the contralateral area of the brain while MEPs are recorded from the contralateral site (EMG-Quattrocento; 400-channel EMG amplifier, OT Bioelettronica, Italy). The mean peak-to peak MEP amplitude will be calculated to assess changes in inhibition. To assess the short-term effects, MEP data will be collected before (baseline), during and 5 minutes (Post) after PES. Changes in MEPs will be measured by comparing the MEPs before (baseline), during and 1 minute after PES (Post). To assess long-term effects, MEP data will be collected at post 24h, post 48h, and post 1 week after PES. The MEPs at 24h, 48h, and 1 week after PES will be compared with the baseline MEPs (before PES).
Changes in cortico-muscular coherence in ET and/or PD participants [Experiment A: N/A. Experiment B: Short-term effects, within sessions (before vs. 1 minute after PES. Long-term effects, across sessions (persistence of changes at post 24 hours, post 48 hours, and post 1 week after PES).]
EEG will be recorded with a 64-channel whole-head device (NeurOne, Bittium, Kuopio, Finland) and HD-EMG with a 64-channels system (EMG-Quattrocento; 400-channel EMG amplifier, OT Bioelettronica, Italy). The coherence between EEG and HD-EMG signals will be computed to assess supraspinal and spinal inhibition. To assess the short- term effects, EEG and HD-EMG data will be collected before (Pre) and 1 minute (Post) after PES. Changes in cortico-muscular coherence will be measured by comparing the cortico-muscular coherence before (baseline) and 1 minute after PES (Post). To assess long-term effects, EEG and HD-EMG data will be collected at post 24h, post 48h, and post 1 week after PES. The cortico-muscular coherence at 24h, 48h, and 1 week after PES will be compared with the baseline cortico-muscular coherence (before PES).
Changes in kinematics [Experiment A: N/A. Experiment B: Short-term effects, within sessions (before vs. 1 minute after PES). Long-term effects, across sessions (persistence of changes at post 24 hours, post 48 hours, and post 1 week after PES).]
Tremor amplitude will be measured with inertial measurement units that quantify variations in wrist angles during tremor. Specifically, the tremor amplitude will be calculated as the mean peak-to-peak amplitude between maximal wrist flexion and wrist extension angles. To assess the short-term effects, tremor amplitude will be collected before (Pre) and 1 minute (Post) after PES. Changes in tremor amplitude will be measured by comparing the tremor amplitude before (baseline) and 1 minute after PES (Post). To assess long-term effects, tremor amplitude will be recorded at post 24h, post 48h, and post 1 week after PES. The tremor amplitude at 24h, 48h, and 1 week after PES will be compared with the baseline tremor amplitude (before PES).

Secondary Outcome Measures

Clinical motor score change [For Experiment A: N/A. For Experiment B: Short-term effects, within sessions (before and after PES). Long-term effects, across sessions (persistence of changes at 24 hours, 48 hours, and 1-week after PES).]
The MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and the Fahn Tolosa Marin (FTM) rating scale are functional scales used by clinicians to assess the functional impairments caused by Parkinson's disease and essential tremor, respectively. The MDS-UPDRS and the FTM scales will be used to assess clinical motor changes induced by the PES. To assess the short-term effects, The MDS-UPDRS or the FTM will be administered before and after PES. Changes in scores will be assessed by comparing the MDS-UPDRS/or FTM scores before (baseline) and after PES (Post). To assess long-term effects, the MDS-UPDRS/or FTM scores will be collected at post 24h, post 48h, and post 1 week after PES. The MDS-UPDRS/or FTM scores at 24h, 48h, and 1 week after PES will be compared with the baseline the MDS-UPDRS/or FTM scores (before PES).
MRI/rs-fMRI connectivity [Experiment A: Baseline and through study completion, an average of 3 months. Experiment B: Baseline and through study completion, an average of 6 months.]
Structural connectivity will be assessed with diffusion tensor imaging (DTI). Functional connectivity will be assessed with resting-state MRI (rs-MRI).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria for Healthy Participants:

Age from 18 to 80 years
No history of a brain and/or skull lesion
Normal hearing and (corrected) vision
Able to understand and give informed consent
No neurological disorders, no tremor
Absence of pathology that could cause abnormal movements of extremities (e.g., epilepsy, stroke, marked arthritis)
Able to understand and speak English

Inclusion Criteria for Patients:

Age from 18 to 80 years
No prior history of skull lesions or craniotomy
Normal hearing and (corrected) vision
Able to understand and give informed consent
Diagnosis of ET (Tremor Research investigation Group criteria) or diagnosis of PD (UK PD Society Brain bank diagnostic criteria) by movement disorder neurologist
Tremor in at least an upper limb with pure flexion-extension wrist tremor with posture (ET) and rest (PD).
Tremor at least moderate-severe by clinician judgment and tremor scales (Fahn Tolosa Marin Tremor Rating Scale, Movement Disorder Society-Unified Parkinson's Disease Rating Scale)
Absence of pathology that could cause abnormal movements of extremities (e.g., epilepsy, stroke, marked arthritis, moderate to severe dyskinesias in PD)
Stable medication doses for at least 30 days prior to study enrollment
Able to understand and speak English

Exclusion Criteria for Healthy Participants:

Cardiac pacemaker or pacemaker wires; neurostimulators; implanted pumps
Metal in the body (rods, plates, screws, shrapnel, dentures, IUD) or metallic particles in the eye
Surgical clips in the head or previous neurosurgery
Any magnetic particles in the body
Cochlear implants
Prosthetic heart valves
Epilepsy or any other type of seizure history
Any neurological diagnoses or medications influencing brain function
History of significant head trauma (i.e., extended loss of consciousness, neurological sequelae)
Known structural brain lesion
Significant other disease (heart disease, malignant tumors, mental disorders)
Significant claustrophobia; Ménière's disease
Pregnancy (ruled out by urine ß-HCG if answers to screening questions suggest that pregnancy is possible), breast feeding
Non prescribed drug use
History of current substance abuse (exception: current nicotine use is allowed)
Recreational marijuana
Tremor, parkinsonism; neurological diseases; medical (cardiological, renal, hepatic, oncological) or psychiatric disease that would interfere with study procedures for asES, HD-EMG, TMS, or EEG
Dementia; severe depression; or prior neurosurgical procedures
Failure to perform the behavioral tasks or neuropsychological evaluation tests
Prisoners

Exclusion Criteria for Patients:

Cardiac pacemaker or pacemaker wires; neurostimulators; implanted pumps
Metal in the body (rods, plates, screws, shrapnel, dentures, IUD) or metallic particles in the eye
Surgical clips or shunts in the head
Any magnetic particles in the body
Cochlear implants
Prosthetic heart valves
Epilepsy or any other type of seizure history
Significant claustrophobia; Ménière's disease
Pregnancy, breast feeding
Medications increasing risk for seizures
History of current substance abuse (exception: current nicotine use is allowed)
Failure to perform tasks (e.g., follow instructions to stay still in the scanner) or fill in safety screening forms
Prisoners
Atypical or secondary parkinsonism
Co-existence of other neurological diseases
Mixed or complex tremors
Inability or unwillingness to discontinue medications for tremor on the day of study assessments
Medical (cardiological, renal, hepatic, oncological) or psychiatric disease that would interfere with study procedures for asES, HD-EMG, TMS, or EEG; dementia; severe depression; prior neurosurgical procedures