Modulation of Motor Function by Stimulation of the Central and Peripheral Nervous System

Sponsor
National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
Overall Status
Completed
CT.gov ID
NCT00453505
Collaborator
(none)
1,007
Enrollment
1
Location
1
Arm
155.2
Actual Duration (Months)
6.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Objectives

Noninvasive stimulation of the central and peripheral nervous system, including transcranial magnetic stimulation (TMS), transcranial direct and alternating current stimulation (tDCS and tACS, respectively) and cutaneous/peripheral nerve stimulation (C/PNS) alone or paired with TMS (paired associative stimulation, PAS), has been increasingly used in the investigation of cortical plasticity and as a possible adjuvant strategy in neurorehabilitation. It has been shown that TMS, tDCS, tACS and C/PNS can modulate motor function in healthy volunteers, as well as in patients with neurological disorders such as stroke.

One fundamental problem is that the optimal parameters of stimulation to modulate motor function by all of these techniques are not known. The purpose of this protocol is to explore within safe guidelines, the effects of different stimulation parameters on motor cortical function, on oscillatory brain dynamics measured with magnetoencephalography (MEG) and electroencephalography (EEG), on eye movements, and on fMRI activation. In addition, this protocol will be used to train new fellows coming to NINDS Human Cortical Physiology Section (HCPS) in the use of TMS, tDCS, tACS and C/PNS techniques.

We expect that information emerging from these studies will allow us to 1) optimize experimental protocols or stimulation parameters to collect pilot data in healthy volunteer for future patient-oriented hypothesis-driven protocols,2)to collect pilot data for power analysis for future patient-oriented hypothesis driven protocols, and 3) to train new fellows in the use of these different methods.

Study Population

Up to 1500 healthy volunteers, age 18 and older.

Design

Healthy volunteers will receive one or more of the following types of stimulation alone or in combination: (1) single- and paired-pulse TMS with inter-stimulus intervals of greater than 1s and up to 20s and intensities of up to 100% of stimulator output; (2) 1 Hz TMS for up to 30mins and up to 115% of resting motor threshold (RMT) intensity; (3) tDCS applied at an intensity of up to 4 mA for a duration of up to 60mins, as long the total charge does not exceed 7.2 C; (4) tACS applied at a peak-to-peak intensity of up to 4 mA for a duration of up to 60 minutes, minutes, as long the total charge does not exceed 7.2 C; (5) C/PNS applied alone with intensities below 130% of the peripherally-elicited-motor-threshold for up to 2 hours, or intensities up to 300% of sensory threshold when C/PNS is paired with TMS. All of these parameters of stimulation and procedures have safely been used as previously reported in the literature. Sham stimulations will be delivered for each modality as scientifically needed. Some substudies may involve recording of behavior or brain activity only (such as behavioral testing, MRI, and MEG) if brain stimulation targets are unknown. This information can help design future brain stimulation protocols.

Each subject may participate in up to 20 sessions. A single session may last no longer than 8 hours to allow for initial testing paradigm followed by retests or performing other components of the same substudy later in the day. Appropriate rest breaks and meal breaks will occur during long sessions. Subjects participate in one experimental session per day under this protocol. The 20 experimental sessions will be scheduled over a twenty-year period. CTDB is used to track the number of sessions per subject so it does not exceed 20 sessions. The AIs are responsible for entering the subjects/sessions into CTDB.

We will test the effects of these different forms of stimulation on motor cortical excitability, cognitive and motor behavioral tasks, and brain state measures derived from neuroimaging data (i.e. - MRI, fMRI, MEG and EEG). Stimulation may be applied before, after, or during physiological (i.e. motor evoked potentials, M-wave, F-wave, or H-Reflexes), neuroimaging or behavioral measures.

Under this protocol, we conduct:

Exploratory Sub-studies: These substudies are exploratory in nature and are conducted in order to develop information to generate better informed future hypotheses and/or power analyses. We have set an upper limit of 40 subjects per sub-study.

Hypothesis-Testing Sub-studies: Hypothesis-testing sub-studies are studies with specific hypotheses to be tested. These sub-studies undergo statistical and PIRC review after 6 subjects per group (e.g., after 12 subjects, 6 per arm, if two groups are studied), before additional subjects can be recruited. Together, the P.I. and PIRC will decide whether to continue the sub-study with more subjects without an amendment or whether an amendment or protocol would be necessary. A memo requesting a review of hypothesis-testing sub-studies for possible additional enrollment (beyond 6) will be sent to PIRC and the statistical reviewer.

This protocol is ...

Condition or DiseaseIntervention/TreatmentPhase
  • Diagnostic Test: MRI
  • Diagnostic Test: fMRI
  • Diagnostic Test: MRS
  • Diagnostic Test: MEG
  • Diagnostic Test: EEG
Early Phase 1

Detailed Description

Objectives

Noninvasive stimulation of the central and peripheral nervous system, including transcranial magnetic stimulation (TMS), transcranial direct and alternating current stimulation (tDCS and tACS, respectively) and cutaneous/peripheral nerve stimulation (C/PNS) alone or paired with TMS (paired associative stimulation, PAS), has been increasingly used in the investigation of cortical plasticity and as a possible adjuvant strategy in neurorehabilitation. It has been shown that TMS, tDCS, tACS and C/PNS can modulate motor function in healthy volunteers, as well as in patients with neurological disorders such as stroke. One fundamental problem is that the optimal parameters of stimulation to modulate motor function by all of these techniques are not known. The purpose of this protocol has been to explore within safe guidelines, the effects of different stimulation parameters on motor cortical function, on oscillatory brain dynamics measured with magnetoencephalography (MEG) and electroencephalography (EEG), on eye movements, and on fMRI activation. In addition, this protocol was used to train new fellows coming to NINDS Human Cortical Physiology Section (HCPS) in the use of TMS, tDCS, tACS and C/PNS techniques.

We expected that information emerging from these studies would allow us to

  1. optimize experimental protocols or stimulation parameters to collect pilot data in healthy volunteers for future patient-oriented hypothesis-driven protocols, 2) to collect pilot data for power analysis for future patient-oriented hypothesis driven protocols, and 3) to train new fellows in the use of these different methods.

As instructed, we had stopped recruitment under this protocol at the time we were informed by the NIH IRB that they determined this to be a thematic protocol (August 6, 2019). The four specific aims addressed under this protocol are:

  1. Aim 1. To identify resting behavioral and physiological substrates for neuromodulation of motor behavior

  2. Aim 2. To identify task-dependent behavioral and physiological substrates for neuromodulation of motor behavior

  3. Aim 3. To understand variability, rigor or/and reproducibility of brain stimulation effects.

As instructed, the purpose of this amendment is to request authorization to proceed with data analysis and publication. No new experiments will be carried out under this protocol.

Study Population

Up to 1500 healthy volunteers, age 18 and older.

Design

No new experiments will be carried out under this protocol. Previously, healthy volunteers receive one or more of the following types of stimulation alone or in combination: (1) single- and paired-pulse TMS with inter-stimulus intervals of greater than 1s and up to 20s and intensities of up to 100% of stimulator output; (2) 1 Hz TMS for up to 30mins and up to 115% of resting motor threshold (RMT) intensity; (3) tDCS applied at an intensity of up to 4 mA for a duration of up to 60mins, as long the total charge does not exceed 7.2 C; (4) tACS applied at a peak-to-peak intensity of up to 4 mA for a duration of up to 60 minutes, as long the total charge does not exceed 7.2 C; (5) C/PNS applied alone with intensities below 130% of the peripherally-elicited-motor-threshold for up to 2 hours, or intensities up to 300% of sensory threshold when C/PNS is paired with TMS. All of these parameters of stimulation and procedures have safely been used as previously reported in the literature. Sham stimulations were delivered for each modality as scientifically needed. Some sessions included recording of behavior or brain activity (such as behavioral testing, MRI, and MEG) if brain stimulation targets were unknown. This information was used to inform the design of brain stimulation protocols.

Each subject was able to participate in up to one experimental session per day, and up to 20 total sessions over a twenty year period under this protocol. A single session lasted no longer than 8 hours. Appropriate rest breaks and meal breaks occured during long sessions. CTDB was used to track the number of sessions per subject to ensure they did not exceed 20 sessions. Protocol AIs are were responsible for entering the subjects/sessions into CTDB.

We previously tested the effects of different forms of stimulation on motor cortical excitability, cognitive and motor behavioral tasks, and brain state measures derived from neuroimaging data (i.e. - MRI, fMRI, MEG and EEG). Stimulation was applied before, after, or during physiological (i.e. motor evoked potentials, M-wave, F-wave, or H-Reflexes), neuroimaging or behavioral measures.

Outcome Measures

No new outcome measures are proposed. Changes in motor cortical excitability were previously measured as the change in the average peak-to-peak amplitude of a motor

evoked potential (MEP) as measured with EMG. Neuroimaging measures included

changes in oscillatory brain activity power as measured with EEG or MEG, changes in

BOLD fMRI activation or changes in functional connectivity (i.e. - covarying fluctuations

in BOLD or spectral power across the brain). Behavioral outcome measures focused on

changes in performance as a function of learning, or as a function of applied brain

stimulation.

Study Design

Study Type:
Interventional
Actual Enrollment :
1007 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Basic Science
Official Title:
Modulation of Motor Function by Stimulation of the Central and Peripheral Nervous System
Actual Study Start Date :
Jan 14, 2007
Actual Primary Completion Date :
Nov 8, 2019
Actual Study Completion Date :
Dec 20, 2019

Arms and Interventions

ArmIntervention/Treatment
Active Comparator: 1

Healthy adults

Diagnostic Test: MRI
The MRI studies were conducted on a 3 or 7 Tesla MRI scanner located in the NIH Magnetic Resonance Imaging Research Facility (NMRF), under the guidelines of the FDA, NIH, and NMRF. Subjects lie down in the scanner in a comfortable position, and will be monitored by investigators in the control room. They are able to communicate with the investigators by intercom at the operating console at all times. If subjects ask to stop the experiment, they will be removed immediately from the scanner. During the scan, the subjects hear a rhythmic tapping sound caused by the switching of the gradient coil that is necessary to produce the image. They are required to wear Nonmagnetic earplugs. The scanning session lasts up to approximately 2 hours.

Diagnostic Test: fMRI
The MRI studies were conducted on a 3 or 7 Tesla MRI scanner located in the NIH Magnetic Resonance Imaging Research Facility (NMRF), under the guidelines of the FDA, NIH, and NMRF. Subjects lie down in the scanner in a comfortable position, and will be monitored by investigators in the control room. They are able to communicate with the investigators by intercom at the operating console at all times. If subjects ask to stop the experiment, they will be removed immediately from the scanner. During the scan, the subjects hear a rhythmic tapping sound caused by the switching of the gradient coil that is necessary to produce the image. They are required to wear nonmagnetic earplugs. The scanning session lasts up to approximately 2 hours.

Diagnostic Test: MRS
MRS was used to assess (1) local changes in neurotransmitter concentrations (ie.- GABA or glutamine/glutamate) due to stimulation or behavioral training, or (2) the relationship between baseline neurotransmitter concentrations and response to stimulation or behavioral intervention(s).

Diagnostic Test: MEG
Magnetoencephalogra phy (MEG) records small magnetic field changes from resulting brain activity145,146. Up to four small coils will be attached to fiducial landmarks with adhesive stickers and tape to localize the subject s head position inside the scanner. Participants will be seated comfortably during recordings, with their head positioned inside a helmet containing magnetic field detectors. The recording may occur while participants are sitting quietly or performing a cognitive or motor behavioral task. Some subjects may be provided with ear- pieces if the task includes auditory stimuli and communicate with the experimenters throughout the session from within the MEG room.

Diagnostic Test: EEG
EEG records the electrical activity of the brain. Small electrodes were either individually placed on the participant s scalp or multi-channel electrode arrays positioned using an electrode cap. The recording might have occurred while participants were sitting quietly or performing a cognitive or motor behavioral task. The electrodes were removed once the EEG was complete. A device consisting of computer hardware and digital signal processing software might have used to enable triggering of a stimulator system in response to a pre-defined EEG-signal. The device was used according to the Collaboration Agreement with University Neurology Hospital T(SqrRoot) bingen and Hertie Institute for Clinical Brain Research. The new device controls the timing of the stimuli based on pre-set parameters. Additional electrodes might have been placed on the scalp or limbs for offline removal of physiological artifacts from MEG or EEG data. Individual MEG or EEG sessions lasted up to 4 hours in length.

Outcome Measures

Primary Outcome Measures

  1. Our overall goal in this protocol has been to optimize experimental protocols or stimulation parameters to collect pilot data in healthy volunteers for future patient-oriented hypothesis-driven protocols. [annually]

    Changes in motor cortical excitability were measured as the change in the average peak-to-peak amplitude of a motor evoked potential (MEP) as measured with EMG. Neuroimaging measures included changes in oscillatory brain activity power as measured with EEG or MEG, changes in BOLD fMRI activation or changes in functional connectivity (i.e covarying fluctuations in BOLD or spectral power across the brain). Behavioral outcome measures focused on changes in performance as a function of learning, or as a function of applied brain stimulation.

Secondary Outcome Measures

  1. Aim 1. To identify resting behavioral and physiological substrates for neuromodulation of motor behavior [annually]

    Changes in motor cortical excitability were measured as the change in the average peak-to-peak amplitude of a motor evoked potential (MEP) as measured with EMG. Neuroimaging measures included changes in oscillatory brain activity power as measured with EEG or MEG, changes in BOLD fMRI activation or changes in functional connectivity (i.e. covarying fluctuations in BOLD or spectral power across the brain). Behavioral outcome measures focused on changes in performance as a function of learning, or as a function of applied brain stimulation.

  2. 2) Aim 2. To identify dependent behavioral and physiological substrates for neuromodulation of motor behavior. [annually]

    Changes in motor cortical excitability were measured as the change in the average peak-to-peak amplitude of a motor evoked potential (MEP) as measured with EMG. Neuroimaging measures included changes in oscillatory brain activity power as measured with EEG or MEG, changes in BOLD fMRI activation or changes in functional connectivity (i.e. covarying fluctuations in BOLD or spectral power across the brain). Behavioral outcome measures focused on changes in performance as a function of learning, or as a function of applied brain stimulation.

  3. 3) Aim 3. To understand variability, rigor or/and reproducibility of brain stimulation effects [annually]

    Changes in motor cortical excitability were measured as the change in the average peak-to-peak amplitude of a motor evoked potential (MEP) as measured with EMG. Neuroimaging measures included changes in oscillatory brain activity power as measured with EEG or MEG, changes in BOLD fMRI activation or changes in functional connectivity (i.e. covarying fluctuations in BOLD or spectral power across the brain). Behavioral outcome measures focused on changes in performance as a function of learning, or as a function of applied brain stimulation.

Eligibility Criteria

Criteria

Ages Eligible for Study:
N/A and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
  • INCLUSION CRITERIA:
  1. Age 18 and older

  2. Willingness and ability to give consent

  3. Normal neurological examination

  4. Clearly dominant handedness (right or left) as assessed by Handedness scales

EXCLUSION CRITERIA:
  1. Any severe or progressive neurological disorder or severe medical condition, or history of seizures

  2. Chronic use of medications acting primarily on the central nervous system, which lower the seizure threshold or significantly alter cortical excitability such as antipsychotic drugs (chlorpromazine, clozapine), tricyclic or other antidepressants, or prescription stimulants.

  3. Pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metallic prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, implanted delivery pump, or shrapnel fragments

  4. Diagnosis of drug dependence made by a health care provider (ICD-9-CM code 304)

  5. Staff from our section

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1National Institutes of Health Clinical Center, 9000 Rockville PikeBethesdaMarylandUnited States20892

Sponsors and Collaborators

  • National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

  • Principal Investigator: Leonardo G Cohen, M.D., National Institute of Neurological Disorders and Stroke (NINDS)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

Responsible Party:
National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier:
NCT00453505
Other Study ID Numbers:
  • 070122
  • 07-N-0122
First Posted:
Mar 29, 2007
Last Update Posted:
Oct 8, 2021
Last Verified:
Oct 6, 2021
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by National Institute of Neurological Disorders and Stroke (NINDS)

Study Results

No Results Posted as of Oct 8, 2021