- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00453505
Modulation of Motor Function by Stimulation of the Central and Peripheral Nervous System
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 ...
Study Overview
Status
Conditions
Intervention / Treatment
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:
- Aim 1. To identify resting behavioral and physiological substrates for neuromodulation of motor behavior
- Aim 2. To identify task-dependent behavioral and physiological substrates for neuromodulation of motor behavior
- 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 received 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 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 be 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 Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
-
-
Maryland
-
Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
INCLUSION CRITERIA:
- Age 18 and older
- Willingness and ability to give consent
- Normal neurological examination
- Clearly dominant handedness (right or left) as assessed by Handedness scales
EXCLUSION CRITERIA:
- Any severe or progressive neurological disorder or severe medical condition, or history of seizures
- 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.
- 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
- Diagnosis of drug dependence made by a health care provider (ICD-9-CM code 304)
- Staff from our section
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: N/A
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 1
Healthy Volunteers
|
<=1 Hz TMS for up to 30mins and up to 115% of resting motor threshold intensity (MT).
|
Sham Comparator: 1a
Healthy Volunteers
|
<=1 Hz TMS for up to 30mins and up to 115% of resting motor threshold intensity (MT).
|
Experimental: 2
Healthy Volunteers
|
tDCS up to 2 mA for up to 60mins.
|
Sham Comparator: 2a
Healthy Volunteers
|
tDCS up to 2 mA for up to 60mins.
|
Experimental: 3
Healthy Volunteers
|
tACS up to 1 mA for up to 10 minutes.
|
Sham Comparator: 3a
Healthy Volunteers
|
tACS up to 1 mA for up to 10 minutes.
|
Experimental: 4
Healthy Volunteers
|
CPNS alone with intensities below 130% of the peripherally-elicited-motor-threshold for up to 2 hours.
|
Sham Comparator: 4a
Healthy Volunteers
|
CPNS alone with intensities below 130% of the peripherally-elicited-motor-threshold for up to 2 hours.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
To identify task-dependent behavioral and physiological substrates for neuromodulation of motor behavior Aim
Time Frame: in data analysis
|
in data analysis
|
in data analysis
|
To understand variability, rigor or/and reproducibility of brain stimulation effects.
Time Frame: in data analysis
|
in data analysis
|
in data analysis
|
To identify resting behavioral and physiological substrates for neuromodulation of motor behavior Aim
Time Frame: in data analysis
|
in data analysis
|
in data analysis
|
Collaborators and Investigators
Investigators
- Principal Investigator: Leonardo G Cohen, M.D., National Institute of Neurological Disorders and Stroke (NINDS)
Publications and helpful links
General Publications
- Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol. 1998 Jan;108(1):1-16. doi: 10.1016/s0168-5597(97)00096-8.
- Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994 Aug;117 ( Pt 4):847-58. doi: 10.1093/brain/117.4.847.
- Muellbacher W, Ziemann U, Boroojerdi B, Hallett M. Effects of low-frequency transcranial magnetic stimulation on motor excitability and basic motor behavior. Clin Neurophysiol. 2000 Jun;111(6):1002-7. doi: 10.1016/s1388-2457(00)00284-4.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Other Study ID Numbers
- 070122
- 07-N-0122
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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