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 2 mA for a duration of up to 60mins; (4) tACS applied at an intensity of
up to 1 mA peak amplitude for a duration of up to 10 minutes; (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 also used to train new investigators and to optimize/develop various
techniques and experimental approaches (e.g., development of appropriate MRI sequences,
parameters of TMS stimulation, behavioral paradigms).

Procedurally, AIs submit each sub-study proposal to the PI describing rationale, methods,
techniques and/or behavioral tasks. The PI then meets with the AI and the Protocol
Coordinator (PC) to discuss the sub-study and make sure all procedures are allowed under
protocol and consent form. The PI discusses the new pilot with the PIRC chair and suggestions
are incorporated accordingly. The status of each sub-study is reported to the IRB at the time
of the continuing review.

- 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