Using Repetitive Transcranial Magnetic Stimulation to Modulate Response Inhibition in Tourette Syndrome
Phase: NA
Conditions: Tourette Syndrome
Sponsor: Children's Hospital Medical Center, Cincinnati

 
 
Clinicaltrials.gov Title: 
Response Inhibition in Tourette Syndrome 
 
NCT03628703 
 
Latest version approved by IRB: 4/2/2020 
Title below is the local IRB protocol title 
 

 
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I. TITLE: Preliminary Investigations of Transcranial Magnetic 
Stimulation (TMS) to understand Diseases and Disorders that affect the 
Motor System in Children 
 
 
 
 

 
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I.  ABSTRACT 
   
   
Automatic and purposeful movements require signaling from the brain and spinal cord 
(central nervous system - CNS) via the nerves (peripheral nervous system - PNS) to 
muscles. Abnormal input into this pathway from the basal ganglia or cerebellum results 
in disorders of movement regulation and coordination. Diseases of the brain and spinal 
cord (central nervous system) can lead to weakness. Motor pathways can be assessed 
through testing of clinical properties of movement, such as strength, bulk, tone, reflexes, 
movement regulation, and coordination. Motor pathways can also be quantified through 
measurement of three fundamental neurophysiological properties: 1) the threshold (the 
amount of energy required to generate nerve firing); 2) the latency (the amount of time it 
takes for an electrical signal to propagate between two points of interest in the nervous 
system); and 3) the amplitude (the size of the response, which reflects the number of 
nerve cells that have activated). This testing is analogous to Peripheral motor system 
assessment performed routinely using Electromyography / Nerve Conduction Studies 
(EMG/NCS). Recent research has shown that Transcranial Magnetic Stimulation (TMS) 
may be used for this purpose but, unlike EMG/NCS, TMS is not yet FDA Approved for 
routine motor system diagnostics in the United States (although repetitive TMS is cleared 
by the FDA for treatment of depression). At Cincinnati Children's Hospital Medical 
Center (CCHMC), our laboratory has been using TMS for research in children and adults 
to understand normal motor system development, and abnormal motor function in 
Attention Deficit Hyperactivity Disorder (ADHD) and Tourette Syndrome (TS) for over 
5 years. In this study we propose a preliminary investigation to assess feasibility of use of 
TMS for diagnostic purposes. Our primary aims are: 1) to use TMS to collect 
neurophysiologic data in children with motor disorders, 2) to use TMS to generate 
hypotheses and preliminary findings in motor system diseases which can be used for 
preliminary data in future scientific studies and grant applications.    
 
 
 
Keywords: Neurological disorders, development, motor evoked potentials, Transcranial 
Magnetic Stimulation

 
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II. PURPOSE OF STUDY 
 
The purpose of this study is to use Transcranial Magnetic Stimulation (TMS) to study 
diseases that affect the motor system. Motor movements are generated through a complex 
system of pathways between the cerebral cortex, basal ganglia, thalamus, cerebellum, 
brainstem, spinal cord, nerve plexus, peripheral nerve and muscle. A disruption anywhere 
along this system can cause abnormal motor function. Such disruptions cannot always be 
seen using neuroimaging. We propose to use TMS to collect neurophysiologic data in 
diseases that affect the motor system in hopes of improving our understanding of and 
ability to care for children. Utility of TMS for these purposes has recently been reviewed 
1 and thus far most studies are in adults. 
 
The clinical applications we propose to investigate, arranged anatomically with selected 
published references include: 
 
Table 1 
Location in the Nervous 
System 
Disease, Disorder, or 
Pathological Process 
Technique 
Cerebrum 2-5 
Stroke/ischemia, cerebral 
palsy, neurodegenerative 
diseases, demyelinating 
diseases 
Single Pulse TMS, Paired 
Pulse TMS, Theta Burst 
Stimulation 
 
Basal ganglia 6-11 
 
Dystonia, chorea, tic, 
stereotypy, Tourette 
Syndrome
Single Pulse and Paired 
Pulse TMS, Theta Burst 
Stimulation
Cerebellum 12,13 
Congenital cerebellar 
malformations, 
Neurodegenerative 
Diseases and ataxias 
Paired pulse cerebellar-
cerebral TMS, Theta Burst 
Stimulation 
 
Spinal Cord 14-16 
Trauma, stroke, 
demyelinating diseases, 
transverse myelitis 
Single Pulse TMS 
  
Brachial plexus, lumbar 
plexus 17 
 
Congenital malformations, 
birth trauma, ischemia, 
tumor, avulsions 
Single Pulse TMS 
 
Nerve roots, peripheral 
nerves 18,19 
Guillain-Barre syndrome 
(AIDP), CIDP 
Single Pulse TMS 
Anywhere along cortico-
spinal pathway 20,21 
Psychogenic paralysis 
Single Pulse, Paired Pulse 
TMS, Theta Burst 
Stimulation
 

 
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This protocol is open, to allow exploration of TMS as a clinical tool (similar to 
NCS/EMG and Somatosensory Evoked Potentials) and hypothesis generating. We 
propose to study the utility of single and paired pulse TMS for understanding central 
nervous system pathology in diseases and disorders affecting the motor system. The 
members of divisions of neurology, neurosurgery, rehabilitation, and orthopedics or other 
divisions would subsequently be able to use these findings as preliminary data for 
hypothesis driven research. 
 
III. SIGNIFICANCE OF STUDY IN RELATION TO HUMAN HEALTH 
 
Routine testing of neurophysiology and function of peripheral nerves and muscle is 
important for patient care in neurological diseases of the peripheral nervous system. 
Testing in the peripheral nervous system of motor and sensory pathways (NCS) in the 
arm and hand are shown in Figure 1. Testing in the central nervous system of visual 
pathways (Visual Evoked Potentials), auditory pathways (Brainstem Auditory Evoked 
Responses), and sensory pathways (somatosensory evoked potentials) are also standard 
medical tests. These types of evoked potential studies are in routine clinical use at 
CCHMC, providing clinically useful information. This protocol extends these principles 
to the CNS motor system. 
 
Noninvasive assessment of neurophysiological properties of the CNS using TMS with a 
hand held magnetic coil was described in 1985 22. Clinical applications of magnetic 
stimulation of brain, spinal cord, and nerves have been expanding since that time. 
Magnetic stimulation of the peripheral nervous system is approved by the FDA. 
Repetitive TMS was recently cleared by the FDA for use in treatment of depression. We 
have used a Magstim TMS device in our laboratory for over 5 years with no significant 
adverse events.  In this study, we propose to use TMS to gather neurophysiologic data to 
characterize different types of diseases and disorders that affect the motor system in 
children, to improve our diagnostic and therapeutic management. Although this is a study 
of feasibility and data gathering rather than hypothesis testing, we anticipate some data 
will be publishable because of the novelty of this emerging technology. 
 

 
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We believe that the current protocol, which involves single or paired pulse TMS 
administered with field strength of 2 Tesla or less, consistent with the field strength of 
clinical MRI, constitutes a minimal risk use of the TMS devices, with potential for direct 
benefit in some applications. 
 
CCHMC has a large and diverse group of specialists that treat diseases and disorders of 
the central nervous system. Clinicians include neurologists, neurosurgeons, orthopedic 
surgeons, physiatrists, radiologists, psychiatrists, and psychologists. A vast array of 
imaging technologies provides exquisitely sensitive and anatomically specific 
information about neurological diseases. Imaging techniques in use at CCHMC include 
Computed Tomography (CT), Magnetic Resonance Imaging (MRI) (1.5 and 3 Tesla 
magnets), Functional MRI, Single Photon Emission Computed Tomography (SPECT), 
and Positron Emission Tomography (PET). Because the nervous system uses electro-
chemical signaling, the central nervous system may also be assessed with 
neurophysiological techniques including electroencephalography (EEG) and 
magnetoencephalography (MEG). Each of these studies provides useful information, but 
has some limits in terms of sensitivity, specificity, time, cost, need for sedation, and 
patient tolerability. TMS may ultimately join these other technologies in providing useful 
clinical information to a wide variety of specialties. 
 
This possibility can be understood through describing some representative scenarios: 
 
Clinical scenarios 
 
Acute Spinal cord disease - transverse myelitis: child presents with progressive and 
ultimately complete flaccid paralysis of the legs. MRI imaging shows signal change for 2 
Figure 1. At left, research 
use of Transcranial 
Magnetic Stimulation over 
motor cortex to measure 
neurophysiology of central 
nervous system. Below, 
routine clinical electrical 
stimulation to measure 
neurophysiology of 
peripheral nerves.

 
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cm in the thoracic spinal cord, consistent with a diagnosis of transverse myelitis. Clinical 
question: is there preservation of motor pathways to the legs? 
TMS tests: Double cone coil over vertex, round coil over lumbar spine/plexus. Surface 
EMG over lower leg (anterior tibial) muscle. 
Possible results: Lumbar plexus stimulation produces normal responses in the legs. Brain 
stimulation shows prolonged latency (slow conduction time) from brain to lower spine, 
with small amplitude motor evoked potential in the leg. This suggests that despite 
complete loss of movement of the legs and signal change in spinal cord, there are some 
preserved, intact motor fibers running through the spinal cord. Injury involves both 
demyelination and axonal damage. (Note - Somatosensory Evoked Potentials are 
currently used clinically to assess sensory pathways in spinal cord. TMS could 
complement this by assessing motor pathways. TMS is also much quicker and probably 
more comfortable.) 
 
Chronic Spinal cord compression due to orthopedic disease: child presents with 
progressive scoliosis. Clinical question: Is there cord compression affecting motor 
pathways? 
TMS tests: Double cone coil over vertex, round coil over lumbar spine/plexus. Surface 
EMG over lower leg (anterior tibial) muscle. 
Possible results: Monitored over a period of months to years, no change in motor 
potentials. This supports deferring surgery in the proper clinical setting. 
 
Chronic Spinal cord and brainstem compression - Chiari I: Child presents with 
asymptomatic or minimally symptomatic Chiari I malformation.  Clinical question: is 
there compression of the spinal cord?  
TMS tests: Double cone coil over motor cortex.  EMG electrodes are placed in either 
upper or lower extremities. 
Possible results: Patients with abnormal central motor conduction time (CMCT) but are 
still asymptomatic or minimally symptomatic may need to be referred for decompression 
surgery. 
 
Brachial plexus - neonatal: Child presents with upper brachial plexus (Erb’s) palsy at 
birth. Clinical question: What is the potential for recovery? 
TMS tests: Figure 8 coil over motor cortex, round coil over cervical spine/ brachial 
plexus. Surface EMG will be placed over the bicep muscle. 
Possible results: Complete absence of bicep signal. If our experience shows we can 
usually reliably obtain biceps signal, then the absence of signal of may be an indication 
of severe damage.  
 
Basal ganglia - Sydenham Chorea: Child presents with SC and is prescribed 
neuroleptics for symptom control.  Clinical question: Can medication be discontinued?  
TMS tests: Figure 8 coil over motor cortex.  Surface EMG is placed over upper 
extremity.  There are currently minimal neurophysiological data regarding SC.  
Possible results: The extent of abnormal neurophysiological data correlates with 
symptom severity, predicts recovery, aids in treatment decisions.  
 

 
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Cerebellum - tremor: Child presents with unusual intention tremor. Clinical question: Is 
the tremor dystonic or cerebellar?  
TMS tests: Paired pulse cerebellar/motor cortex. 
Possible results: Failure to find the normal cerebellar cortical inhibition (interstimulus 
interval 6 msec). This suggests cerebellar pathology is present and may guide further 
testing or pharmacological treatment with medications used for essential tremor. 
 
Cerebellum - ataxia: A new therapy is developed for a degenerative ataxia, e.g. for 
Freidreich’s 23. Investigators wish to monitor the effects with a simple, short clinical test 
that does not require sedation. Ataxia is challenging to accurately rate. Question: Is 
cerebellar-cerebral inhibition a biomarker of cerebellar response to treatment?  
TMS tests: Paired pulse cerebellar/motor cortex. 
Possible results: Drug treatment, but not placebo treatment, is associated with a 
normalization of neurophysiological measures. 
 
Metabolic or genetic leukodystrophies: A new therapy is developed for a degenerative 
white matter disease. Clinical rating scales of disability and impairment are insensitive to 
early effects of treatment. Clinical question: Is central conduction a biomarker of white 
matter regeneration and repair? 
TMS tests: Single pulse TMS in motor cortex; paired pulse cerebellar/motor cortex. 
Possible results: Beneficial treatment modifies central conduction velocities, predicting 
clinical subsequent improvement. 
 
Possible Psychogenic Disorder: Patient presents with abnormal movement(s) or 
paralysis.  There is suspicion that the symptoms are psychogenic in origin.  Clinical 
question: Are symptoms psychogenic? I.e. is motor system physiologically intact? 
TMS tests: Double cone coil over motor cortex.  Electrodes are place over limb. 
Possible results: In psychogenic conditions, neurophysiologic results should be normal.  
This may save time and resources as it may eliminate the need for other costly or risky 
diagnostic tests.  
 
IV. PREVIOUS WORK DONE IN THIS AREA  
 
Transcranial Magnetic Stimulation (TMS) has been used in humans, in essentially its 
current form, for 20 years 22. Several companies make TMS devices. Each involves a 
pulse generator which stores electrical energy (from a wall outlet) connected to a hand-
sized coil, usually round or figure-of-eight shaped. The operator or a computer can 
trigger the generator to release electricity into the coil which produces a transient 
magnetic field beneath the coil. When the field change occurs near neurons, they may 
depolarize (fire), producing a measurable response. The maximum field strength for the 
Magstim TMS device which we have used at CCHMC is 2 Tesla (comparable to 1.5 and 
3 Tesla magnets used for clinical MRI scans).  
 
The Magstim TMS BISTIM (used at CCHMC since 2001) and Rapid2 Stimulators (used 
at CCHMC since 2008) are approved in the United States for peripheral nervous system 
stimulation, but not for routine clinical diagnostic or therapeutic central nervous system 

 
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applications at this time. Many neurophysiology laboratories, including ours, have used 
TMS as a non-invasive technique to measure neurophysiological properties of the central 
nervous system in children. TMS is ideal for studying the motor system, but has other 
applications as well. It is well tolerated by most children, with minimal or no discomfort. 
In our prior IRB-approved studies, we have used series TMS to study motor cortex 
physiology in healthy children as well as children with Tourette Syndrome and Attention 
Deficit Hyperactivity Disorder (ADHD). 
 
V. PRELIMINARY DATA IN CHILDREN 
 
For the scenarios above and described in Table 1, we do not have preliminary data. This 
study is exploratory. However, we are currently using TMS as part of an NIMH-funded 
study to understand motor development in typical and ADHD children (CCHMC 06 10 
35). In this ongoing study of ADHD vs. typical children between the ages of 8 and 12 
years, we do have some data that might be useful for comparison. For example, motor 
threshold correlates highly with age: r = -.63, p < .001; n = 72 children (preliminary 
analysis, data unpublished, study ongoing). The mean threshold is 68% of maximal 
stimulator output, and the Standard Deviation is 16%. 
 
VI. RESEARCH PLAN  
 
1. Number of subjects and methods of selection:  
i. 
For this study, we are requesting permission to recruit up to 300 children and 
adults at CCHMC. 
ii. 
Study eligibility will be determined by the principal investigators Dr. Gilbert or 
Dr. Wu in consultation with the managing physician, based on presence of motor 
system problems described in Table 1.  
 
2. Inclusion and Exclusion criteria: 
 
Inclusion Criteria 
i. 
Either gender, any race, ethnicity or socioeconomic status 
ii. 
Children greater than 2 years old and adults less than 60-years old with diseases 
affecting the motor system and interfering with voluntary movement. Adult 
diseases would typically have childhood onset, e.g. spinocerebellar ataxia, 
degenerative leukodystrophies, spinal cord disease. 
iii. 
Healthy individuals recruited for comparative normative data.  
Exclusion Criteria 
i. 
Standard contraindications to TMS: Implanted brain stimulator, vagal nerve 
stimulator, VP shunt, aneurysm clip, cardiac pacemaker, or implanted medication 
port. 
ii. 
Other situations where it is reasonable to avoid TMS: Pregnant females or 
sexually active females not using birth control. Significant medical conditions 
including kidney disease, anemia, thyroid disease, lung disease, heart disease. In 

 
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addition, any conditions, in the judgment of the investigators, for which external 
magnetic stimulation might risk harm. 
3. Randomization:  
NA 
 
4. Study Procedures: 
Prior to participation, parents will sign consent forms and children older than 11 years 
will sign assent forms. 
 
Participation in this study and use of TMS will not in any way influence standard medical 
care, in order to minimize coercion.  
 
Diagnostic information obtained through this study is not part of standard medical care 
and will not be available to clinicians. 
 
This study has 4 parts, listed here and described in greater detail below: 
 
1. Collection of routine clinical data obtained during standard of care evaluations in 
children with neurological conditions. 
2. Administration of TMS as described in Table 1 and in the clinical scenarios 
above.   
3. Data storage, analysis, comparison with prior CCHMC and published data.  
4. Use of data for hypothesis generation, effect and sample size calculations for 
future studies. 
 
Routine Clinical Data Acquisition 
Clinical and demographic information will be obtained after informed consent. This 
information will include diagnosis, results of imaging, laboratory, or neurophysiological 
studies as appropriate. When appropriate, the following clinical rating scales may be used 
– Yale Global Tic Severity Scale 24, Premonitory Urge Rating Scale 25, Children’s Yale-
Brown Obsessive Compulsive Scale 26 and DuPaul ADHD Rating Scale 27. 
 
TMS – details:  
TMS will be performed using a Magstim 200® stimulator (Magstim Co., New York, NY, 
USA) connected through a Bistim® module to a TMS coil as described in CHMC 06-10-
11; 05-05-19; 03-05-52; 03-05-53. A 70 mm double cone coil will be used for lower limb 
stimulation – see below.  Currently the lab has 90 mm circular, 70 mm figure-8 and 40 
mm figure 8 coils. 
 
The subject sits in a comfortable dental chair or lies prone on a hospital bed. The TMS 
devices are maintained in the EEG suite, which is under direct supervision of laboratory 
personnel during business hours and is locked with restricted key access during all other 
hours. 
 

 
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Motor cortex stimulation for upper limb: The TMScoil is placed with its center near the 
vertex in the optimal position and orientation for producing a motor evoked potential 
(MEP) in the bicep, tricep, abductor pollicis brevis (APB) muscle, first digital inter-
osseous (FDI) muscle, or abductor digiti minimi (ADM) muscle, as the clinical context 
requires. 
 
Motor cortex stimulation for lower limb: The motor cortex that controls leg and foot lies 
along the inter-hemispheric frontal lobe and can be better stimulated using the double 
cone coil over the vertex. 
 
Cerebellar stimulation The cerebellum will be stimulated 1-2 cm lateral and caudal 
(below) the inion (the protuberance at the back of the head) as described by Ugawa and 
colleagues.12 
 
Plexus stimulation The spinal cord will be stimulated with the patient prone and the 
figure 8 or round coil placed at the level of the cervical/brachial plexus or lumbar 
spine/plexus. 
 
Priming cortex for children with high thresholds Some young children and all infants 
have high thresholds for stimulation. The low intensity, intermittent Theta Burst 
Stimulation (iTBS) potentiation protocol used in IRB approved protocols CHMC 2008-
1237 and 2008-1256 will be used as needed to facilitate single and paired pulse TMS 
measures. 
 
Repetitive Stimulation Repetitive stimulation of the cortex will be performed using Theta 
Burst Stimulation (TBS).  TBS protocols are currently used in IRB approved protocol 
CHMC 2008-1256.  The use of these protocols is well documented in the medical 
literature 28-31.  For the CHMC 2008-1256 study, we have already performed TBS on 63 
pediatric/adult subjects and all the subjects have tolerated the protocols well without 
serious adverse events. 
 
Functional TMS Single and paired pulse TMS, as above, performed dominant or non-
dominant motor cortex during bimanual tasks, response inhibition tasks, and reward 
paradigms.  Functional TMS will also target cortical regions that are important for motor 
control and motor response inhibition.  These regions will include supplementary motor 
complex and inferior frontal gyrus. 
 
Goniometer The investigators will quantify motor movements of the 
hand using a goniometer. The device was used in a prior IRB-approved 
study (#2008 – 0061) 32. The device quantifies finger movements 
through a soft, bendable plastic transducer. The transducers are attached 
to the fingers by a Velcro (see figure to the right). This device is strictly 
used to detect finger movements and does not involve delivering any 
energy (i.e. electrical current) to the hand; therefore, the addition does not change the 
adverse risk profile of the study. Part of the goniometer procedure requires videotaping of 
hand movements. 

 
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Electroencephalography (EEG) EEG will be used to assess the electrophysiologic 
correlates of movements and/or TMS. EEG will be recorded with whole dense array 
electrode caps using continuous recording EEG system (Electrical Geodesics, Inc. (EGI), 
Eugene, OR, USA) or BrainVision actiCHamp EEG system (Brain Vision LLC, 
Morrisville NC). Dense array electrode caps include 32, 128 or 256-channel electrodes. 
The sensor net uses a mild, fragrance-free, saline-based solution or gel to contact the 
scalp, requires approximately 10 minutes to position the net and does not require abrasion 
of the skin as the EGI amplifiers are design to tolerate normal skin impedances.  This 
system of electrodes and amplifiers can be left in place during TMS stimulation. 
 
The position of the EGI electrodes are captured with the Geodesic Photogrammetry 
System (GPS), which is a precision geodesic dome of 11 cameras that quickly 
simultaneous photograph the net on the subject’s head. The time of the photographing is 
just the time required to seat the subject in the chair and take the photograph. The precise 
3D location of the sensors is digitized offline afterwards with software supplied with the 
system. 
 
Brain MRI 
Brain MRI may be performed to help with neuronavigation for TMS.  This will be 
done in the Imaging Research Center 3.0 Tesla MRI scanner. A registered 
radiological technologist will explain the procedure and review the standard 
checklist of patient questions used for MRI protocols. In preparation for the scan 
the participant will first be asked to remove all jewelry, pens, pencils, credit cards, 
belt buckles and any other metallic objects from clothing. The participant will be 
given a pair of disposable foam ear plugs and instructed on how to insert them for 
optimal ear protection. The technologist will ensure that the earplugs are inserted 
prior to scanning. Fiducial markers will also be placed in three different locations 
on the face for facial landmarks . Easily-removeable and disposable fiducial 
markers are small, soft, circular stick-ons that are placed in the area of interest 
during imaging as reference points. In the case of this study, three will be placed 
around the face that will show up clearly on the images post-scan to guide 
neuronavigation during TMS. Since 2009, neuronavigation in the lab has been 
conducted using BrainSight® (Rogue Research, Montreal, Canada). Current 
version is 2.3.12 but will be updated in the future per manufacturer 
recommendations. 
 
All brain MRI images will be reviewed by a pediatric neuroradiologist. If any 
clinically significant findings is present, the PI will discuss with the family. In 
such case, if the subject or guardian consents, the PI may discuss these findings 
with primary care physician and ensure that appropriate referral is made. Neither 
sedation nor contrast will be used in the brain MRI. 
 
Behavioral Tasks Various behavioral task(s) may be performed to assess the effects on 
motor control. 
 

 
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Eye Movements Participants will be monitored or asked to make specific 
eye/eyelid movements. A false belief behavioral task may be used in conjunction 
to monitor eye movements 33. This task involves the subject to look at a sequence 
of an actor and a puppet moving a ball between two boxes. The resulting ocular 
movements will be recorded using a Tobii Eye Tracker (Tobii Technology AB, 
Danderyd Sweden). 
 
Probabilistic Learning Probabilistic classification learning is a task that requires 
activation of the frontostriatal network, which modulates motor preparation and 
movements. The task performance has been shown to be abnormal in several 
movement disorders – Parkinson’s disease, Tourette Syndrome, Huntington 
Disease 34-36. This task involves the subject to predict a binary outcome (positive 
or negative) based on looking at a sequence of four items (i.e. cards). 
 
Bimanual Tasks In each experiment, the child has both hands relaxed on his lap, 
on a pillow supporting at the elbows.  For the single finger tapping motor task, the 
child is instructed to repeatedly tap the task hand index finger while keeping the 
non-task hand in the same position, but relaxed.  To ensure consistency in 
performance speed and coordination, the a computer instructions will be shown to 
indicate resting, tapping one finger, tapping all fingers sequentially, and 
sustaining a squeezing of the index finger to the thumb. TMS will be administered 
as above but during the task. 
 
Response Inhibition Tasks In each experiment, the child keeps both hands relaxed, 
but on a cue from the computer has to push an X button with the right hand or O 
button with the left hand, on a game controller. On some trials, a “stop” auditory 
tone will occur.  At time = 0ms, an image of either an X or O will be displayed on 
the screen. TMS will be administered as above but during the task. Slater-
Hammel procedure, another response-inhibition task, may also be used to assess 
motor response time 37. This task requires the subject to hold a button and release 
before a moving marker reaches a predefined time point (800 milliseconds after 
the start signal). If the marker stops in its trajectory, the participant is instructed to 
not let go of the button. Another method of comparing response inhibition is to 
present conditions of just staring at computer screen vs. instructing subjects to 
activate or inhibit motor movement. 
 
Reward Paradigm In each experiment, the participant watches while smiling or 
frowning faces appear on the computer screen. Three smiles will result in the 
participant receiving a monetary award ($0.25). TMS will be administered as 
above, but during the task.  
 
Money Bags Paradigm In each experiment, the participant clicks the mouse 
control each time a quarter appears above the money bag on a computer screen. If 
they click accurately, the quarter drops into the money bag and ($0.25) is 
registered as gained by the participant. The difficulty and perceived degree of 
difficulty varies. TMS will be administered during the task. 

 
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Selective Suppression via Real Time Feedback In each experiment, the participant 
receives an instruction to think about moving or not moving either their index 
finger or their pinky. TMS is then administered and the participant receives 
immediate feedback on computer monitor about the size of the motor evoked 
potential (MEP). 
 
 
EMG recording and signal processing The EMG is recorded with surface electrodes 
taped to the skin. This is comfortable for the patient as no needle is required to be 
inserted in the muscle. The signal is amplified, and filtered (100/1000 Hz) (Coulbourn 
Instruments, Allentown, PA) before being digitized at 2 kHz and stored for analysis using 
Signal® software and a Micro1401 interface (Cambridge Electronic Design, Cambridge, 
UK).  
 
Neurophysiological parameters Thresholds defined using conventional criteria as the 
lowest stimulator intensity that produces measurable responses in 3 of 6 trials. Short 
intracortical inhibition (SICI) and facilitation (ICF) are measured with a paired-pulse 
paradigm using three conditions: single pulse, paired pulse at 3 msec interstimulus 
intervals, paired pulse at 10 msec interstimulus intervals. Subthreshold pulse precedes 
suprathreshold pulse for paired pulses. Peripheral conditioning pulses are administered 
20-30 msec prior to motor cortex. Short ICF will be also performed with a paired-pulse 
paradigm 38-40. Long intracortical inhibition (LICI) involves using 100-200 msec 
interstimulus intervals. In other forms of paired-pulse stimulation such as cerebellar 
conditioning, pulses are administered 5-10 msec prior to motor cortex. Twenty trials are 
performed for each ISI and for the test stimulus alone. The order of the intervals is varied 
randomly, and the interval between trials varies randomly by <10% around a mean of 6 
seconds. Transcortical inhibition to the left dominant hemisphere/ right dominant hand is 
measured by stimulating over right motor cortex, while the child simultaneously contracts 
muscles in both hands. This produces an evoked potential in this ipsilateral and 
contralateral hand, followed by periods of EMG silence (the “silent period”). Latency and 
duration of this silent period are affected both by age and by ADHD diagnosis 41.  
Latencies are measured by subtracting MEP onset time from TMS artifact time. 
Amplitudes are measured as peak to peak and area under the curve. 
 
5. 
Questionnaires:  
NA 
6. 
Blood Specimens:  
NA 
 
7. 
Previous research studies in which the projected patient population may be 
involved:  
There are no issues related to cumulative risk. Participation in several different TMS 
protocols is allowed but no individual would participate in 2 or more protocols the same 
day. 
 

 
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8. 
Data Analysis and Sample Size Calculations: 
 
Sample size- general issues 
We are requesting permission to enroll up to 300 children and adults. We wish to 
offer TMS as a potential clinically useful tool and for hypothesis generation in a 
variety of motor disorders. Statistical analyses otherwise are not planned. 
 
a. The utility of TMS in motor disorders 
In adults, the sensitivity of TMS for spinal cord disease has been published as 
100% and specificity 85% 16. Similarly, in adults loss of and preservation of 
motor potentials are highly predictive of poor vs. good long term outcomes after 
stroke 5. 
 
b. Quantitative biological markers of motor system disease, assessed using 
TMS. We anticipate that TMS measurements listed in Table 1 will yield 
quantitatively abnormal responses, compared to the same measures in healthy 
children. However, this is a preliminary study, not a formal case-control study. 
Some of these data, such as complete absence of a response localizing to spinal 
cord or cerebrum, will be unambiguous. Other measures, similar to some 
neuroimaging results, may be interpretable in a clinical context. Finally, some 
measures may ultimately be useful for understanding disease, based on disease vs. 
control between group differences, in future studies. 
 
c. Reliability and Consistency of TMS Data in our Lab. 
Certain measures, such as central motor conduction times, have normative data 
published. We can use available data as a reference for the data we generate 
through use of TMS to determine whether data in our laboratory are broadly 
consistent with those published, but formal statistical analysis is not planned for 
this aim at this time. In addition, although we do not have funding at this time for 
generating normative and disease related pediatric datasets and test-retest 
datasets, we plan to store our data and thereby have some ability to assess this. 
We have previously published test-retest data in Tourette Syndrome and ADHD 
for a measure of motor cortex inhibition 42.  
 
9.   Facilities:  
Studies will be performed in the Division of Neurology and Neurophysiology/TMS 
/MEG/EEG Laboratory at Cincinnati Children’s Hospital Medical Center. 
 
VII. SPECIAL CONSIDERATIONS 
 
1. Radiation Safety: NA 
2. Investigational Devices: The TMS apparatus is investigational, although it has 
recently been cleared for treatment of refractory depression. We consider 2 Tesla 
or less stimulation or brain, cerebellum, spinal cord, and nerves to be a non-
significant risk use of the TMS device. Manufacturer’s information for the 

 
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Magstim device has previously been submitted to the IRB and is available on 
request.  
3. IND (Investigational New Drug): NA 
4. Emergency Use: NA 
5. CCHMC Pharmacy: NA. 
6. Discarded Tissues: NA 
7. Tissue Banks: NA 
8. Genetic Studies: NA 
9. Institutional Biohazard Committee: NA 
10. Imaging: NA 
 
VIII. POTENTIAL BENEFITS 
 
There is a potential for direct benefit by participating in this study if the clinical 
neurophysiological information is useful to the managing physician. 
 
IX. POTENTIAL RISKS, DISCOMFORTS, INCONVENIENCES, AND 
PRECAUTIONS  
 
1. 
Known and potential discomforts or hazards of single and paired pulse TMS: 
Single and paired pulse TMS has been used at CCHMC under Dr. Gilbert’s direction 
since 2001 for research only. Potential discomforts are mild and transient. In a prior study 
of 40 healthy and ADHD children, Garvey et al asked children to rank TMS compared to 
other childhood activities. TMS was ranked preferable to 1) a “shot”; 2) going to the 
dentist; and 3) a long car ride 43. The following mild, transient effects were reported in 
our prior study of 35 children and adults: scalp discomfort (12%), hand weakness (9%), 
headache, neck pain, arm pain, and arm tingling (6%), hand pain, decreased hand 
dexterity, hearing changes, and tiredness (3%). All of these had resolved by the following 
day. There were no physical findings after TMS supporting the subjective descriptions of 
loss of strength or dexterity. Furthermore, a consensus statement from the international 
TMS community concluded that “single-pulse and paired-pulse TMS in pediatrics is safe 
for children two years and older.”44 A prior common concern about use of TMS was the 
risk of seizures45. We follow recommended guidelines 45 and have seen no seizures in 
children or adults studied at our center. In addition, more recent studies even in children 
with epilepsy suggest that the risk of TMS inducing seizures is quite low.  
 
2. 
Precautions, risk minimization: 
The protocols include a number of precautions to minimize risk. The TMS laboratory was 
established in 2001 in consultation with Dr. Eric Wassermann, an internationally known 
researcher in transcranial magnetic stimulation. Dr. Gilbert or Dr. Wu will be present 
during TMS. All subjects will wear 34 NRR earplugs or headphones during TMS if the 
head is stimulated at an intensity of over 90%. Standard exclusion criteria are applied for 
participation in this study. Detailed questioning for any adverse events will occur after 
the experiment and the next day after the study. 
 
3. 
The method of monitoring study conduct.  

 
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Adverse events will be reviewed using direct questions with a detailed review of systems 
on the day of the study and by phone the next day. The principal investigator is 
responsible for reporting adverse events to Cincinnati Children's Hospital Medical Center 
Institutional Review Board. 
 
4. 
Methods for maintaining data quality and confidentiality:  
Data are maintained in case report folders identified only by an anonymous subject ID, in 
the locked principal investigator’s office which is situated in a locked office suite. All 
data kept in computerized files are in computers or a server with restricted, password-
protected access. 
 
5. 
An assessment of accrual (timely enrollment) and the handling of dropouts.  
Accrual rates will be monitored by the principal investigator.  
 
7. 
Data Safety Monitoring Plan:  
The data safety monitoring plan is to review adverse events at weekly meetings of the 
TMS research group.  
 
X. PROPOSED RISK BENEFIT ANALYSIS 
 
In the opinion of the investigative team, this study, based on our experience 
administering TMS as well as the published literature on TMS, involves minimal risk, 
with potential for direct benefit.  
 
XI. SECURITY/CONFIDENTIALITY 
Privacy of the individuals participating in this proposed study will be maintained through 
non-identifying subject ID codes, locked storage and password protected files.   The 
study log will be maintained in a password protected folder on the desktop computer of 
the principal investigator.   Case reports and spreadsheets will refer to subjects by number 
only.  Subjects will be informed that, if necessary, the IRB or FDA may review the data. 
 
XII. DURATION 
We estimate the proposed study to take 6 years to complete. 
 
XIII. FUNDING 
Movement Disorders Research Fund.  
Tourette Association of America until 4/30/2020. 
 
XIV. PAYMENT FOR STUDIES 
There will be no charges to patients or to third party payers related to participation in this 
study. Subjects will be paid $15/hour (prorated) for completing this study. 
 
Payment will be in the form of a reloadable debit card (ClinCard). We will provide the 
card and load money onto the card after each completed visit based on the schedule listed 
above. We will also administer a handout that will explain how to use it.   
Because this research study involves payment for participation, we are required by 
federal Internal Revenue Service (IRS) rules to collect and use participants’ social 

 
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security or tax ID number (SSN) in order to track the amount of money that we pay.  
Unless we have been given specific permission for another use of participants’ SSN 
related to this research, we will only use the participants’ SSN to keep track of how much 
money we pay to them and their SSN will not be used as part of this research. 
 
XV. RECRUITMENT 
Potential participants will come from several sources: 
 
Clinically affected subjects will be recruited from the neurology inpatient service, the 
neurology consult service, and subspecialty clinics in neurology, neurosurgery, 
orthopedics, rehabilitation medicine, developmental and behavioral pediatrics, and 
psychiatry. For many physicians in these subspecialties, basic neurophysiological 
principals are already understood because these physicians use peripheral nerve 
Electromyography (EMG)/Nerve Conduction Studies (NCS) in patient care. We will 
inform relevant subspecialties at faculty meetings or through individual, in-person 
meetings. Persons interested in referring a patient for TMS will call or email the study 
staff and there will be physician to physician discussion of the neurological condition. 
Healthy persons will be recruited via advertisement.  
 
Before any study measures are performed, the patient’s physician, or the study 
physicians, will explain to the subject/parent that TMS is cleared by the FDA for treating 
refractory depression but is not approved for diagnosis of conditions affecting the motor 
system. The patient will be told that the TMS measures will only be used for research 
purposes. The children/parents will be given an informed assent/consent form to read.  
This will include a number at which the subject/parent may reach the study physicians, in 
the case that they have any questions.  After all questions are answered and 
assent/consent signed, the study can proceed. 
 
Individuals have the option to choose not to participate in the study without revealing the 
reason.  Participation or non-participation will not affect the provision of health-care to 
the subject in any way. 
 
XVI. PERMISSION OF PATIENT’S ATTENDING PHYSICIAN 
Managing physicians interested in these TMS procedures will directly contact members 
of the TMS study team, so they will be aware of the study. 
 
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