Impact of Repetitive Transcranial Magnetic Stimulation (TMS) on Spike Frequency and Brain Connectivity in Children With Benign Epilepsy With Centrotemporal Spike (BECTS)
Phase: NA
Conditions: Benign Epilepsy With Centrotemporal Spikes, Language Problems, Learning Disorders
Sponsor: Stanford University

Transcranial Magnetic Stimulation (TMS) for Benign 
Epilepsy with Centrotemporal Spikes (BECTS) 
[TMS4BECTS] 
Protocol Number: 37514 
National Clinical Trial (NCT) Identified Number:  04325282 
Principal Investigator: Fiona Baumer, MD 
Funded by:  NIH NINDS 
Version Number:  1.1 
30 June 2020 
 
OVERVIEW 
 
Epilepsy affects 1% of all children, and patients with epilepsy report that cognitive problems 
diminish their quality of life as much or more so than seizures. [1,2] Benign epilepsy with 
centrotemporal spikes (BECTS) is the most common pediatric epilepsy syndrome, accounting for 
15-25% of all cases. Children have frequent, focal, sleep-potentiated interictal epileptiform 
discharges (IEDs) emerging from one or both motor cortices, but typically have only rare seizures 
occurring nearly exclusively out of sleep. BECTS self-resolves in adolescence, so treatment is 
often not initiated.[3] Despite the relatively mild course, children with BECTS develop a variety of 
cognitive deficits, most prominently in language[4–6] that may persist even after the epilepsy 
resolves.[7,8] Language difficulties correlate with atypical maturation of the language network. 
Specifically, lateralization of language function to the left hemisphere is either delayed[9–11] or 
permanently disrupted[8] and functional connectivity within the language network[10–13] is 
decreased. We do not understand the pathophysiology of language dysfunction in BECTS and 
have no specific treatments to target it. 
 
Many speculate that frequent IEDs disrupt language development in BECTS, but studies focusing 
on the correlation between IED frequency and cognition have had variable results.[8,14–18]  
Several lines of evidence suggest that the interaction between IEDs and the language network 
may be critical. First, children with BECTS and left-lateralized IEDs have greater language 
dysfunction than those with right-lateralized IEDs.[8,17,18] Second, functional magnetic 
resonance imaging (fMRI) shows that the inferior frontal gyrus, a key structure in the language 
network, has increased blood flow during IEDs. Third, plasticity of the motor cortex correlates 
strongly with children’s performance on language learning tasks.[19] Current pharmacologic 
therapies for BECTS focus on stopping seizures but not IEDs. The impact of IEDs on language 
presents a critical gap in our knowledge with both biological and clinical significance. 
 
High-density electroencephalogram (HD-EEG) alone and high-density EEG paired with single 
pulses of transcranial magnetic stimulation (spTMS-EEG) can help map the impact of IEDs on 
brain connectivity in children with BECTS. HD-EEG is a minimally-invasive, well-established 
method for assessing connectivity between brain regions with much greater temporal specificity 
than fMRI. TMS-EEG is the only non-invasive way to directly assess the influence of one brain 
region over another. In TMS, an extracranial magnetic field is used to induce an intracranial 
electrical current, which can be traced to structurally and functionally linked regions. While 

spTMS-EEG interrogates the brain state at the moment of stimulation, repetitive trains 
administered in specific patterns (repetitive TMS or rTMS) can change underlying cortical 
excitability.[20] Studies of rTMS to treat seizures[21] as well as our preliminary data in BECTS 
patients suggest that IEDs transiently decrease in frequency after rTMS. Therefore, rTMS will 
allow us to test how connectivity changes with IED suppression. 
 
The purpose of this study is to evaluate if rTMS to the motor cortex: (1) reduces IEDs in children 
with BECTS; and (2) changes brain connectivity between the motor cortex and language 
regions.  
Literature Review 
i. Children with BECTS have disturbed language skills. Detailed neuropsychological profiles show 
deficits in many language domains, including reading, expressive and receptive language, and 
phonological processing.[4,5] Children have near-normal language abilities at the time of 
diagnosis of BECTS but their language skills lag behind their peers over time,[4,22] suggesting 
that BECTS can be classified as a mild epileptic encephalopathy. The few studies to formally 
assess language in adults with a history of BECTS have found persistent deficits.[7,8] 
 
ii. Maturation of the language network is also altered in BECTS. Language typically lateralizes to 
the left hemisphere in childhood. Neurocognitive, evoked potential,[8,18] and fMRI[23–25] studies 
find that this process is delayed[9–11] or permanently disrupted[8] in BECTS. Language 
performance varies with the degree of disruption.  
 
iii. Interictal epileptiform discharges (IEDs) may interrupt normal language development. 
Substantial evidence indicates that IEDs cause transient changes in perception, processing, and 
reactivity.[26] Disorders like Landau-Kleffner Syndrome – in which patients experience a sudden 
language regression accompanied by constant IEDs throughout sleep but few EEG abnormalities 
during the day – suggest that frequent nocturnal IEDs may be sufficient to disrupt cognition.[27] 
In BECTS, the effects of IEDs have largely been inferred from studies correlating diurnal[14] and 
nocturnal[15,16] IED burden with degree and type of cognitive dysfunction, though not all studies 
have found a correlation.[4] Location of IEDs likely matters; of the 60% of BECTS patients with 
unilateral discharges, those with left-lateralized IEDs have greater language dysfunction while 
those with right-lateralized IEDs have greater spatial dysfunction.[8,17,18] 
 
iv. Brain connectivity is altered in BECTS, potentially due to IEDs. fMRI studies suggest that in 
BECTS, the epileptogenic motor cortices have abnormal structural and functional connections 
with various regions.[10–13,28–33] Broader resting state networks[33–35] are also altered. A 
series of studies[9–11,36] found that BECTS patients have decreased connectivity between the 
motor cortex and language regions, but these studies did not account for the effect of IEDs. In 
contrast, Xiao et al.[33] found that connectivity between the motor cortex and inferior frontal gyrus 
increases after IEDs, and that greater connectivity correlates with worse language function. This 
literature suggests that the immediate impact of IEDs on connectivity may differ from persistent 
connectivity changes that develop with chronic IED exposure. This highlights a need to investigate 
both types of connectivity. Furthermore, connectivity differences may be especially prominent 
during language tasks compared to when at rest.[24]  
 
v. EEG-based connectivity analysis offers superior temporal specificity for the study of IEDs. 
Assessment of IEDs using fMRI is limited by the poor temporal specificity of fMRI. IEDs last 
hundreds of milliseconds whereas blood flow changes measured by fMRI require multiple 
seconds. In contrast, EEG is a temporally-precise method for studying the impact of IEDs on 
network connectivity.[37] High-density EEG (HD-EEG) specifically estimates the underlying 
source of this activity. Surprisingly, however, few EEG connectivity analyses have been done in 
children with  BECTS.[38–41] Only one study assess the impact of IEDs in wakefulness and it is 
limited by a small sample size of children with only right hemispheric IEDs, thus obscuring the 
impact of IEDs on language network connectivity. Furthermore, all EEG connectivity studies in 
BECTS have been done in the resting state, whereas language network connectivity is likely to 
be better measured when the network is engaged in a task. Therefore, a significant gap persists 
in understanding connectivity in BECTS. 
 

EEG connectivity analysis has been limited by the concern for volume conduction, a problem that 
arises when activity in nearby electrodes is correlated not because the regions are connected but 
rather because the electrodes are picking up neuronal activity from a single common source. 
Fortunately, new connectivity metrics, such as the weighted Phase Lag Index (wPLI),[42] are 
quite robust against volume conduction. To calculate wPLI, the EEG signal is broken down into 
frequency bands (i.e. alpha, beta) and the phase of the waveforms in each band is compared 
across brain regions; non-zero phase lags are considered true connectivity.[42] wPLI is a 
continuous metric ranging from 0-1, where 0 indicates no connectivity and 1 indicates perfect 
connectivity. wPLI offers better spatial-specificity when it is calculated from a high number of EEG 
electrodes. 
 
vi. Combining transcranial magnetic stimulation with EEG (TMS-EEG) will shed new insight into 
BECTS by directly probing the epileptogenic motor cortex. TMS is the only non-invasive method 
to directly interrogate the influence of one brain region over another. Single pulses of TMS 
(spTMS) introduce a current into the stimulated cortex, the immediate downstream effect of which 
can be mapped by EEG on the order of milliseconds.[20] The strength of the magnetic pulse 
required to induce a muscle twitch (typically in an intrinsic hand muscle like the abductor pollicis 
brevis [APB]) is known as the motor threshold (MT). The EEG data recorded immediately after 
TMS pulses can also be analyzed with connectivity measures like wPLI. Additionally, TMS elicits 
motor evoked potentials (MEPs) recorded by surface EMG as well as TMS-EEG evoked 
potentials (TEPs) broadly across the brain. Finally, repetitive trains of TMS (rTMS) induce long-
lasting changes in brain excitability,[43,44] and inhibitory rTMS can reduce IED frequency in 
epilepsy patients.[21,45] rTMS can therefore be used to model how changes in IED frequency 
affect brain connectivity.   
 
 
Significance 
 
The impact of IEDs on children with BECTS and other epilepsies is not understood. We typically 
do not treat IEDs due to our poor understanding of their significance. In this trial, we will evaluate 
if rTMS could be a treatment for focal IEDs in pediatric epilepsy and will assess the impact of such 
a treatment on the language network. Successful completion of the proposed studies will 
determine if IEDs directly alter connectivity between the motor and language regions in children 
with BECTS, if such connectivity differences persist even during IED-free periods, and whether 
connectivity differences correlate with language dysfunction. We will utilize rTMS as a novel 
method to suppress IEDs in BECTS in order to determine if rTMS could be a treatment for focal 
IEDs and what the impact of such treatment on the language network might be. Together, these 
data lay the groundwork for highly innovative future neurostimulation trials targeting IEDs in not 
only BECTS but also a wide range of pediatric epilepsy syndromes. 
 
 
 

RISKS/BENEFITS 
 
Potential Risks:  
(1) Risks of EEG Recording: EEG does not cause harmful effects, though some children 
may find the EEG caps uncomfortable.  
(2) Risks of TMS: TMS is considered very safe in both adults and children.[46–49] The main 
concern is that TMS could induce a seizure, but this is a truly rare phenomenon. In our 
preliminary study of 14 children with BECTS, none had seizures with TMS; a separate 
study also reported no seizures in children with BECTS.[19]  
a. In considering the TMS literature more broadly, the main risk of seizures is in 
individuals: a) receiving high-frequency repetitive (>2Hz) stimulation or 
stimulation using the H-coil (which allows for deeper stimulation); or b) taking 
certain psychiatric medications.  
b. TMS is safe in children. In the most recent review of over 4000 children with and 
without neuropsychiatric disease, the 3 reported new seizures all occurred with 
high frequency TMS; in addition, 2 of these children were on psychiatric 
medications and one child received H-coil stimulation.[49] Another recent study 
found no seizures in 165 healthy children receiving a form of repetitive TMS.[50]  
c. Risks of seizures induced by TMS is also not clearly elevated in patients with 
epilepsy. In one study of 152 patients with epilepsy having weekly TMS at 1 Hz 
or less, none had induced seizures.[47] A review[51] found that 4 of 280 epilepsy 
patients had a seizure around time of TMS, reflecting a risk of 1.4%. However, 
these patients also had refractory and frequent spontaneous seizures at other 
times. In children with epilepsy, TMS is very safe; some children with very difficult 
to control seizures (multiple per day at baseline) self-reported a slight increase in 
seizures for 3 days after TMS but then a return to baseline. The authors felt this 
was a minimal increase in risk in this population.[49]  
d. Other potential risks of TMS include hearing problems from the sound of the coil 
or scalp burns if the EEG electrodes are excessively heated by the magnet. 
These are mitigated by the use of noise-cancelling ear protection and by 
specially-cooled coils. Minor potential side effects include scalp discomfort, 
headache, lightheadedness and boredom. There is a theoretical risk that rTMS 
could lead to a change in mood, but this is highly unlikely when applied to the 
motor cortex. Procedures to minimize the risk of TMS are described in more 
detail below. 
(3) Risks of Collecting Personal Information: One potential risk is breach of confidentiality 
related to the collection of sensitive information, but this will be minimized by following 
standardized procedures to protect all such information.  
 
Protection Against Risk:  
Risk of EEG: We will monitor the children during the studies and can adjust or remove the EEG 
caps if there is any discomfort. 
Risk of TMS: We protect against the risk of seizure by having a pediatric epileptologist (Dr. 
Baumer) in the room during all TMS procedures and actively monitoring the EEG during 
stimulation so that stimulation can be stopped if there are any concerns. Furthermore, we use 
only single pulse stimulation and low-frequency repetitive stimulation (<1Hz), both of which 
have been well studied and are quite safe. Dr. Baumer will be present for all TMS sessions. 
She has extensive experience performing TMS in children and clinical expertise in the 
management of seizures in children. Furthermore, all TMS will be done at Stanford University 
in close proximity to Lucile Packard Children’s Hospital. Any persons assisting with the TMS 
will undergo TMS safety training and seizure training. All children wear noise-cancelling 

headphones to protect their ears from the TMS click. Scalp burns are prevented using cooled-
coils. We speak with children throughout the TMS session so will actively monitor them for any 
other discomfort. If there is minor discomfort due to the TMS, the study will be paused and 
potentially halted.   
Risk of Loss of Privacy: To maintain confidentiality, we will restrict access of private health 
information exclusively to the PI, necessary personnel of the Data Safety Monitoring Board 
and research staff.  We will de-identify all data obtained from subjects. We will store all data 
on a PGP encrypted server within the School of Medicine at Stanford University. All hard 
copies of data, including medical records and copies of informed consent, will be maintained 
in a locked file cabinet in the lab. All members of the research team will undergo HIPPA 
training. 
 
Additional Protections for Children:  The study is recruiting children as BECTS is a pediatric 
condition not present in adults; there are also no good animal models of this condition. The 
study procedures will be reviewed with the children in language they can understand before 
the protocol begins and children will be told they can stop the study at any time. Parents of 
children participating will also be informed that they are free to choose not to participate and 
may withdraw at any time. We will obtain assent from children who are of an appropriate age 
(typically >8yo of age). We will frequently check-in with children throughout the study to 
ensure that they are comfortable with continuing the procedures.  
 
Potential Benefits: IEDs lead to cognitive problems in some children. Participants may benefit by 
having a reduction in IEDs at least temporarily. Additionally, we will learn more about the 
pathophysiology of BECTS, which may improve treatment in the future. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

OBJECTIVES & ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
RATIONALE 
 To evaluate if rTMS 
reduces the frequency 
of IEDs in children with 
BECTS. 
Change in IEDs/minute 
induced by active rTMS 
vs. change induced by 
sham rTMS. Change will 
be calculated by 
comparing IED count in 
the 20 minutes after 
rTMS with IED count in 
the 20 minutes before 
rTMS. 
 This will assess if rTMS 
reduces IED frequency 
when compared to a 
sham control. 
 There is evidence that 
rTMS reduces cortical 
excitability and hence may 
reduce generation of IEDs. 
To evaluate if rTMS 
reduces connectivity 
between the motor and 
language regions in 
children with BECTS. 
Change in weighted 
phase lag index (wPLI) 
(an EEG-based 
connectivity measure) 
between the stimulated 
motor cortex and the left 
inferior frontal gyrus 
induced by active rTMS 
vs. sham rTMS. Change 
will be calculated by 
comparing wPLI in the 
20 minutes after rTMS 
vs. the 20 minutes 
before rTMS. 
  
We will collect 2 types of 
EEG data before and 
after the active/sham 
rTMS: (a) spTMS-EEG, 
and (b) resting-state 
EEG; and Connectivity 
will be calculated for 
each of these data types 
separately.   
This endpoint will help us 
determine the 
downstream effect of 
rTMS on other brain 
networks. 
Epilepsy is a network 
disorder and fMRI studies 
suggest that IEDs from the 
motor cortex increase 
connectivity between the 
motor cortex and inferior 
frontal gyrus. Therefore, 
inhibition of IEDs and 
increased inhibition of the 
motor cortex may 
decrease connectivity 
between the motor cortex 
and inferior frontal gyrus. 
 
 
 

STUDY DESIGN 
Overview: Children with BECTS will undergo both active rTMS and sham rTMS to the 
epileptogenic motor cortex. We will compare the impact of active vs. sham rTMS on: (a) IED 
frequency; and (b) motor-to-language connectivity. We hypothesize that active rTMS induce a 
greater decrease in: (a) IED frequency and (b) motor-to-language cortex connectivity than sham 
rTMS.  
 
Study Stage: Stage 0 
 
Study Design: Sham-controlled cross-over study in which all participants will receive both active 
and sham rTMS, with randomization of order of intervention. We will have repeated-measures 
data as subjects will undergo both sham and real rTMS on different days. The potential missing 
data issue will be evaluated thoroughly prior to the analysis. Multiple imputation will be applied if 
needed. 
 
Assignation Methods: Not applicable, subjects will undergo both active and sham rTMS. 
 
Study Arms: All subjects will participate in each arm, and arm order will be randomized on a per-
subject basis. Participation in each arm will take approximately 4 hours (including set-up of 
equipment and data recording). Arms will be separated by at least 1 week.  
Arm 1 (active rTMS): 1000 pulses of rTMS administered via an active TMS coil at 1Hz to 
the motor cortex. EEG and spTMS-EEG data will be recorded during the 20 minutes prior 
to and following the rTMS.  
Arm 2 (sham rTMS): 1000 pulses of rTMS administered via a sham TMS coil at 1Hz to the 
motor cortex. EEG and spTMS-EEG data will be recorded during the 20 minutes prior to 
and following the rTMS. 
 
Control Groups: As above, each subject will receive sham rTMS and thus serve as their own 
control. This within-subject analysis is meant to reduce the influence of inter-subject variability in 
IED frequency (which can be high) on the results. A potential limitation is that a sham-control may 
be excessively stringent, given that other studies have found clinically meaningful improvements 
when sham rTMS is used (i.e. in post-stroke motor recovery), suggesting that even sham rTMS 
can exert a meaningful physiologic influence. A second limitation is that IED frequency and 
connectivity may be influenced by behavioral state, which may change between days or 
behavioral states; we will interact with participants and monitor EEG to maintain behavioral state. 
 
rTMS Intervention: The 1000 pulses of 1Hz rTMS will be delivered in 2 blocks of 500pulses 
administered over a total of 16-20minutes. Changes in cortical excitability after 1Hz rTMS 
typically last approximately the duration of the rTMS itself, so we will measure changes to IEDs 
and connectivity in the 15-20minutes directly before and after rTMS. If a subject only tolerates 
500 pulses, we will restrict measurements to the 10 minutes before and after the rTMS; we will 
shorten the second intervention accordingly. If a subject does not tolerate 500 pulses, they will 
be excluded for inability to tolerate the protocol. We will separate the active and sham rTMS 
session by at least 1 week to ensure adequate wash-out of effects, as is standard in rTMS trials. 
 
RECRUITMENT & RETENTION 
Anticipated number to be screened: We expect to recruit 36-40 subjects and anticipate 
screening 70-80 subjects to reach this target enrollment. 
Anticipated Sample Size: We expect to recruit 36-40 subjects over 4 years, at a rate of 9-10 
subjects per year. Subjects will be between the ages of 5-16 years. Based on the typical 
epidemiology and presenting age of BECTS, we expect 60-70% of subjects to be male and 80% 
of subjects to be between the ages of 7-12 years. Based on the demographics of the patient 

population served by Lucile Packard Children’s Hospital and other Bay Area medical centers, 
subjects are expected to be 35% Caucasian/Non-Hispanic, 25% Caucasian/Hispanic, 30% 
Asian, 4% African American, and 6% Mixed/Other. Adults will not be included as BECTS 
resolves in adolescence. 
Planned Recruitment Strategies: The study will recruit children with BECTS seen at Lucile 
Packard Children’s Hospital (LPCH) outpatient neurology clinic or the neurophysiology 
laboratory. Additionally, children will be recruited if they are referred to the study from 
surrounding child neurology practices. The catchment area for LPCH extends south into 
California’s Central Valley, north to the Oregon border and east to Reno, Nevada. The patient 
population is ethnically and socioeconomically diverse. In addition to direct referrals, we will 
screen the LPCH medical records to identify potential participants and request referrals from 
their treating providers. We will advertise the trial online and during speaking/outreach events 
with patient advocacy groups to allow for direct referrals from interested patients and their 
families. Screening and data gathering will not occur in a public setting. 
Retention: Subjects must return for 2 sessions separated by at least 1 week. To improve 
retention, we will endeavor to schedule the 2 sessions as close together as possible, and 
specifically within 4-8 weeks of one another. We will frequently check-in with the participant, 
allow for flexibility in the scheduling, send reminder emails and phone calls, and provide a 
reasonable stipend for the child’s time ($25/session). 
Participant Incentives: Children will be given a $25 gift card at the completion of each session. 
This is meaningful enough to thank the child for his or her effort without being significant enough 
to unduly influence the parents when they are providing informed consent. The parents will also 
be reimbursed for travel costs such as parking. 
 
JUSTIFICATION FOR STUDY DESIGN AND DOSE 
Active rTMS: The active intervention is 1Hz rTMS applied with an active coil to the motor 
cortex. Low frequency (1Hz or slower) rTMS can induce changes in brain excitability lasting 
minutes to hours [43,44] and has been shown to reduce IED frequency in patients with 
refractory focal epilepsy.[21,45] Focal changes induced by rTMS have downstream effects on 
brain regions connected to the stimulated motor cortex. Theoretically, 1Hz active rTMS will 
reduce cortical excitability of the epileptogenic motor cortex, thus reducing IED frequency. 
Furthermore, it will alter connectivity between the epileptogenic motor cortex and other 
connected cortices. Thus, we are measuring IED frequency and EEG-based connectivity. 
 
Sham rTMS: The sham control is 1Hz rTMS administered with a sham coil, which will help 
account for the impact of other components of the experimental session (i.e. fear, boredom, 
variable attention).  
 
rTMS Administration: The rTMS (sham and active) will be administered by a study team 
including Dr. Baumer and a research assistant over the course of 2 sessions separated from 
one another by at least a week. This will occur in a room dedicated to the TMS session. The 
rTMS will be administered as 2 blocks of 500 pulses applied at 1Hz to the motor cortex. A break 
of 2-3 minutes between blocks is acceptable if needed to allow for maximum participation. The 
sham rTMS will be administered using the same parameters and same stimulation site, but the 
intensity of the sham coil is such that it is not expected to induce an intracranial current.  
 
 
 

RANDOMIZATION & BLINDING:  
The order of conditions (active vs. sham rTMS) will be randomized on a per-subject basis. A 
random number generator will be used to create a random list using numbers 1-40. Subjects 
whose recruitment lines up with an even number will receive active rTMS in the first session and 
sham rTMS in the second session and vice versa for odd numbers. Participants will be blind to 
the condition order. The sham rTMS will be administered using the same parameters and same 
stimulation site as the active stimulation. The intensity of the sham coil is such that it is expected 
to create a scalp sensation without inducing an intracranial current. It is possible that some 
subjects will recognize a difference between the 2 sessions, and we will ask them after each 
session to assess if it was active vs. sham rTMS. If subjects can consistently identify a 
difference, than we will report that blinding was not successful in our final analyses. 
 
Researchers will not be blinded during the session, but the data will be coded prior to analysis 
and the person performing the analysis will be blinded to the session type.  
 
STUDY PROCEDURES 
Screening: For subjects referred by their physician, the study team will confirm the diagnosis of 
BECTS with the referring provider. Parents of participants will then be called by a member of the 
research team and screened on the inclusion and exclusion criteria. If the parents primarily 
speak a different language than English, the screening will be conducted with the help of an 
interpreter or by a study team member fluent in that language.  
 
For subjects who self-refer to the study, the study team will review the inclusion and exclusion 
criteria with the family. Subjects who screen-in and consent to the study will be asked to bring a 
physician's note stating their diagnosis and prior EEG findings. 
 
Screening will be done within 2 months of participation. If this time window is delayed, the 
inclusion/exclusion criteria will be reviewed on the day of the first intervention to ensure the 
subject is still eligible.  
 
Informed Consent & Assent: Since informed consent is required from both parents and/or 
legal guardians if they are reasonably available (i.e. not deceased, imprisoned, whereabouts 
unknown or not involved in the care of the child), informed consent will be first obtained over the 
telephone with the help of an interpreter if necessary. Assent will be obtained from the 
participating child on the day of the first rTMS session. 
 
Coding of Subjects & Randomization: Subjects will be assigned a study-number based on 
the order of consent. This will be used to label all information and the CRF. In addition, the 
study number will be compared against a list of randomly generated numbers to determine if the 
subject will receive active or sham rTMS first (as described in the section on randomization). 
 
Baseline Assessments:  
Clinical & Demographic Data: We will collect the following variables: age, gender, age of first 
seizure, number of lifetime seizures, anti-seizure medications, and side of centrotemporal IEDs 
(left, right or bilateral) from the medical chart. We will measure degree of right-handedness with 
the Edinburgh Handedness Questionnaire51 and parental education and socioeconomic status 
with The Hollingshead Four-Factor Index. This coded data will be kept in subject-specific binders. 
 
Anti-Seizure Medication Dose and Level: We will record the daily dose (both absolute and 
dose-by-weight) of all medications that the subject is receiving. If the subject is on an anti-
seizure medication, we will record a level within 2-4 weeks of the first intervention day. We will 

use a clinically-drawn level if this is available or otherwise draw a serum level as part of the 
experimental procedure.  
 
Neurocognitive Testing: All subjects will complete the Weschler Abbreviated Scale of 
Intelligence – Second Edition (WASI-II)52 to measure IQ and the Test of Variable Attention 
(T.O.V.A.)53 to provide a continuous measure of attention. The Clinical Evaluation of Language 
Fundamentals 5 (CELF-5)54 core language score will be collected to provide an age-normalized 
measure of language function. These may be collected anytime in the 2-8 weeks prior to the 
first intervention. 
  
MRI: If subjects have undergone an MRI as part of clinical care, we will request that they bring a 
copy of this MRI on disc to be used for neuro-navigation for the rTMS session. If an MRI is not 
available, we will use a dummy head model. 
  
First rTMS Session: BECTS subjects will wear a 64-channel TMS-compatible high-density 
EEG cap while watching a video and listening to white noise. We will use neuro-navigation 
software to co-register the head and electrode positions to a representative pediatric brain or to 
the subject’s MRI if one is clinically available. At the beginning of the session, we will monitor 
the EEG recording to determine if IEDs are unilateral or bilateral. We will then measure the 
resting motor threshold (rMT) for the hemisphere with the higher IED burden or the left 
hemisphere if IEDs are bilateral. The rMT will be established in the standard way.55 We will 
apply 150 single pulses of TMS (spTMS) at 90% rMT in 2 blocks, with additional resting-state 
EEG (without spTMS) data gathered between these blocks. The patient will then receive either 
1000 pulses of 1Hz rTMS at 90% rMT or 1000 pulses of sham 1Hz rTMS to the motor cortex, 
depending on the prior randomization. After the rTMS, we will repeat the blocks of spTMS 
interspersed with resting-state EEG.  
 
Second rTMS Session: The second session will occur at least one week after the first session, 
but ideally will be done within 2-4 weeks of the first. In the second session, the procedures will 
be repeated as above except the other intervention will be administered. Of note, occasionally 
IED-predominance shifts hemispheres between EEGs. We will stimulate the same side as 
received rTMS during the first session unless >80% of IEDs are emerging from the contralateral 
hemisphere. If this occurs, we will stimulate the contralateral hemisphere and request that the 
subject come in for a third “tie-breaker” session. 
 
 
 
 
 

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Other Rationale