TMS Related Biomarker Assessments
Phase: NA
Conditions: Schizophrenia Schizoaffective, Schizophrenia
Sponsor: University of Maryland, Baltimore

Title:   
 
TMS Related Biomarker Assessments   
NCT number:  
NCT05660018 
Document date:  
01/18/2023  
PI:  
 
 
XIAOMING (MICHAEL) DU, PHD 
 
 
 

Study protocol 
Background 
Electrical neural oscillations of the brain can be measured at many levels, ranging from 
single cell to local ﬁeld potentials in animals, to large-scale synchronized activities in the 
human scalp. New evidence suggests that there may be common underlying abnormalities 
in oscillatory activities that are associated with schizophrenia-related cognitive and 
functional impairments. There is currently no treatment for these electrical oscillation 
dysfunctions. Transcranial magnetic stimulation (TMS) provides a non-invasive means for 
altering brain electrical neural activity. TMS has been approved by FDA for the treatment of 
depression and many other mental disorders. It has been used in a wide range of clinical 
research, especially in neurology and psychiatry. The investigators aim to develop TMS 
paradigms that will modulate brain responses during basic sensory to more complex 
cognitive performance and determine the parameters in anatomic locations and TMS 
modalities that may e\ectively and safely modulate neural activities. If the current 
experiments successfully identiﬁed TMS methods/paradigms that improve neural 
oscillation and cognitive performances in schizophrenia patients, in the future (not part of 
the current protocol), the investigators can then develop speciﬁc TMS treatment that may 
correct abnormal brain function and improve cognition and clinical symptoms of 
schizophrenia. 
The purpose of this research is to better understand how brain electric activities are 
changed during TMS. We will test the hypothesis that repetitive TMS pulses, such as theta-
burst stimulations, and conventional low- and high-frequency stimulations (Huang et al 
2005 Neuron; Williams et al 2018 Brain), will facilitate EEG neural oscillatory activities, 
cognitive behaviors, TMS-related responses, and fMRI brain circuitry measure 
improvement in schizophrenia patients. 
 
Study Procedures 
General TMS procedures: Motor threshold (MT): Motor threshold testing will start with 
around 50% intensity and an inter-stimulus interval (ISI) of about 0.2 Hz. The coil is moved 
in di\erent directions and TMS intensity is gradually increased or decreased to ﬁnd the site 
that most reliably elicits ﬁnger twitches. The intensity is then adjusted until about 5 of 10 
consecutive pulses (100% MT) result in a ﬁnger twitch or ﬁnger muscular evoked potential 
(MEP). Motor evoked potential (MEP): MEP will be recorded from surface electrodes placed 
on one of the ﬁngers. The minimal intensity required to elicit an EMG response of at least 
50 uV with 50% probability in a fully relaxed muscle (Rossini et al., 1994) is the resting 

motor threshold (RMT). We may mark the stimulation sites in the neural navigation system. 
During RMT tests, subjects are asked to keep their muscle relaxed. During active motor 
threshold (AMT) tests, subjects are instructed to make an isometric contraction between 
the thumb and index ﬁnger at certain percentage of maximum force before the TMS pulse. 
Subjects are instructed to relax, with head holding still or maintained by resting on 
chinrest. TMS will be administered using a Magstim or PowerMAG TMS machine. TMS single 
pulses are applied to the brain guided by the Brainsight (Rogue Research, Montreal, 
Canada) brain navigation system and the subject's anatomical MRI. The brain navigation 
system permits more precise TMS placement on the proposed anatomic regions. TMS will 
not exceed 120% magnetic ﬁeld intensity relative to the patient's observed RMT. The TMS 
coils are ﬁxed using a mechanical arm to keep the coil to scalp relationship constant 
throughout the experiment. Patient participants are required to give adequate responses 
on the Evaluation to Sign Consent (ESC) form prior to study entry to ensure that they 
understand the risks of the study and how to respond if they experience any distress or 
wish to withdraw from the study. A score of 10 or more out of the total possible score of 12 
on ESC will meet the inclusion criteria. 
 
MRI procedures: MRI will be done in a 3.0 Tesla magnet. During MRI, the subjects will 
perform resting and behavioral and cognitive tasks with visual and auditory presentations 
to be shown through a screen and head/ear phones. In some tasks the subject will be 
asked to simply rest, or to use a response pad. The speciﬁc tasks may include structural 
images for gray and white matter, resting scan, tasks that measure eye movement, motion 
perception and prediction, attention/working memory, learning and reversal learning tasks, 
ﬁnger tapping, and/or simple auditory and visual stimulus tasks. Each subject will perform 
only a subset of these tasks. Behavioral response, eye movement, basic physiological 
measures including breath, blood pressure, pulse, skin conductance can be recorded 
during imaging. Each subject will be inside the scanner for about 1 hour at di\erent time of 
the rTMS treatment procedure. About four fMRI scans will be done in each sub-study. A 
repeat of scan is possible if other issues have led to incomplete or poor quality imaging 
data in previous scans. If a participant is not sure whether there are metal in their head or 
eye, for example past gunshot wound or involving in welding or metal drilling without eye 
protection, we may ask the participant to have a head x-ray of the head to make sure there 
is no metal in eyes or head before the MRI scan. The x-ray will involve a small amount of 
radiation, although the risk associated with a one-time x-ray is similar to any x-ray a doctor 
may prescribe during a clinic visit. They can refuse the x-ray and not participate in the MRI 
portion of the study. We may use some clinical assessments such as SCID done in other 
studies or previous clinical assessments if repeating them is not necessary. Similarly, data 

collected here may be combined with data from other studies when appropriate. Data 
collected from this study may be combined with other related studies (e.g., brain imaging 
data collected from other protocols where combining data is stated) during data analyses. 
Subjects may not necessarily be excluded or withdrawn if they complete some but not all 
of the tests and assessments although we encourage them to complete all tasks.  
 
EEG/ERP recording: subjects will be asked to wear a cap containing electrodes. Electrode 
paste will be used to facilitate the connection. Subjects may listen to sound stimulations 
by wearing a pair of headphones, hearing tubes, or through loudspeakers. Tests may 
include resting EEG, passive and active cognitive tasks. In resting EEG, subjects are asked 
to relax during brain wave recording. In brain wave recording during passive task: subjects 
may be asked to relax while sounds at di\erent frequencies and durations are presented to 
elicit evoked potentials, which can be accompanied by visual presentations. No 
performance is required except to be alert. In brain wave recording for attention and 
memory tasks: subjects are asked to pay attention to auditory and visual stimuli while 
holding a response pad. They are trained and then perform the tasks by responding, 
remembering, or recalling certain items and ignoring the other items. These tasks are 
computerized auditory and visual stimuli and data are digitally recorded. Each test may last 
a few minutes to about half an hour; they are repetitive but with breaks between tasks to 
reduce subject fatigue. All recordings are stored in secure servers/computers using only a 
code. 
 
TMS will be given in 2 sessions in 2 di\erent days that are separated by one or more days. In 
one session you will receive active TMS. In another session you will receive sham TMS. The 
active or the sham TMS are delivered to one, two or three locations on your scalp. The TMS 
is given in about 4 minutes for each location. Therefore, in the active TMS day, you will 
receive 3 TMS administrations in three locations, one after another, for a total of about 12 
minutes. In the sham TMS session, you may feel or hear similar TMS, but no actual TMS is 
stimulating your brain. TMS-evoked responses, brain waves, and MRI will be measured 
before and after each session to determine the TMS e\ects. It will take about 4 to 5 hours. 
It includes about 2 hours before and 2 hours after the TMS where we will perform clinical 
assessments, TMS-evoked responses, brain wave, and MRI assessments as described 
above. It also includes time to wear the electrode cap and remove the electrode cap and 
cleaning the hair after the experiment. About 30 participants will participate in this study. 
 

Research Related Risks 
General: There is a possibility of breaching of conﬁdentiality. We plan to keep all your 
records conﬁdential. Some of the procedures can cause boredom. In some of the 
interviews and questions we will be discussing and asking sensitive information (for 
example, feelings of sadness, unusual experience, alcohol use, mental illness in family 
members). You may feel embarrassed or distressed talking or giving out information. It is 
important to obtain accurate information from you to make the research valid and 
worthwhile. However, you can always stop and not participate without penalty. Our 
interviewers are experienced and should provide needed counseling.  
 
TMS: TMS has been safely used in thousands of subjects at the US and throughout the 
world each year. Occasionally people may ﬁnd the stimulations uncomfortable or even 
painful or causing headache, scalp or facial twitching or pain, or dental or muscle pain. If 
you ﬁnd the procedure too uncomfortable you may discontinue it at any time. Headaches 
and pain usually go away promptly with over the counter pain medications. The magnetic 
pulse could heat up the scalp metal electrodes that could cause burning. The electrodes 
we use do not have metal that directly contacts the scalp. However, you should promptly 
inform the sta\ if you feel any increased heating. The skin stimulation sham electric pulses 
may cause skin discomfort, tingling, muscle twitching, headache or pain. As in real TMS, if 
you ﬁnd the procedure too uncomfortable you may discontinue it at any time.  
 
TMS can be loud and could cause temporary and, in one case, permanent decreases in 
hearing especially without hearing protection. You will be ﬁtted with earplug or ear phones 
to wear during the study. This is to protect your hearing from the noise. You will sit in a 
position with minimal head motion. Sitting in a ﬁxed position for a long time could be 
uncomfortable with possible body ache. There will be frequent breaks. You can ask for a 
break at any time.  
 
Magnetic stimulation will not be performed in people who have pacemakers, implanted 
pumps or stimulators, or who have metal objects inside the eye or skull. Please inform the 
investigators if you have any of these conditions.  
 
The most severe risk from TMS is seizure. The possibility that TMS used in this study will 
cause a seizure is very low. According to best current evidence, risk of seizures induced by 

TMS is about <0.03%. A seizure has never resulted in permanent damage. Seizure, if 
induced by rTMS, occurs only during the application of stimulation. Beyond studies 
conducted speciﬁcally in patients with epilepsy, there has been no reported incidence of 
rTMS-associated seizure that had onset within hours or days after the stimulation 
procedure concluded. You will be carefully watched during each session. Sta\ is trained to 
promptly manage a seizure should one occur. Having a seizure could a\ect your future 
ability to drive, hold a job, or get insurance. Therefore, there may be ﬁnancial risk with being 
in this study. Sleep deprivation, recent change in medication, alcohol consumption or too 
much ca\eine intake may increase the risk of seizure. You might be at higher risk of having 
a seizure with TMS if you are taking clozapine. You will not be eligible for this study if you are 
taking >400mg clozapine daily. We will ask you to postpone the study if you had a recent 
change in certain medication, did not have a good night sleep, or consumed too many 
ca\einated drinks on the day of TMS or any alcohol within the 24 hours before TMS. 
 
Other possible adverse events include fainting, nausea, changes in blood pressure and 
heart rate. If you feel you are not comfortable and weak, you should inform sta\ 
immediately, or you can stop at any time.  
 
Another potential side e\ect from TMS treatment is changing of mood and occasionally 
other psychiatric symptoms such as increased psychosis, temporary changes in attention 
and memory. Heightened euphoria (mania) has happened to some people, most of whom 
had a history of mania or depression when they started TMS treatment.  
 
The e\ects of TMS during pregnancy are unknown. If you are a female and are possibly 
pregnant (if you have child-bearing potential but are not taking contraceptives and missing 
menstrual period; or by your own report; or by positive a pregnancy test), you should not 
participate in this study. No one should enter the study that plans on fathering or 
conceiving a child between the times of study enrollment and completing the study. If you 
are female and are able to have children you must agree to use an approved birth control 
method. Acceptable birth control methods include the birth control pill, intrauterine 
device, or depot hormonal preparation (ring, injection implant). Correct use of a 
diaphragm, sponge with spermicide, or condom is also acceptable. We do not know if the 
experimental procedure a\ects fetal development. 
 

MRI: The process itself is painless. There will be no x-rays or radioactivity in the MRI. 
However, you will be exposed to a high magnetic ﬁeld. The magnetic ﬁeld and radio waves 
used for MRI scans are considered too weak to do any damage to your body. However, 
nothing can be proven to be absolutely safe. There are potential side e\ects from the MRI 
scans. The ﬁrst possible side e\ect is a mild backache from lying still for about one hour. 
You may experience claustrophobia, which is fear of small enclosed places. The MRI 
machine makes loud banging noises. You will be given earplugs or headphones that will 
lessen the sound. You may still experience some brief problems hearing soft sounds after 
the exam. Lying still for many hours may be a risk for the development of Deep Vein 
Thrombosis. This is blood clotting, usually in the legs, in persons with certain medical 
conditions. Persons with a history of thrombosis, family history of thrombosis, or medical 
conditions that may lead to an increased chance to develop blood clots cannot take part in 
this study. Please inform us immediately if you believe you should not take part for this 
reason.  
 
Brain wave recording: A paste is used to attach the electrodes during brain wave testing, 
which may irritate the skin on the scalp or face. Irritation is mild and usually resolves 
quickly. We may ask you to not use hair products on the day of testing (or it has to be 
washed out prior to testing, which may be inconvenient). The electrode cap you wear can 
be tight and not comfortable, but it can be adjusted. The tasks can be quite long, boring, or 
even annoying. Some of the sounds can be loud and uncomfortable. We will give frequent 
breaks in-between. You can always ask for a break or re-schedule for another time to 
complete the study. 
 
All safety measures to lessen any side e\ects will be taken. If you feel that you want to 
leave the study, you are free to do so at any time. If we feel that you should not continue, we 
will end the study. We may do this even if you do not want to end the study. 
 
Because TMS is relatively new, its long-term e\ects are still unknown. We will monitor you 
at every visit. There may be risks in this study which are not yet known. You will be told of 
any new ﬁndings during the course of this study that may a\ect your participation. If you 
feel that you have an illness or symptoms related to your being in the study you should call 
us. 
 

Statistical Analysis Plan 
Demographics were compared using ANOVA or χ2 tests. We will examine the di\erences in 
performances of biomarkers in active TMS compared to sham TMS. We will explore e\ects 
of age, sex, baseline medication, cognition, smoking status, and functional measures on 
biomarkers, and signiﬁcant ﬁndings will be included as covariates. Exploratory analyses 
were conducted comparing active TMS vs. sham at di\erent time points using 
independent-sample t-test and comparing baseline vs. post-TMS measurements using 
paired-sample t-tests at p<0.05. E\ect sizes were calculated for nominally signiﬁcant 
measures using Cohen’s d. All tests were two-tailed.