Testing TMS Enhancement of Visual Plasticity in Schizophrenia
Phase: NA
Conditions: Schizophrenia
Sponsor: University of Maryland, Baltimore

Full Title: Testing TMS Enhancement of Visual Plasticity in Schizophrenia 
 
 
Excerpt from IRB Protocol 7/31/2017, modification 10/17/2017  
 
 
 

Lay Summary 
Learning and memory impairments are commonly observed in schizophrenia spectrum 
disorders. Alterations in "long-term potentiation" (LTP), a basic mechanism underlying learning 
and memory, may explain this impairment. This project will assess fMRI visual plasticity, 
thought to reflect LTP, in participants with and without schizophrenia spectrum disorders. 
Previous studies have shown that visual plasticity is impaired in schizophrenia. The major goal is 
to determine if Transcranial magnetic stimulation (TMS) enhances visual plasticity in 
schizophrenia. Transcranial magnetic stimulation (TMS) provides a non-invasive means for 
altering brain electrical neural activity. TMS has been approved by FDA for treatment of 
depression. Other applications have not been approved but it has been used in a wide range of 
clinical research especially in neurology and psychiatry. TMS sessions will be conducted before 
two MRI scans (sham/placebo and real TMS) with two weeks in-between to assess whether 
TMS stimulation to the visual cortex will enhance visual plasticity in patients with 
schizophrenia-spectrum disorders. This project may provide a better understanding of the 
underlying neurobiological mechanisms responsible for learning and memory deficits in 
schizophrenia. 
 
Describe the purpose, specific aims, or objectives of this research. State the hypothesis to be 
tested: 
To test the hypothesis that TMS simulations to the occipital cortex will modulate capacity for 
visual plasticity in patients with schizophrenia spectrum disorders. The TMS location of the 
occipital cortex site will be individually localized. 
 
Discuss the research design including but not limited to such issues as: probability of group 
assignment, potential for subject to be randomized to placebo group, use of control subjects, 
etc.: We will implement a between-subject study design such that order of sham and active 
rTMS will be allocated to subjects randomly.  
 
Provide the scientific or scholarly background, rationale, and significance of the research and 
how it will add to existing knowledge: 
There are no studies that have directly investigated plasticity mechanisms with TMS in 
conjunction with multimodal neuroimaging to determine if LTP-like plasticity is 
impaired in schizophrenia, or if plasticity can be modulated with TMS. This project serves to 
extend a project carried out by our group in which multimodal neuroimaging methods such as 
functional MRI (fMRI), arterial spin labeling (ASL), and proton magnetic resonance spectroscopy 
(1H-MRS), learning and memory tasks, and a novel visual plasticity paradigm drawn from basic 
science known to induce LTP-like changes were utilized to conduct exploratory research. 
Findings indicated that this novel visual plasticity paradigm was able to induce LTP changes in 
control volunteers and that glutamatergic metabolites predict visual plasticity in humans 
(Wijtenburg et al., under review). Previous human studies that used this visual plasticity 
paradigm successfully demonstrated robust visual plasticity in healthy subjects as reflected by 
an increase in fMRI BOLD activation, and impaired visual plasticity in schizophrenia as indicated 
by reduction in visual evoked potentials, but this would be the first study to incorporate a TMS 
component in an effort to enhance visual plasticity in schizophrenia. 

Supporting Literature 
Learning deficits are linked to poorer functional outcomes and quality of life in schizophrenia. 
These deficits may reflect alterations in the basic cellular mechanism underlying learning, long-
term potentiation (LTP). Our previous work indirectly supports this hypothesis. First, we found 
robust impairments on translational hippocampal dependent 8 radial arm task (Spieker et al., 
2013) and hippocampal-relational learning task (Spieker et al.,2014; Rowland et al., 2010) in 
schizophrenia. We also showed altered fMRI BOLD response in the hippocampus, the brain 
region important for successful declarative learning and memory formation in schizophrenia 
(Rowland et al., 2010). Last, our pilot data in schizophrenia suggests altered glutamate (Glu), 
the neurotransmitter fundamental to LTP.  
LTP is typically studied in rodents. Briefly, LTP is induced through high-frequency 
electrical stimulation. LTP in the hippocampus is the most studied region, but LTP-like changes 
occur in other regions such as the visual cortex. Using a modified visual plasticity paradigm 
known to induce LTP-changes in rodents, several human studies successfully demonstrated 
robust visual plasticity in healthy subjects as reflected by an increase in fMRI BOLD activation or 
visual evoked potentials (Clapp et al., 2005; Clapp et al., 2012). Relevant this project, one study 
demonstrated impaired visual plasticity in schizophrenia as indicated by reduction in visual 
evoked potentials (Cavus et al., 2012). However, there are no multimodal imaging studies with 
a TMS component to assess visual plasticity in schizophrenia. This study will extend the 
previous EEG study and multimodal neuroimaging work conducted in our lab. It will determine 
whether TMS will enhance visual plasticity in schizophrenia-spectrum disorders.  
In TMS literature, high-frequency rTMS (900 stimulations; 15 mins in total) has been 
shown to facilitate an effect in the occipital cortex for at least 15 minutes (returned to baseline 
about 15 minutes later) (Fierro et al., 2005). An alternative approach is theta-burst stimulation 
(TBS), in which a three-pulse 50-Hz burst is applied at 5 Hz. TBS over motor cortex can induce 
similar or even longer lasting effects than conventional rTMS with less number of stimulations, 
less intensity and better tolerability (Huang et al., 2005). TBS over frontal cortex for depression 
treatment has been established as equally efficacious and safe compared to high frequency 
rTMS (Li et al., 2014). However, the effects of TBS over occipital are not well-demonstrated yet. 
We will apply conventional high-frequency TMS or TBS over occipital cortex. For both TMS 
protocols, no more than 3000 pulses will be delivered in each session. 
 
Study Procedures 
 
Informed Consent Process:  A member of the research staff will describe in full the protocol and 
risks/benefits of the study to the potential participant. The potential participant will be 
informed that, if enrolled in the study, s/he will have the right to withdraw from the study at 
any time for any reason. The consent form will be reviewed in detail, and the subject will have 
an opportunity to read it and ask any questions he/she might have concerning the study 
procedures. All subjects will receive a copy of the signed consent form for their records. The 
consent process will be conducted in a private office with the door closed in order to protect 
the subject's privacy. 
In addition, we use the Evaluation to Sign Consent form with prospective participants 
with schizophrenia to ensure their understanding of the study. A member of the research staff 

will meet as many times as needed with potential participants to discuss the research study 
with them. Further, participants are required to give adequate responses on the Evaluation to 
Sign Consent 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 withdrawal from the study at any 
time. 
 
After each eligible volunteer is consented, the volunteer will participate in clinical and cognitive 
assessments, MRI training (if needed), and two TMS/MRI sessions conducted 2 weeks apart. 
This study will take from 9 to 11 hours to complete over the course of three visits to MPRC. 
 
Visit 1: Consent procedures and clinical / cognitive assessments. 
All participants will complete informed consent procedures and will be screened for MRI safety 
compatibility. All participants will be interviewed using the Levels of Functioning Scale (LOFS) 
and will complete the SCID-5-RV interview if one from the past year is not already on file from 
engagement in another study with our program. Patients will be evaluated for psychopathology 
with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative 
Symptoms (SANS), and the Brief Negative Symptom Scale (BNSS). All subjects will complete: (1) 
learning/memory and processing speed tasks drawn from the MATRICS (Measurement and 
Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery; (2) 
computerized tests of learning and memory ; (3) the Levels of Functioning Scale (LOFS) to assess 
overall functioning. This visit will vary in length based on diagnostic group and individual 
variance on factors such as openness during interviews, speed of processing during 
assessments, whether the SCID interview will be needed, etc. Visit length is estimated to be 
between 3-5 hours in total. 
 
Visit 2: TMS and MRI. 
TMS. Two separate TMS sessions will be conducted (one sham and one active, randomly 
assigned) that will take up to 1.5 hours each. These sessions will precede MRI 
scans, which will take place on the same visit. TMS pulses are applied to the brain guided by the 
Brainsight (Rogue Research, Montreal, Canada) brain navigation system. The TMS coil will be 
operated by a trained operator during the whole session to allow for optimal fixation and 
correction whenever slippage threatened to occur. Sham rTMS will use a sham coil or will use a 
real coil tilted away from the scalp at an angle of 90° for sham treatment. Sham mimics the 
sound of the TMS without actually stimulating the brain with TMS. 
 
MRI Training. Participants may be asked to do training on the fMRI tasks in a mock scan session. 
This training session will give participants a chance to become familiar with the MRI process if 
they have never had an MRI for research purposes. Participants will follow the same procedures 
as with the "real" MRI, in a mock scan environment. If requested, this session would take 5-30 
minutes depending on comfort level of the individual participant. 
 
MRI. The MRI will measure structure, function, and chemistry of the brain. The MRI session will 
take about 1.5 hours. Prior to the MRI, participants will be asked to complete a standard 
questionnaire. The purpose of this questionnaire is to ensure that it is safe for them to enter 

the MRI. For the MRI, participants will be asked to lie still on a bed in the MRI, which is a big 
donut-shaped magnet. During the structural MRI, MRS, and ASL, participants simply lie still. 
During the functional magnetic resonance imaging (fMRI), participants will be asked to look at a 
fixation cross on a projection screen. Participants will stare at a flashing checkerboard pattern, 
and a camera will be mounted such that eye movement/closure can be monitored. Participants 
will be trained prior to the MRI. The MRI will take place at the UM Center for Brain Imaging 
Research (CBIR) at the Maryland Psychiatric Research Center (MPRC). 
 
*As noted in visit 1 breakdown, we may use some assessments done in other studies 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 during data analysis. Modifications in task 
parameters and equipment settings, such as fMRI scanning sequences, sound level, number of 
presentations, target speed and so on, are unavoidable. Some subjects 
maybe asked to return to repeat a task due to such changes. They may also be asked to repeat 
various tasks if data from a previous session was incomplete or became 
corrupted in some way. 
 
Sample size and data analysis: 
The power analysis is based previous published research using this visual plasticity 
paradigm in healthy participants and one published EEG study using this paradigm in 
schizophrenia since there are no multimodal imaging studies of visual plasticity in SZ. Estimating 
a magnitude of effect, Cohen’s f2= 0.8 (based on between group differences), a sample size of 
35-40 per group provides power greater than 90%. Even if we conservatively estimate 
approximately 10% of data loss due to subject attrition (5%) and poor quality data due to 
movement (5%), we can expect complete data on approximately 35 subjects per group for the 
main aim. This sample size should provide sufficient power to detect an effect. 
Statistical analysis will be performed using the SPSS software package. The main 
dependent variable is fMRI visual cortex BOLD signal, before and following the high frequency 
stimulation. This is the measure of visual plasticity. Between group differences will be 
investigated with 2 (group) X 2(time) ANOVA with repeated measure on time. The relationship 
between the fMRI visual cortex and MRS glutamate will be examined for each group separately 
with correlation analysis. 
 
Participant Eligibility 
Inclusion criteria: 
1 Male or Female between the ages of 18-65 
2 Ability to give informed consent (18 and above) 
3 For patient participants, Evaluation to Sign Consent (ESC) score of 10 or above 
Exclusion criteria  
1 Any history of seizures or seizure disorder 
2 Any family history of epilepsy in first-degree relatives 
3 Significant alcohol or other drug use (substance dependence within 6 mos. or substance 
abuse within past 1 month) other than nicotine or marijuana dependence 

4 Any major medical illness that may affect normal brain functioning; examples include, but are 
not limited to, stroke, CNS infection or tumor, or other significant neurological conditions 
5 Taking > 400 mg clozapine per day 
View 6 Failing TMS screening questionnaire 
7 Cardiac pacemakers, implanted medical pumps, intracardiac lines, or any acute, unstable 
cardiac disease with intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear 
implants, or electrodes) or any other metal objects within or near the head, excluding the 
mouth, that cannot be removed safely 
8 History of head injury with loss of consciousness for over 10 minutes or history of brain 
surgery 
9 Cannot refrain from using alcohol and/or marijuana for 24 hours prior to experiments, or 
cigarette smoking 30 minutes prior to experiments 
10 Women who are or may be pregnant (child-bearing potential but not on contraceptive and 
missing menstrual period, self-report, or by positive pregnancy test) 
 
Recruitment 
Healthy control subjects will be recruited from the Maryland Psychiatric Research 
Center (MPRC) subject pools. We provide the list of inclusion and exclusion criteria for 
the volunteers (see inclusion/exclusion criteria). All persons who qualify for this study are 
referred to the research team (PI and/or PI staff) and then contacted and asked if they would 
like to participate in this study. 
Potential subjects with schizophrenia will be recruited through the Maryland Psychiatric 
Research Center clinics. Clinic staff members will be provided with the inclusion/exclusion 
criteria for the current study. They will identify subjects who are likely to be interested in 
participation and referred to the research team (PI and/or PI staff). Study coordinators may also 
recruit from local clinics and day programs that the Neuroimaging Research Program has 
recruited from in the past for other studies. 
Contact information would be obtained from all qualified, interested persons for 
scheduling purposes. 
Our participants with schizophrenia are not decisionally impaired. We use the 
Evaluation to Sign Consent (ESC) form to ensure their understanding of the study. A 
member of the research team on this protocol will meet as many times as needed with 
potential participants to discuss the research study with them. Further, participants 
are required to give adequate responses on the 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 at any time. If the patient expresses a further 
desire to participate, the research team member will proceed with the 
consent process. 
Our participants with schizophrenia are not decisionally impaired. Participants are 
required to give adequate responses on the 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 withdrawal from the study at any time. 
Participation in this study is voluntary. All participants are free to withdraw consent at 
any time. A participant's refusal to participate will not affect current or future medical 

care in any way at the University of Maryland Baltimore, University of Maryland Medical 
System. Participants will be told of any significant new findings that develop during the study 
that may affect their decision to participate in the study. Subjects will be paid $15.00 per hour 
for the clinical and cognitive testing, interviews, and mock scan training session (if needed). 
They will be paid $100.00 for each MRI. These amounts are standard for this type of testing and 
not considered coercive. 
 
Research Related Risks 
 
Confidentiality: 
There is a possible risk of loss of confidentiality. However, we take precautions to 
prevent such an event from happening. All research data are stored, in both electronic 
and hard copy form, with ID numbers rather than names or other personal identifiers. Research 
data is not recorded on any form that requires identifiers. All data with identifiers are 
maintained separately from research data. Hardcopies of all research forms are stored under 
double-locked conditions. Computer files are handled via a local area network (LAN) maintained 
behind a Juniper SSG-550 firewall with multiple layers of protection against unauthorized 
intrusion. Databases are maintained on the center's server and are additionally protected by a 
5-tiered system involving restricted access at the desktop, directory, database, reporting and 
table levels. Permissions for data access are set by the PI. 
 
Risks associated with clinical assessments, interviews, cognitive and neuropsychological testing: 
Cognitive tests and psychological ratings are generally considered benign. The subject 
may become frustrated and tense when he or she encounters difficulty when performing the 
tests. Careful planning and observation of the subject's response to these sessions will allow 
the testing to be completed with a minimum of discomfort. Subjects will to take breaks when 
necessary to help alleviate any discomfort. We ask sensitive clinical information that can be 
uncomfortable to some patient participants. Some assessments and testing may be boring. Our 
clinical staff are trained to be sensitive to subjects' emotional response and can provide 
consultation. Subjects are reminded their participation is voluntary and they can always decline 
to participant in study activities or withdraw from the study. We provide frequent breaks and 
also regularly ask subjects whether they need breaks during assessment and testing. 
 
MRI risks: 
Magnetic resonance uses strong magnetic fields and weak electromagnetic fields (i.e. 
radio waves), which have not been associated with adverse effects in patients or 
laboratory animals. Subjects may experience a feeling of being isolated or confined by the 
scanner (i.e. claustrophobia). We minimize these discomforts by explaining the 
procedure in great detail and by maintaining voice contact with the subject at all times. The 
most likely difficulty will be that a subject is unable to hold still for the MR 
scan. This would degrade the quality of the image obtained, but it would not be dangerous for 
the subject. Subjects with a cardiac pacemaker or any piece of metal (e.g. 
surgical clips or plates, heart valves, cochlear implants, shrapnel fragments) in their body may 
not participate in this study. 

MRI has never been shown to harm a fetus or a pregnant woman (American College of 
Radiology) but there may be unknown risks Therefore, we will exclude women who are 
pregnant. Women of child bearing potential will be given a urine pregnancy test to rule out 
pregnancy. 
Risks associated with MR equipment malfunction also exist. MR Safety Officers at the 
imaging center monitor compliance to safety procedures. Daily quality assurance is conducted 
each morning to ensure the MR scanner is running properly. 
 
TMS Risks (numbered 1-7): 
1) The most serious risk side effect reported for TMS is the accidental causing of seizures, but 
such episodes have been very rare. We are aware of about 8 cases of TMS related seizures 
reported in the literature (Rossi et al 2009; Kratz et al 2011). Numerous sham-controlled trials 
and several meta-analyses support its efficacy in treating depression (reviewed in Loo and 
Mitchell, 2005; Loo et al., 2007). For example, one of the largest rTMS sham-controlled trials 
involved 301 pharmacotherapy refractory depressed subjects and showed positive results 
(O'Reardon et al., 2007). rTMS sessions (120% of motor threshold, 10 Hz, 3000 pulses per 
session) were conducted for 4 to 6 weeks five times per week. rTMS was well tolerated, with 
low dropout rate for adverse events (4.5%) that were generally mild and limited to transient 
scalp discomfort or pain. The incidence of rTMS-induced seizures worldwide is low and roughly 
comparable to the estimated incidence of spontaneous seizures with antidepressant therapy 
(0.1– 0.6%) (Pisani et al, 2002), with the safety advantage that seizures occur during or just 
after the TMS treatment session (rather than after a delay) and are therefore more easily 
treated. There have been no reports of any subject developing epilepsy or repeated 
spontaneous seizures after single pulse, double pulse, or repetitive TMS. All TMS-induced 
seizures to date have been transient and self-limiting, without long-term sequelae (Loo et al, 
2008; Rossi et al 2009; Kratz et al 2011). In the current proposed study, the TMS parameters are 
within published safety guidelines. rTMS is a relatively new technique; the long-term effects of 
its use are unknown. 
Concurrent medication has been implicated as a risk factor in some of the seizures 
reported with TMS. Early on, some have suggested that certain medications, e.g. 
tricyclic antidepressants, clozapine and other neuroleptics, should be contraindicated in those 
receiving TMS (Wassermann, 1998). Since then, hundreds of depressed, schizophrenic and 
other psychiatric patients, many on concurrent medications, have received TMS in clinical trials 
with no reports of serious adverse events. In two of the reported seizures cases, psychotropic 
medication was changed during the TMS course in the days preceding the seizure, i.e., rTMS 
was continued at the same absolute intensity in the presence of a possibly altered seizure 
threshold. We will seek to avoid this problem by establishing each subject's resting motor 
threshold (RMT) at the start of TMS experiments and setting the stimulus intensity relative 
to that RMT. To further decrease this risk, subjects in the current study are required to stay on 
prescribed medications and inform research staff before each TMS session of any change in 
medication regimen. These precautions are based on the premise that medications which alter 
seizure threshold should also alter the RMT. Studies with drugs such as lorazepam (Ziemann et 
al., 1996), haloperidol (Ziemann et al., 1997), and anticonvulsants (sulthiame [Siniatchkin et al., 
2006]; carbamazepine, gabapentin, topiramate [Inghilleri et al., 2004; Turazzini et al., 2004]; 

levetiracetam [Reis et al., 2004]) yield partial support for this premise, with some studies 
showing no change in RMT, while others found the expected increases in RMT in the presence 
of anticonvulsant medication. The safe application of TMS in subjects given stimulants such as 
amphetamine or methylphenidate supports the safety of TMS in subjects using these drugs 
(Tegenthoff et al., 2003; Gilbert et al., 2006). Clozapine is associated with lowering seizure 
thresholds. The first study involved patients on clozapine used rTMS at a frequency of 1 Hz and 
an intensity of 80% of the motor threshold for 20 min for 10 sessions in 7 patients on clozapine 
(d'Alfonso et al 2002). Subsequent studies on rTMS in treatment-resistant schizophrenia 
patients (many of them are on clozapine) have generally reported rTMS and other TMS 
modalities to be safe (d'Alfonso et al 2002; Liu et al 2009; Rosa et al 2007; Daskalakis et al 2008; 
de Jesus et al 2011). We will involve patients on clozapine or other neuroleptics only if they 
have been on stable dose of clozapine and other neuroleptics for at least 1 month, and inthe 
case of clozapine, currently taking no more than 400mg/day. Other factors, such as sleep 
deprivation, alcohol or excessive caffeine intake, may lower seizure threshold. One subject 
received rTMS uneventfully until he had two sleepless nights, after which he experienced a 
seizure (Prikryl and Kucerova, 2005). Subjects in the current study will be issued guidelines for 
TMS treatment, advising that alcohol and caffeine intake should not be altered (and should be 
within reasonable limits), medications should be unchanged, and subjects should inform 
research staff if there is any change in the above, if they have had a sleepless night, or 
developed any medical illness. Acute alcohol withdrawal is associated with seizures. To 
minimize this risk subjects with current alcohol dependence are excluded from this study. 
 
Seizure monitoring and management procedures: 
All staff administering the TMS are certified in basic adult life support (CPR) and have 
training in seizure first aid, how to engage the emergency response system, including 
contacting the covering study physician available in the building. Only staff with the appropriate 
education and training will actually provide TMS or supervision to subjects. 
Subjects will be monitored throughout each TMS session by trained staff who will 
visually monitor subjects for signs of seizures such as involuntary muscle movements 
or loss of consciousness. In the event of a seizure, the following procedure will serve to guide 
staff in order to minimize additional trauma: 1. Protect patient’s head and 
limbs from injury. 2. Ensure an adequate airway. 3. Provide supportive care after the seizure 
resolves. 
a. When jaws are clenched do not attempt to pry open the mouth to insert a mouth gag. At no 
time should anything be placed in the patient’s mouth. 
b. When safely able, turn the patient to the side to prevent aspiration and promote drainage of 
mucus and saliva. Do not force any part of the patient’s body during the 
seizure. 
c. Loosen any constrictive clothing. 
d. Call for assistance from an in-house physician or by dialing 911 in order to have the patient 
transferred to the nearest emergency room. 
e. Observe patient for initial movements/ sensations, progression of movements, change in 
respiratory status, skin color, incontinence, level of consciousness, ability to 

communicate, level of orientation, duration of seizure activity. If after two minutes, the seizure 
has not resolved, the treatment option can include administering lorazepam 4 mg IM. May give 
an additional 4 mg if needed. 
If immediate medical assessment or intervention is required, the subject will be referred 
to the appropriate medical facility. Unexpected or serious adverse events will be 
promptly reported to the IRB in accordance with IRP policy. Information on all adverse events 
will be cumulated and reported to the IRB with each continuing review 
application. 
 
2) Scalp pain, headache, dental pain. The most frequently seen side effects with TMS therapy 
have been headache, dizziness, scalp pain or discomfort, and muscle twitching. Less frequently 
reported side effects of TMS therapy include increased auditory threshold. Transient scalp pain 
may occur with TMS stimulation. The TMS coil may heat up with prolonged use (Pascual-Leone 
et al., 1991). The coils used in this study will automatically shut off when temperature is over 
specific limit so this risk is very small. In sham-controlled studies that reported rates of side-
effects, about 28% of subjects experienced headache and 39% experienced pain or discomfort 
during stimulation with active rTMS, compared with rates of 16% and 15%, respectively, after 
sham rTMS (Loo et al., 2007). There is one report of nausea in two subjects from 
rTMS over the cerebellum (Satow et al., 2002). A small number of reports described focal pain, 
discomfort, and other minor symptoms. While headache is common it is not serious and 
responds well to over the counter analgesics. In a single case report, a 57-year-old women 
being treated for major depressive disorder reported a pulsating, localized dental twitching in 
the region of the upper left jaw associated with the rTMS treatment (Ropohl et al., 2004). The 
pain disappeared during the intertrain interval but emerged again during the next train of 
stimuli. The pain was dependent on the stimulus intensity and remained despite repositioning 
of the coil. The cause of the pain is unclear, but may be due to stimulation of the trigeminal 
nerve by the rTMS magnetic field (Ropohl et al., 2004). The likelihood of this minor transient 
side effect is minimal, and the participant can stop the intervention if it occurs. 
 
3. Hearing change: Rapid excitation of the stimulation coil produces clicks that have resulted in 
transient increase in the auditory threshold of human subjects (Wassermann, 1998; Loo et al., 
2001). Permanent threshold shift has been observed in a single individual (Rossi et al 2009). Loo 
et al. (2001) assessed the auditory threshold before and after 30 sessions of rTMS given over 6 
weeks in a depression treatment trial. No significant mean changes were detected. Guidelines 
require testing of auditory threshold only if subjects receive rTMS at a frequency higher than 1 
Hz for four or more weeks. The amount and duration of stimulation a subject will receive from 
this study is less. 
 
4. Exacerbation or emerging psychiatric symptoms. While TMS is increasingly employed to 
investigate its therapeutic effects for psychiatric illnesses, it is expected that it 
can also induce or worsen psychiatric symptoms in some patients. Mania has been induced in a 
small number of healthy and depressed subjects by high-frequency rTMS to the left 
dorsolateral prefrontal cortex. Nedjat and Folkerts (1999) reported hypomanic symptoms after 
a single session of rTMS in three female subjects without a prior history of mood disorder. 

Stimulation parameters were comparable to those used in depression treatment studies and 
studies of mood changes in healthy subjects. Two subjects with unipolar depression have 
shown manic changes with rTMS treatment. George et al. (1995) reported mild hypomania in a 
patient with refractory recurrent unipolar depression. This female patient had responded well 
to previous shorter courses of rTMS, but became hypomanic after nine treatment sessions in 
the third course. The hypomanic symptoms resolved when rTMS was reduced to treatment 
every second day. Sakkas et al. (2003) reported on a 55-yr-old depressed male who became 
hypomanic for the first time after 3 weeks of twice daily rTMS to the left dorsolateral prefrontal 
cortex and concomitant citalopram. Over the following week, medication was stopped, but 
rTMS continued. His symptoms deteriorated into mania and rTMS was also stopped. Five 
months later, a second course of 2 weeks of twice-daily rTMS also resulted in hypomania. rTMS 
may also have a therapeutic effect in mania, with high-frequency application to the right 
prefrontal cortex (Erfuth et al., 2000; Grisaru et al., 1998). 
There are several reports of mania induced by rTMS in patients with bipolar disorder 
(Dolberg et al., 2001; Garcia-Toro, 1999; Hausmann et al., 2004; Huang et al., 2004; 
Sakkas et al., 2003), even while taking mood-stabilizing medications. Cohen et al. (2004) 
conducted a trial of right prefrontal rTMS for post-traumatic stress disorder, during which two 
patients developed a manic episode after the third session. One patient was randomized to 1 
Hz rTMS and one to 10 Hz. Another subject in this trial developed a ‘mild rage attack, probably 
related to the stimulation’ (Cohen et al., 2004). There is a single case report of high-frequency 
left prefrontal rTMS inducing transient persecutory delusions in a depressed, non-psychotic 
subject (Zwanzger et al., 2002). Treatment-emergent mania has been reported for low and high 
frequency rTMS in patients with uni- and bipolar depression (Xia et al., 2008). The overall rate 
(13 cases) across 53 randomized controlled studies in depression appears to be low 
(0.84% mania for active rTMS vs. 0.73% for sham rTMS) and even below natural switch rates in 
patients with bipolar disorders receiving mood stabilizers (2.3–3.45%) (Xia et al., 2008; Rossi et 
al 2009). Cases of rTMS induced psychotic symptoms, anxiety, agitation, suicidal ideation and 
insomnia have been reported (Zwanzger et al., 2002; Janicak et al., 2008; Rossi et al 2009); 
again whether these occur at higher rates compared to the natural course of these symptoms 
remain unclear (Rossi et al 2009). 
In all the above cases, the psychiatric side-effects induced by rTMS were transient, 
resolving with the cessation of rTMS or rapidly responding to pharmacological 
treatment. In the current proposed study, subjects will be warned of the possible risk of 
developing psychiatric complications, in particular, mania or hypomania. While 
statistically TMS treatments have showed improvement or no effect in psychotic symptoms in 
schizophrenia, worsening of psychosis has been reported in some patients. For example, 
d'Alfonso (2002) reported that rTMS has worsened psychotic symptoms in patients on 
olanzapine but meanwhile all 7 patients on clozapine showed improvement on the voice rating 
scale. We will use far less total TMS stimulation. If worsening symptoms are identified, we can 
readily assess and refer patients to proper psychiatric care. 
 
5. Other potential adverse effects. Heart rate and blood pressure: No significant changes in 
blood pressure and heart rate have been detected during rTMS (Foerster et al., 1997; 
Jahanshahi et al., 1997). A recent paper (Udupa et al., 2007) reported that rTMS treatment 

''corrected'' the subclinical cardiac autonomic imbalance which was associated with depression 
in the trial patients. 
Other possible adverse events include syncope, transient local pain, neck pain, 
toothache, paresthesia, transient cognitive/neuropsychologial changes, burns from scalp 
electrodes. Staff are trained to keep subject safe in the event of syncope following procedures 
similar to seizure. Participants are encouraged to report discomfort and 
take breaks. Visual changes: Two patients with major depression were reported to develop 
transient visual changes after rTMS of the left DLPFC (Marcolin, 2006). TMS could potentially 
have aftereffects on EEG/ERP: a safety guideline review of literature showed that most 
EEG/TMS studies report no after effect although in several studies such effects were noted in 
the absence of any behavioral effects (Rossi et al 2009). 
 
6. Pregnancy: Safety guidelines suggest that pregnant women be routinely excluded from rTMS 
trials (Wassermann, 1998). Nahas et al. (1999) reported the uncomplicated inclusion of a 
depressed and anxious woman in her second trimester of pregnancy in a depression treatment 
trial. She received 14 daily treatments at 5Hz and 100% motor threshold, with marked clinical 
improvement. Given the limited knowledge available in this area, pregnant women are 
excluded from the current study. Women of child bearing potential will be given a urine 
pregnancy test to rule out pregnancy. 
 
7. Equipment malfunction: As with all instruments, there is a risk of equipment malfunction. 
The Magstim Rapid2 Plus 1 System (TMS stimulator) is designed to comply with the 
requirements of the Safety Standard EN60601-1 (90) which is a family of standards whose 
scope covers the safety, essential performance and electromagnetic compatibility of Medical 
Electrical Equipment and Systems. Particular designs and requirements are made to minimize 
the potential risk of TMS unit malfunctions (e.g., grounding issues, coil overheating, abrupt coil 
disconnection etc).  
To ensure grounding safety, all main power connections are made directly to separate, 
permanent, hospital grade wall outlets. The coil may heat up during the test. If the coil surface 
temperature reaches its set limit (40oC), the stimulator will automatically stop and go to the 
inactive mode. The TMS coil is the only parts that contacting or close to participant and it will 
be removed from participant immediately if there is any sign of TMS malfunction (including coil 
overheating). If the coil is disconnected from the TMS stimulator during the test, the TMS 
system will automatically go to the inactive mode and discharge internally so that no 
stimulation will be given. The TMS stimulator will also automatically go to inactive mode if the 
stimulator has not been triggered for over 10 minutes. 
The TMS System and its accessories are checked for any signs of damage on a weekly 
basis and double-checked prior to use on a participant. They will not be used if there are any 
signs of external damage or if any parts are damp or wet. Other electrical devices in the lab and 
liquids are kept away from the TMS system to prevent potential electrical interference and 
water damage. The stimulator is covered by a customized cover to repel dust and moisture 
when not being used. 
 
Potential Benefits and Alternatives 

There will be no direct benefit from participation in this study aside from payment. We 
expect to learn important information about the brain function of persons with schizophrenia 
from this study. Generally, these study results will contribute to a better understanding of the 
pathophysiology of schizophrenia. These study results will contribute to a better understanding 
of abnormal brain activity and chemistry that is associated with learning and memory in 
schizophrenia. We hope that the results of this study will help facilitate the development of 
novel treatments (drug and behavioral) for the treatment of cognitive impairments in 
schizophrenia. 
 
The level of risk associated with this study is outweighed by the potential benefits by 
contributing to better scientific understanding of key biological and cognitive deficits 
associated with schizophrenia and for development of better treatment methods. The risk can 
be effectively managed by carefully designed study and by closely following safety guidelines. 
 
There are no alternatives. Participation is voluntary and the alternative is not to 
participate. 
 
Withdrawal of Participants 
Subjects can be withdrawn if they were found no longer meeting incl/excl criteria or 
non-compliant to research schedule or appointment, or cannot follow instruction to complete 
experiments. 
The potential participant will be informed that, if enrolled in the study, s/he will have 
the right to withdraw from the study at any time for any reason. 
Further, patients are required to give adequate responses on the Evaluation to Sign 
Consent 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 withdrawal from the study at any 
time. 
The Principal Investigator may terminate a subject's participation in the study if there 
are any circumstances that change the stated risks. In that case, the subject would be 
compensated for time spent on the study. If a participant voluntarily leaves the study or is 
terminated by the PI, we will still use any data that has been collected. Once a subject is 
withdrawn, no further data collection will occur. If a subject withdraws from the study, we plan 
to use any collected data in our analyses unless the research volunteer explicitly requests that 
their data not to be used. Subjects will be reimbursed for the portion of the study that they 
have been participated in. 
 
Privacy and Confidentiality 
 
 
 
The consent process will be conducted in a private office with the door closed in order 
to protect the subject's privacy. All discussions with potential subjects during the consent 
process will take place in a private room behind closed doors. All individual research 
assessments will be conducted in a private room behind closed doors. 
 
Data will be stored in locked file cabinets within locked rooms designated for research 
files. Computerized research data is de-identified will be stored on university computers with 5 
levels of password protected security. Scientific reports include only aggregate data; no names 
or identifying information will be included. 

 
Facilities where research procedures are conducted: 
This study will take place at the Maryland Psychiatric Research Center (MPRC) in 
Baltimore, MD. Office space, computer facilities, and support staff will be provided by MPRC. 
We are dedicated to providing treatment to patients with schizophrenia and related disorders, 
educating professionals and consumers about schizophrenia, and conducting basic and 
translational research into the manifestations, causes, and treatment of schizophrenia. 
Components of this study will take place in closed office spaces, the TMS Lab, and at the UM 
Center for Brain Imaging Research (CBIR), located on-site at MPRC.  
 
Laboratory and Research Space: 
Neuroimaging Research Program and MRI center. The Neuroimaging Research Program (NRP) 
and UM Center for Brain Imaging Research (CBIR) are located in a new research facility that 
houses a research-dedicated human MRI scanner, high performance computational cluster, 
laboratory space, and office spaces. This center features a state-of-the-art 3-Tesla Siemens 
MANGETOM Prisma MRI scanner (FDA-approved). It is an interdisciplinary facility dedicated to 
research and features extensive MRI expertise. It is staffed with two full-time IDEAlicensed 
pulse-sequence programmers and staff members, including two technologists. An RF laboratory 
includes a network analyzer, spectrum analyzer, and oscilloscope. The scanner is configured for 
fMRI experiments including a LCD projector system, fiber optic response boxes, and a PC for 
stimulus presentation via E-prime. Other home-made software is available that controls the 
triggers from or to the scanners. Responses from the subjects, if needed, are captured digitally 
using the same computers. We also have the capability of collecting both the cardiac and 
respiratory information digitally during any MRI scan. Because a significant portion of 
the research conducted at both the MR facilities pertains to fMRI, the scanning rooms have 
been designed with optimum radiofrequency (RF) shielding. All electronic equipment that is 
brought into the scan room pass through a penetration panel which is conveniently located at 
the scanner console. Preventive maintenance that involves measurement of temporal stability 
and noise characteristics are done on a monthly basis over and beyond what is performed by 
the vendors of the respective machines. A 100 Kilowatt uninterruptible power supply (UPS) 
provides continuous conditioning of the electrical power for the scanners, shielding the 
gradient and radiofrequency amplifiers from any fluctuations in building power. 
This facility is served by a high-performance computational cluster of 300 processors 
and five Tesla K20 GPU nodes powered by Rocks Cluster Distribution. The cluster is directly 
connected to the scanner reconstruction computer via Infiniband network for real-time data 
reconstruction and analysis. The facility has over 200TB of raid 5 network-based storage with an 
off-site, real-time back-up and Amazon-cloud based long-term storage backup. A full range of 
data analysis tools including FSL, AFNI, FreeSurfer, Mango, SOLAR-Eclipse, BrainVisa, LCModel, 
MIPAV, MRIcro, SPM, and TrackVis are available to be executed in three parallel computational 
environments: LONI-Pipeline, JIST and SGE. Additional MPRC-developed software including 
BrainVisa Morphologist (http://www.nitrc.org/projects/brainvisa_ext/) and SOLAR ECLIPSE 
tools for imaging genetics analyses (http://www.nitrc.org/projects/se_linux/) are available to 
extramural and intramural researches. Online documentation is available in the form of an 
Intranet “Wiki” website that provides procedural and other collaborative documentation within 

the NRP group and collaborators. A secure FTP and DICOMPACS sites are available for transfer 
of anonymized imaging data. As part of the NRP, a TMS Lab (15' x 20') houses a Magstim 
Bistim2 TMS system, a Magstim super rapid2 rTMS system, and a Brainsight brain navigation 
system (Rogue Institute). A full-time, PhD level TMS specialist is available to support the lab. 
The TMS systems are integrated with a 64-channel EEG/ERP system to allow recording 
electrophysiological response of TMS. 
 
Monitoring Plan 
Safety monitoring will be conducted by an Independent safety monitor who has been 
involved in technology intervention, including TMS, and clinical trial studies of schizophrenia. 
The independent safety officer will review adverse events, enrollment numbers, raw data, 
procedures reports, and preliminary analyses annually. Safety monitoring results will be 
reported to the IRB.  
 
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