Interactions of Fronto-Parietal High Frequency Repetitive Transcranial Magnetic Stimulation on Anterior Cingulate Cortex Activation in Schizophrenia
Phase: NA
Conditions: Schizophrenia
Sponsor: Indiana University

Interactions of Fronto-Parietal High Frequency Repetitive Transcranial Magnetic Stimulation on Anterior Cingulate 
Cortex Activation in Schizophrenia 
 
v.11.05.20 
 
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Interactions of Fronto-Parietal High Frequency 
Repetitive Transcranial Magnetic Stimulation 
on Anterior Cingulate Cortex Activation in 
Schizophrenia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator:  
Michael Francis, MD 
Department of Psychiatry 
IU School of Medicine 
 
 
NCT04309370 
 
 

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Table of Contents: 
1.0 
Background and Rationale 
2.0 
Specific Aims and Hypothesis 
3.0 
Study Design 
4.0 
Study Population (Inclusion/Exclusion Criteria)  
5.0 
Subject Recruitment 
6.0 
Clinical Assessments and Procedures 
7.0 
Safety Assessments 
8.0 
Laboratory Assessments 
9.0 
Concomitant Medication 
10.0 Adverse Events 
11.0 Criteria for Repeat Assessments, Rescreening, and 
Discontinuation 
12.0 Data Safety Monitoring Board  
13.0 Statistical Considerations 
14.0 Data Management 
15.0 Privacy/Confidentiality Issues 
16.0 Record Retention 
17.0 References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 
Background and Rationale 
 
Schizophrenia is a chronic and disabling illness that is associated with impairments in 
independent living as well as social and vocational functioning1. Schizophrenia also represents 
an important societal burden; only 10% of individuals maintain employment, translating into 
annual lost wages of nearly $15 billion2,3. Cognitive dysfunction is a core facet of schizophrenia, 
contributing to profound social and vocational difficulties4-6. Cognitive control (CC) is an 
important mental process that is reliably impaired in schizophrenia7-9.  
 
CC facilitates flexible, goal-directed behavior through real time adjustments in perceptual 
selection, response biasing, and on-line maintenance of contextual information10,11. CC deficits 
in schizophrenia are associated with poor treatment compliance, social and occupational 
dysfunction and decreased quality of life7-9. There are no effective treatments for CC 
impairment, due in large part to a gap in knowledge regarding the neural mechanisms of 
cognitive dysfunction in schizophrenia. In light of the significant functional disability and poor 
outcomes associated with impairment in CC there is a critical need for more effective 
therapeutic options for this important illness domain.  
 
Recently research has suggested that CC is subserved by a functionally related neural circuit, 
referred to as the cognitive control network (CCN), that includes the left dorsolateral prefrontal 
cortex (LDLPFC), the left superior parietal cortex (LSPC), and the anterior cingulate cortex 
(ACC)10,12-14. The ACC is a key node within the CCN and is believed to act as a network hub 
that strongly affects processing and connection efficiency15. Though previous work has 
demonstrated that disruption within the CCN, particularly decreased activity in the ACC, is 
associated with deficits in CC functioning12,16-18, a clear understanding of the impact of ACC 
dysconnectivity remains elusive. There is a critical need to identify investigational techniques 
that clarify the neural underpinnings of CC impairment in schizophrenia, such as ACC 
dysfunction, and contribute to the development of effective treatments for this important 
cognitive deficit in schizophrenia. 
 
Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation 
technique that received FDA clearance for use in treatment resistant major depressive disorder 
in 2008 and has become commonly used in clinical practice19.  rTMS utilizes the application of a 
repetitively pulsed magnetic field over the scalp to induce an electric field within a discrete area 
of the cerebral cortex. This electric field results in altered ion flow across the neuronal cellular 
membrane and ultimately changes in neuronal polarization. rTMS modulates cortical activation 
depending on the stimulation parameters used20,21. Physiological studies have provided 
evidence that high-frequency (HF) rTMS produces an increase in local cortical excitability20-24. 
Studies have also demonstrated that rTMS may increase functional connectivity between 
separate but related cortical structures, utilizing high frequency stimulation25-28. Thus, rTMS 
allows investigators to manipulate focal brain activity in a target region and distal function in 
associated circuitry25. The ability to affect activity downstream from the point of stimulation is 
important, as this enables investigators to modulate structures not directly accessible to rTMS, 
such as the ACC. 
 
Work by our group and others have shown that rTMS is a viable option for investigating 
cognitive dysfunction in schizophrenia26,28-30. We recently completed a pilot-study investigating 
the effects of HF rTMS, compared to sham stimulation, on cognitive dysfunction in an early 
phase psychosis (EPP) population. This study administered bilateral, sequential, double-blinded 
sham stimulation or HF (20 Hz) rTMS targeting the DLPFCs in twenty subjects with EPP. Ten 

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sessions of rTMS or sham were administered over the course of two-weeks. Our pilot-study 
demonstrated not only a beneficial effect of rTMS on cognition but also that the intervention is 
safe and well tolerated in subjects with EPP. There were no serious adverse events during the 
course of this study and there were no significant differences in adverse events between the 
rTMS and sham group. 
 
  
In spite of existing work studying rTMS as a treatment modality in schizophrenia, there are no 
studies that have examined the effects of rTMS targeting superficial CCN structures (LDLPFC 
and LSPC) on ACC activity or CCN connectivity in schizophrenia. It is also important to note 
that the vast majority of studies using rTMS in schizophrenia have examined chronic 
populations where confounds associated with prolonged duration of illness may be present. 
EPP is a desirable population to study because these individuals tend to have fewer psychiatric 
and physical comorbidities and less antipsychotic drug exposure, all of which are factors that 
may confound investigations of new treatment interventions for this illness. In light of the 
significant unmet medical need associated with schizophrenia and the grave clinical effect of 
disrupted CC in the illness, rTMS modulating the ACC, and potentially CCN circuitry, represents 
an unexplored and novel potential treatment option.  
 
The goal of this project is to utilize HF (20 Hz) rTMS, in conjunction with functional magnetic 
resonance imaging (fMRI), to provide evidence that rTMS targeting superficial CCN structures 
(LDLPFC and LSPC) modulates: 1) activation in the ACC during in-scanner CC task 
performance and 2) functional connectivity between the CCN structures during in-scanner CC 
task performance. This study will provide vital preliminary data on target engagement informing 
future clinical trials seeking to investigate rTMS as a novel treatment for CC impairment in 
schizophrenia. This study will also seek to refine the understanding of the brain circuitry that 
mediates the potential pro-CC effects of rTMS through the use of fMRI at baseline and following 
the course of rTMS administration. 
 
2.0 
Specific Aims and Hypothesis 
The first primary aim is to define the impact of HF (20 Hz) rTMS 
targeting the LDLPFC and LSPC on ACC activation in individuals 
with schizophrenia during in-scanner CC task performance. We 
predict that HF rTMS targeting the LDLPFC and LSPC will result in 
increased functional activation in the ACC during performance of an 
in-scanner CC task. The second primary aim of this study is to 
define the impact of HF rTMS targeting the LDLPFC and LSPC on 
CCN functional connectivity (FC). We hypothesize that HF rTMS of the 
LDLPFC and LSPC will result in increased FC between the LDLPFC, 
LSPC, and ACC during performance of an in-scanner CC task. An 
exploratory aim of this study is to determine the effects of HF rTMS 
targeting the LDLPFC and LSPC on CC performance. We will 
examine if HF rTMS targeting the LDLPFC and LSPC is associated 
with improved performance during on in-scanner CC task. 
 
 
 
 
 
Primary Aim 1 Prediction 
Primary Aim 2 Prediction 

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3.0 
Study Design 
 
This will be a single site pilot study. 20 
subjects with EPP, defined as medical 
record documentation of the onset of 
clinically significant psychotic symptoms 
within the past 10 years, will be enrolled. 
Prior to randomization subjects will 
undergo fMRI during CC task (Stroop 
Color-Word paradigm) and resting-state 
paradigms. This baseline scan will also 
include a high-resolution structural sequence for neuronavigation purposes. Then, on two 
separate days, each occurring one-week apart, subjects will receive one session of excitatory 
(20 Hz) rTMS targeting the LDLPFC and one session targeting the LSPC. The order of 
stimulation sites will be randomized and counter-balanced. Immediately following each session, 
subjects will undergo repeat fMRI during CC and RS paradigms. We will also examine the effect 
of rTMS on CC performance. 
 
rTMS Set up and Administration 
rTMS will be delivered using the Magventure MagPro X100 Magnetic Stimulator (Magventure 
Inc., Alpharetta, Georgia). Motor threshold (MT) will be determined using single pulse 
stimulation over the left primary motor cortex, assessed as the lowest intensity producing five 
visible movements of the right abductor pollicis brevis out of ten stimulations.  
 
High Frequency rTMS  
High frequency rTMS, or rTMS greater than 5 Hz, leads to faciliatory effects on brain 
excitability20-24,31. Previous studies have demonstrated that administration of as little as a single 
train or a small number of trains are able to produce an immediate increase in cortical 
excitability24. Additionally, earlier investigations have utilized high frequency rTMS in 
schizophrenia populations, demonstrating that the treatment is safe, well-tolerated and capable 
of altering cognitive performance30,32. Our group has employed 20 Hz rTMS at 110% of motor 
threshold in a stimulation protocol in-line with the current proposal to improve cognitive function 
in an EPP cohort30. High Frequency rTMS Protocol: Subjects will receive two sessions of HF 
rTMS, targeting the LDLPFC and LSPC, within the following stimulation parameters: 20 Hz, at 
120% of MT, 60 trains (1.0 second per train), 20 pulses per train, inter-train interval of 20 
seconds, for a total of 1200 pulses over 21 minutes. This stimulation protocol is within safety 
limits for rTMS21,33,34.  
 
Neuronavigation 
Brainsight software (Rogue Research, Montreal Canada) will be used to reliably target the 
LDLPFC and LSPC for stimulation. First, the subject’s individual anatomy will be registered 
stereotactically using the acquired structural MPRAGE brain image and fiduciary points on the 
scalp visible with a Polaris vicar camera (Brainsight software). We will use the centers of mass 
of the LDPLFC and LSPC (derived via Freesurfer parcellation; Destrieux Atlas35; left/right 
combined) to identify the specific coordinates for stimulation. Stimulation sites will be marked on 
a swim cap worn by the subjects at each stimulation session, consistent with prior TMS 
studies25.  
 
Electrical field modeling  
The processed structural image will be used to generate E-fields based on realistic conductor 
head models using SimNIBS (2.1 or latest version). SimNIBS includes volume conductor 
Fig 1. Study Outline 

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modeling (following FreeSurfer segmentation), TMS coil specific magnetic dipole estimations, 
and finite element modeling of the electric field at each tetrahedral element of the subject’s head 
mesh. In anticipation of actual TMS sessions with each patient, we will find the optimal TMS 
positioning to most strongly influence the LDLPFC and LSPC, which will be the target for 
neuronavigated rTMS delivery. 
 
rTMS administration monitoring 
All subjects will be instructed to wear earplugs during each rTMS session and will be monitored 
by medically trained research staff throughout the entirety of each rTMS session.   
 
Duration of Treatment 
Subjects will complete two stimulation sessions over two weeks, with one session occurring 
each week. Previous work has demonstrated that a single session of rTMS is sufficient to 
modulate target site functional activation as well as functional connectivity between the 
stimulation target and associated circuitry25. 
 
Sample Size 
We plan to enroll 20 subjects and anticipate a 20% drop out rate, yielding 16 completers. This is 
consistent with our previous clinical trial efforts, including a study of adjunct rTMS in an EPP 
cohort30,36. For all planned analyses, a total of 16 subjects in a counter-balanced design will 
result in 0.8 power to detect an assumed stimulation effect at medium effect size 0.6; using an 
alpha level of 0.05 and conservatively assumed a within-subject correlation of 0.5. As no CCN 
rTMS pilot data was available, this standardized effect size of 0.6 is considered a conservative 
estimate to detect significant results. 
 
Clinical Research Site  
The IU Psychotic Disorders Program (IUPDP), which is directed by Dr. Alan Breier and is part of 
the IU Department of Psychiatry, is located in Indianapolis, Indiana.  IUPDP research personnel 
will manage the day-to-day activities of conducting the trial, including subject recruitment, 
consenting and screening subjects, conducting study visits, and performing assessments.  The 
IUPDP has 2 research psychiatrists, a fully dedicated study manager, a fully dedicated study 
coordinator, one dedicated subject recruiter, one dedicated research technician, and two raters 
(1 PhD, 1 Masters level) who have been trained and have extensive experience in conducting 
the assessments and cognitive tests used as outcome measures. 
 
4.0 
Study Population (Inclusion/Exclusion Criteria) 
 
Inclusion criteria:  
1. Between 18 and 40 years of age 
2. Within 10 years of illness onset as defined by entry into treatment for psychotic 
symptoms 
3. Able to give informed consent 
4. Willing and able to adhere to the study schedule 
5. Structured Clinical Interview for DSM-5 (SCID-5-RV) diagnosis of schizophrenia 
6. Clinical stability defined by:  
a. Subjects must not have experienced an exacerbation of their illness within 4 
weeks prior to randomization, leading to an intensification of psychiatric care 
in the opinion of the investigator. Examples of intensification of care include, 
but are not limited to: inpatient hospitalization, day/partial hospitalization, 
outpatient crisis management, or psychiatric treatment in an emergency room 
AND 

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b. Antipsychotic treatment stability for at least 4 weeks prior to randomization 
(no change in antipsychotic dosing or addition of new antipsychotic 
medication) 
 
Exclusion criteria:  
1. Lifetime history of a seizure, excluding febrile seizures and those induced by 
substance withdrawal 
2. First degree relative with idiopathic epilepsy or other seizure disorder 
3. History of significant neurological illness 
4. History of head trauma as defined by a loss of consciousness or a post-concussive 
syndrome 
5. Pregnant or breast feeding  
6. Known IQ < 70 based on subject report  
7. Current acute, serious, or unstable medical conditions 
8. Metallic objects planted in or near the head, including implanted pacemaker, 
medication pump, vagal stimulator, deep brain stimulator, TENS unit, 
ventriculoperitoneal shunt, or cochlear implants 
9. Contraindications to MRI or otherwise unable to tolerate MRI procedures 
10. History of electroconvulsive therapy 
11. Subjects taking clozapine 
12. Subjects who have participated in a clinical trial with any pharmacological treatment 
intervention for which they received study-related medication in the 4 weeks prior to 
randomization  
13. Subjects considered a high risk for suicidal acts – active suicidal ideation as 
determined by clinical interview OR any suicide attempt in 90 days prior to screening  
14. Current DSM-5 diagnosis of alcohol or drug use disorder (excluding nicotine or 
caffeine)  
15. Subjects who require concomitant treatment with prohibited medication, as specified 
in Attachment 2 
 
5.0 
Subject Recruitment 
 
Subjects will be recruited through referring community mental health centers, treatment 
providers, the IUPDP registry, and self-referrals through advertisement and word-of-mouth. 
 
6.0 
Clinical Assessments and Procedures 
 
The following assessments will be administered according to the Study Procedures Table 
(Attachment 1). All assessments will be completed by study personnel trained to administer the 
instruments and will be based on interviews with the subject or questionnaires completed by the 
subject. 
 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS captures the occurrence, severity, and frequency of suicide-related thoughts and 
behaviors during the assessment period. The definition of behavioral suicidal events used in this 
scale is based on those used in the Columbia Suicide History Form41. During the baseline 
assessment, questions are in relation to lifetime experiences and all subsequent questioning is 
in relation to the last assessment. 
 
 

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The Positive and Negative Syndrome Scale (PANSS)  
The PANSS is the primary assessment instrument for psychopathology. The PANSS contains 
30 items that assess symptoms of psychotic disorders including positive, negative and general 
psychopathology. The PANSS was chosen because of its widespread use in clinical studies of 
psychosis, and its demonstrated reliability in assessing psychopathology across diverse patient 
populations42. 
 
Diagnostic Interview 
The Structured Clinical Interview for DSM-5 (SCID-5-RV) will be used to confirm the diagnosis 
of a psychotic disorder and/or rule out other diagnoses. The SCID-5-RV is a semi-structured 
interview designed to evaluate DSM-5 Axis I diagnoses37. 
 
Clinical Global Impressions Severity Scale (CGI-S)  
The CGI-S is used for repeated evaluations of global psychopathology43. The CGI-S scale is 
widely used in schizophrenia research and is a single 7-point Likert scale rating severity of 
psychopathology on a scale of 1 (normal, not ill) to 7 (very severely ill). 
 
Clinical Global Impressions Severity Improvement Scale (CGI-I)  
The CGI-I is used to assess the clinical change as compared to symptoms at baseline using a 
7-point Likert scale, ranging from very much improved (1) to very much worse (7)43. 
 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a 12-item scale designed to record the occurrence of dyskinetic movements44. 
Items 1 to 10 are rated on a 5-point scale, with 0 being no dyskinetic movements and 4 being 
severe dyskinetic movements. Items 11 and 12 are yes/no questions regarding the dental 
condition of a subject.  
Magnetic Resonance Imaging (MRI) Procedures 
Subjects will practice tasks on a personal computer during Visit 1 and prior to the scan at 
subsequent visits. Subjects will complete all pre-MRI procedures (e.g., completion of MRI 
screening form) before stimulation sessions to minimize the time in-between the stimulation 
session and MRI. We intend to conduct post-stimulation scans within fifteen minutes of 
completing a stimulation session. Siebner et al. (2009) noted in a consensus paper on 
combining transcranial stimulation with neuroimaging that protocols applying prolonged trains of 
rTMS can induce changes in neuronal excitability that may last for more than one hour post-
TMS45. We believe that an interval of 15 minutes between rTMS session and fMRI will capture 
changes in excitability. 
 
MRI will be performed at the IU Center for Neuroimaging using an integrated 45-minute exam, 
including structural and fMRI. Scans will be completed on a research-dedicated Siemens 
MAGNETOM Prisma 3T scanner. Subjects will undergo a high-resolution 3D magnetization 
prepared rapid gradient echo (MPRAGE) scan for individual anatomical reference.  An MRI-
compatible response box will be utilized for tasks, recording reaction time and accuracy. fMRI 
will employ a computerized version of the Stroop Color-Word task.  A task-free resting state 
fMRI scan will also be acquired to measure functional connectivity between CCN structures. 
 
 

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Stroop Color-Word Task 
Subjects will perform an in-scanner computerized version of the 
Stroop Color-Word task. This and similar paradigms have been 
shown by our group and others to elicit reliable ACC activation 
during task performance46. In this task, stimuli consist of three 
words: “Red”, “Green”, or “Yellow”, displayed in the 
corresponding color. Trials are either “congruent” (word matches ink color), “incongruent,” 
where the word and the color of the word differ in incongruent colors, or “nonwords,” which are 
“XXX”, “XXXX”, or “XXXXX”. The Stroop Color-Word task requires participants to press one of 
three buttons to identify the ink color of a presented word (red, green, or yellow; randomly 
assigned). Subjects are instructed to indicate the color but ignore the word and to respond as 
quickly and accurately as possible via button press. There are multiple iterations of this task 
available, mitigating potential practice effects. Participants will practice examples of the CC task 
on a personal computer during Session 1 and prior to the scan at subsequent visits. 
 
Emotional Stroop Color-Word Task 
Subjects will also perform an Emotional Stroop Color-Word task during the scan. This task is 
identical to the standard Stroop Color-Word, except emotional words (e.g., poor, sick, hurt) and 
neutral words (e.g., note, run, spin) are used instead of congruent and incongruent words. 
Subjects are again instructed to indicate the ink color of the word via button-press. This task will 
be practiced prior to each scan as well.  
 
 
Positioning and motion 
Subjects are instructed to remain still during scanning and deformable foam cushioning is used 
to stabilize the head. Real time image reconstruction and processing are used for quality 
assurance at the time of scanning. For fMRI, minor subvoxel-level translation or rotation is 
adjusted during post-processing. Noise: Noise-attenuating headphones and ear stopples 
provide excellent noise reduction and permit adequate auditory perception.  
 
Functional Imaging Stimulation and Physiological Monitoring Procedures 
A comprehensive physiological monitoring system will be used with synchronized digital 
recording including pulse oximeter, respiratory belt, HR and BP measures, which will be 
available for analysis in relation to BOLD fMRI time series. 
 
7.0 
Safety Assessments 
 
Vital Signs 
A seated blood pressure and pulse will be assessed at study visits per Study Procedures Table 
(Attachment 1).   
 
Medical History 
The subject’s lifetime medical history will be taken during the screening period. Medical history 
includes previous and current diseases.  
 
Physical Examination  
A physical examination including a neurological examination will be conducted as outlined in the 
Study Procedures Table. 
 
 
Stroop Color-Word Task 
 
Yellow 

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8.0 
Laboratory Assessments 
 
A urine pregnancy test will be conducted in all female subjects, and a urine drug screen will be 
conducted in all subjects, as outlined in the Study Procedures Table.  
 
9.0 
Concomitant Medication 
 
See Attachment 2. 
 
10.0 Adverse Events 
 
Adverse events (AEs), especially those for which the relationship to study treatment is not 
“unrelated,” will be followed up until they have returned to baseline status or stabilized at the 
discretion of the PI. If after the follow-up period, return to baseline or stabilization cannot be 
established an explanation will be recorded in the source documentation.  
 
11.0 Criteria for Repeat Assessments, Rescreening, and Discontinuation 
 
Repeat Assessments 
Screening assessments can be repeated within the screening window under the same 
screening number with the exception of eligibility criteria related rating scales/questionnaires. 
Subject diagnosis confirmation will not be repeated.  
 
Rescreening 
Subjects who screen fail may be rescreened one time, under the same screening number. If a 
subject is rescreened, all screening assessments (with the exception of the diagnosis 
confirmation) must be repeated and the stability criteria timelines must be met.  
 
Discontinuation  
Subjects will be discontinued under the following circumstances: 
1. Subjects unwilling or unable to complete study assessments or procedures 
2. Subjects who experience seizure occurrence at any point during study participation 
3. Subjects who require a change in dose of antipsychotic medication or the addition of a 
new antipsychotic medication 
4. Subjects experiencing an exacerbation of illness requiring an increased level of care or 
one judged to be clinically significant by the PI. 
 
If subjects discontinue from the study, completion of discontinuation assessments will be at the 
discretion of the PI. A subject may withdrawn from the study at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the PI for safety, behavioral, or 
administrative reasons.  
 
12.0 Data Safety Monitoring Board 
 
The Indiana University Adult Psychiatry Data Safety Monitoring Board (DSMB) will be 
responsible for data and safety monitoring. The DSMB is responsible for reviewing study 
procedures, adverse events, safety mailings (if applicable), enrollment, active subjects, and 
ongoing conduct of the research. The DSMB members can ask questions and make comments 
and/or recommendations. The IRB is notified of significant findings by way of the DSMB meeting 

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minutes at the time of continuing review. Due to the small sample size and single site design of 
this protocol, there is not sufficient justification for conducting interim analyses to examine 
trends. Data on the number of subjects enrolled and the number of adverse events will be 
reviewed by the DSMB every six months and more frequently if needed. The resultant report will 
be issued to the Indiana University IRB at least at the time of continuing review or more 
frequently by request. Any unanticipated events will be immediately directed to the PI who will 
follow the Indiana University IRB reporting procedures.  
 
13.0 Statistical Considerations 
 
Analyses 
 
Power Analyses 
 
In terms of the power to detect a significant effect of HF rTMS on CC neurocircuitry or 
performance, there are no known calculations with EPP patients. However, previous 
investigations, including our own, used similar stimulation designs when investigating the effects 
of rTMS on overall cognitive performance. These studies demonstrated statistically significant 
results with sample sizes consistent with the current proposal32, and Cohen’s effect sizes of d = 
0.92 and 1.15, respectively30,32. Though these previous studies examined different cognitive 
constructs than the CC task in this current protocol, these studies do provide evidence that a 
similar stimulation design is sufficient to elicit a biologic response and assumedly appropriate for 
investigating the effects of rTMS on CC.  
 
We believe that for the purpose of this pilot study, we can demonstrate significant results with a 
sample size of 16 (eight per group). This accounts for the effect size estimate derived from the 
literature, d = 1.1, and the estimation of power to detect an effect at .75, utilizing a one-sided 
independent test and significance levels of 0.05. 
 
Statistical Analyses 
 
Preliminary analyses will consist of descriptive statistics for all outcome variables, including 
summary statistics, graphical displays of distributions, and spaghetti plots of individual data over 
time to detect possible data errors. Demographic and clinical characteristics at baseline will be 
examined using parametric or nonparametric test statistics as appropriate. Any demographic 
variables that show significant differences will be added to the final models as covariates in 
order to ensure that the observed stimulation effects are not spurious or due to demographic 
confounds.  
 
To minimize the potential for Type II error, all treatment comparisons will be evaluated based on 
a one-sided significance level of 0.05. To compare overall effect of stimulation over time for the 
two groups, a set of multivariate repeat measures analysis of variance (ANOVA) will be utilized, 
with stimulation as the between-group factor and time as the within-subject factor.   
 
14.0 Data Management 
 
Primary data will be collected via paper source documents, phone interviews, and direct data 
capture from clinical and symptom measurements. Data will be stored electronically in REDCap 
and paper source documents will be stored in a double locked and access controlled research 
records room. REDCap will be backed up automatically weekly. Imaging data will be stored in 

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separate electronic files and merged with primary data as needed. The imaging data will 
automatically be stripped of all PHI prior to uploading to the database. Quality assurance steps 
will include: 1) Quality control data checks after each visit, 2) Single data entry by study staff, and 
3) Data verification procedures throughout the study to ensure proper transfer of data from paper 
source to REDCap.  
 
15.0 Privacy/Confidentiality Issues 
 
Confidentiality will be protected by ensuring all research staff have been properly trained in 
confidentiality and human subject research procedures, coding all subject information when 
possible, and by securing subject files in a locked filing cabinet or on secured databases with 
access available only to the PI and research staff. Furthermore, data entered into a computer 
database will only use subject codes on secured computers that will be password protected with 
access available only to the PI and research staff. Any screening information obtained from 
potential research subjects who subsequently do not participate in the research study will be 
destroyed. 
 
16.0 Record Retention 
 
Paper copies of medical records and source documentation will be kept for seven years after 
the study is closed with the IRB. One year after study closure, the documents will be shipped to 
the Indiana University Department of Psychiatry long-term storage facility until destruction. 
 
 
 

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Sevy S, Davidson M. The cost of cognitive impairment in schizophrenia. Schizophrenia research. 
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4. 
Harvey PD, Bowie CR, Friedman JI. Cognition in schizophrenia. Current psychiatry reports. 
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Palmer BW, Heaton, R.K., Paulsen, J.S., Kuck, J., Braff, D., Harris, M.J., Zisoonk, S., Jesta, D.V. Is it 
possible to be schizophrenic and yet neuropsychologically normal? Neuropsychology. 
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6. 
Sponheim SR, Jung RE, Seidman LJ, et al. Cognitive deficits in recent-onset and chronic 
schizophrenia. Journal of psychiatric research. 2010;44(7):421-428. 
7. 
Burdick KE, Goldberg JF, Harrow M, Faull RN, Malhotra AK. Neurocognition as a stable 
endophenotype in bipolar disorder and schizophrenia. The Journal of nervous and mental 
disease. 2006;194(4):255-260. 
8. 
Lesh TA, Niendam TA, Minzenberg MJ, Carter CS. Cognitive control deficits in schizophrenia: 
mechanisms and meaning. Neuropsychopharmacology : official publication of the American 
College of Neuropsychopharmacology. 2011;36(1):316-338. 
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ATTACHMENT 1: Study Procedures Table 
 
Visit Number 
1c 
2 
3 
4d 
Dayb 
 
0 
7 
21 
Informed Consent 
X 
 
 
 
Screening (Demographics, Inc/Exc, 
Medical & Psychiatric History of Self and 
Family) 
X 
 
 
 
SCIDa 
X 
 
 
 
Physical Exam 
X 
 
 
 
CGI-S 
X 
 
 
 
CGI-I 
 
X 
X 
 
Vitals 
X 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
Pregnancy Test 
X 
X 
X 
 
Motor Threshold Determination 
X 
 
 
 
MRI – Baseline 
X 
 
 
 
Randomization (Order of Study 
Intervention) 
 
X 
 
 
Neuro Navigation 
 
X 
X 
 
rTMS Administration (LDLPFC or LSPC) 
 
X 
X 
 
Post Stimulation MRI-CC Task  
 
X 
X 
 
PANSS 
X 
 
 
 
AIMS 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
aIf subject received a SCID interview within 6 months of screening, it may not be 
repeated at the discretion of the PI 
bIdeal time frame for administration will be on the same day of two consecutive 
weeks. A total of 2 sessions. Visit window deviations will be granted at the 
discretion of the PI and will not be a protocol violation. 
cVisit window for Visit 1 is 0-30 days 
dVisit 4 may occur by phone and ideally will occur 14 days after Visit 3. Visit 
window deviations will be granted at the discretion of the PI and will not be a 
protocol violation. 
 

Interactions of Fronto-Parietal High Frequency Repetitive Transcranial Magnetic Stimulation on Anterior Cingulate 
Cortex Activation in Schizophrenia 
 
v.11.05.20 
 
17 
 
Attachment 2:  Concomitant Medication Table 
 
Medication 
Allowed 
Notes 
Amitriptyline 
No 
 
Amphetamines et., methylphenidate, 
dextroamphetamine)  
No 
 
Antiemetics (eg., metoclopramide, 
domperidone, others with dopamine 
blocking properties) 
No 
 
Antiepileptic mood stabilizers 
Yes 
Stable dose, no changes or 
additions 
Antihistamines, nonsedating (eg., 
loratidine, fexofenadine, cetirizine) 
Yes 
 
Antihistamines, sedating (eg., 
diphenhydramine, hydroxyzine, 
meclizine, benztropine) 
Yes-Episodic Use Only 
No use within 24 hours of cognitive 
assessments 
Antipsychotic medications 
Yes 
Stable dose over four weeks prior 
to randomization, no changes or 
additions during duration of trial 
Barbiturates 
No 
 
Benzodiazepines 
Yes-Episodic Use Only 
No use within 24 hours of cognitive 
assessments 
Chlorpromazine 
No 
 
Bupriopion 
No 
 
Clozapine 
No 
 
Decongestants (eg., 
pseudophedrine) 
Yes-episodic use only 
No use within 24 hours of cognitive 
assessments 
Doxepine 
No 
 
Dicyclomine 
No 
 
Herbal medications or Over the 
Counter Medications w/ primary CNS 
activity 
No 
 
Lithium 
Yes 
 
MAOIs 
Yes 
 
Methadone 
No 
 
Mirtazepine 
Yes 
Stable dose, no changes or 
additions 
Muscle Relaxants 
Yes-Episodic Use Only 
No use within 24 hours of cognitive 
assessments 
Nicotine Replacement 
Yes 
 
Nortriptyline 
No 
 
Opiates 
No 
 
Benzodiazepine derivative sleep 
agents (eg., Zolpidem) 
Yes-Episodic Use Only 
No use within 24 hours of cognitive 
assessments 
SNRIs 
Yes 
 
SSRIs 
Yes 
 
Tricyclic antidepressants 
Yes 
 
Trazodone 
Yes-Episodic Use Only