Repetitive Transcranial Magnetic Stimulation (rTMS) as a Probe of Episodic Memory (EM) Neurocircuitry in Schizophrenia
Phase: NA
Conditions: Schizophrenia
Sponsor: Indiana University

Repetitive Transcranial Magnetic Stimulation as a Probe of Episodic Memory Neurocircuitry in Schizophrenia 
 
v.03.15.22 (D) 
 
 
 
 
 
Repetitive Transcranial Magnetic Stimulation as a 
Probe of Episodic Memory Neurocircuitry in 
Schizophrenia  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator:  
Michael Francis, MD 
Department of Psychiatry 
IU School of Medicine 
 
 
NCT04182113 
 
 
 

Repetitive Transcranial Magnetic Stimulation as a Probe of Episodic Memory Neurocircuitry in Schizophrenia 
 
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Table of Contents: 
Study Schema 
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. Episodic memory (EM) is an 
important cognitive domain that is commonly impaired in schizophrenia7.  
 
EM combines event-specific autobiographical experiences and information regarding the 
context in which events took place8, aiding in making decisions and guiding actions in the 
present. EM deficits are associated with poor insight, poor treatment compliance, and significant 
social and occupational dysfunction8-13. There are no effective treatments for EM impairment, 
due in large part to a gap in knowledge regarding the neural mechanisms of EM dysfunction. In 
light of the significant functional disability and poor outcomes associated with deficits in EM 
there is a critical need for more effective therapeutic options for this important cognitive deficit.  
 
Recently research has identified that dysconnectivity in key EM structures, such as the 
precuneus, may be associated with EM impairment, though the precise role of disordered 
cortical circuitry remains elusive7,14-17. The precuneus is believed necessary for autobiographical 
and episodic memory retrieval and mentalizing18-22. Cabeza et al. (2008) suggested that the 
precuneus is involved in supporting retrieval search, monitoring, and verification14. Altered 
function in the precuneus could be related to deficient EM functioning in various ways, including 
an impaired ability to make accurate assessments of familiarity7. Disrupted precuneus function 
may also impair attentional networks, interfering with the ability to retrieve previously encoded 
information23. The precuneus has reciprocal connections with other brain regions, including EM 
relevant structures such as the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate 
cortex (ACC)19, and the hippocampus24. Previous studies, including our own, have 
demonstrated that altered precuneus activity is associated with EM deficits in 
schizophrenia7,14,16,17,25. However, relative to other structures, the specific role of the precuneus 
in cognitive dysfunction in schizophrenia has not yet been determined. Clearly defining the role 
of structures, such as the precuneus, in EM dysfunction will enable investigators to develop 
more targeted therapeutic interventions for this important clinical phenomenon.  
 
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 practice26.  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 used27,28. Physiological studies have provided 
evidence that low-frequency (LF) rTMS produces an inhibitory effect on local cortical 
excitability14,17-19,21. In contrast, evidence suggests that high-frequency (HF) rTMS produces an 
increase in local cortical excitability27-31. Studies have also demonstrated that rTMS may 
increase or decrease functional connectivity between separate but related cortical structures, 
utilizing high and low frequency stimulation, respectively32-35. 
 
 Work by our group and others have shown that rTMS is a viable option for investigating 
cognitive dysfunction in schizophrenia33,35-37. We recently completed a pilot-study investigating 
the effects of HF rTMS, compared to sham stimulation, on cognitive dysfunction in an early 

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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 
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 significant 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 precuneus directed rTMS on either EM deficits or the 
neurocircuitry subserving EM 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 EM in the illness, rTMS 
modulating the precuneus, and potentially EM circuitry, represents an unexplored and 
potentially novel potential treatment option.  
 
This study proposes to combine functional magnetic resonance imaging (fMRI) with inhibitory 
LF (1 Hz) and excitatory HF (20 Hz) rTMS protocols to interrogate the effects of rTMS targeting 
the precuneus on: 1) precuneus activation during EM task performance; 2) functional 
connectivity between the precuneus and key EM circuitry, specifically the DLPFC, ACC, and 
hippocampus and 3) performance during an in-scanner scene encoding and recognition EM 
task. This study will provide vital preliminary data on target engagement informing future clinical 
trials seeking to utilize rTMS to treat EM impairment in schizophrenia. This is an important 
population for study because if effective, rTMS may represent a novel treatment for EM deficits 
in schizophrenia. This study will also seek to refine the understanding of the brain circuitry that 
mediates the potential pro-EM 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 demonstrate how targeting the precuneus with rTMS impacts 
functional activation (FA) in individuals with schizophrenia during EM tasks. We predict that, 
compared to sham stimulation, 1 Hz rTMS will result in decreased FA of the precuneus and 20 
Hz rTMS will result in increased FA of the precuneus. The second primary aim is to 
demonstrate how targeting the precuneus with rTMS impacts precuneus functional connectivity 
(FC) in individuals with schizophrenia. We predict that compared to sham stimulation, FC 
between the precuneus, the DLPFC, the hippocampus, and the ACC will be decreased in 
response to 1 Hz rTMS and increased in response to 20 Hz rTMS. The third primary aim is to 
characterize the relationships between EM performance and changes in precuneus functional 
activation and connectivity. We predict that improved EM performance will be associated with 
increased precuneus functional activation and connectivity, while poorer EM performance will be 
associated with decreased precuneus functional activation and connectivity. The secondary 
aim is to characterize how targeting the precuneus with rTMS affects episodic memory 
performance in individuals with schizophrenia. We predict that compared to sham stimulation, 1 
Hz rTMS will impair EM performance and that 20 Hz rTMS will improve EM performance. 
 

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3.0 
Study Design 
 
This will be a single site pilot study. 30 
subjects with EPP, defined as medical 
record documentation of the onset of 
clinically significant psychotic symptoms 
within the past ten years, will be enrolled. 
Prior to randomization (Session 1), 
subjects will undergo fMRI during EM and 
RS paradigms. This baseline scan will 
also include a high-resolution structural 
sequence for neuronavigation purposes. Then on three separate days each occurring one-week 
apart, subjects will receive one session of inhibitory (1 Hz) rTMS, one session of excitatory (20 
Hz) rTMS, and one sham stimulation session targeting the precuneus. The order of the three 
interventions will be randomized. Immediately following each rTMS or sham session, subjects 
will undergo repeat fMRI during EM and RS paradigms. We will also examine the effect of rTMS 
on EM 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. The Magventure 
MagPro X100 is equipped with a research-dedicated coil with combined active and sham 
stimulation capabilities. The active and sham functions share the same acoustic properties and 
sham mimics cutaneous stimulation, facilitating double-blinding. Study conditions (20 Hz, 1 Hz, 
sham) will be assigned a label, such as A, B, or C, by a non-blinded staff member who is not 
directly involved with the research team. Subjects will be assigned a sequence of blinded study 
conditions in randomized and counterbalanced fashion. 
 
High Frequency rTMS: High frequency rTMS, or rTMS greater than 5 Hz, leads to faciliatory 
effects on brain excitability27-31,38. 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 excitability31. Additionally, earlier investigations have utilized high frequency rTMS in 
schizophrenia populations, demonstrating that the treatment is safe, well-tolerated and capable 
of altering cognitive performance37,39. 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 cohort37. High Frequency rTMS Protocol: Subjects will receive one session of high 
frequency rTMS 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 15 seconds, for a total of 1200 
pulses over 16 minutes.  
 
Low Frequency rTMS: Low frequency rTMS, or rTMS at 1 Hz or less, is able to produce an 
inhibitory effect on local brain activity. This has been observed in healthy subject motor 
corticospinal output28. Previous studies have demonstrated that a single session of 1 Hz rTMS 
is capable of inhibiting local brain activity and modulating distal but related circuitry32. This work 
is in-line with the use of 1 Hz stimulation proposed in this study. Low Frequency rTMS Protocol: 
Subjects will receive one session of low frequency rTMS within the following stimulation 
parameters: Continuous 20-minute train of 1 Hz rTMS, at 120% of MT, for a total of 1200 
pulses. This protocol was shown by Chen et al. (2013) to produce an inhibitory effect on local 
cortical excitability as well as effects on connectivity of related circuitry32. 
Fig 1. Study Outline 

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Both high and low frequency stimulation protocols are within safety limits for rTMS28,40,41.  
 
Neuronavigation 
 
Brainsight software (Rogue Research, Montreal Canada) will 
be used to reliably target the precuneus 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 center of 
mass of the precuneus (derived via Freesurfer parcellation; 
Destrieux Atlas42; left/right combined) to identify the specific 
coordinates for stimulation. Stimulation site will be marked on a swim cap worn by the subjects 
at each stimulation session, consistent with prior TMS studies32.  
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 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 precuneus, 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 three stimulation sessions (HF, LF, and sham) over three 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 circuitry32. 
 
Sample Size 
We plan to enroll 30 subjects and anticipate a 20% drop out rate, yielding 24 completers. This is 
consistent with our previous clinical trial efforts, including a study of adjunct rTMS for cognitive 
impairment37,43. For all planned analyses, a total of 24 subjects in a cross-over design will result 
in 0.8 power to detect an assumed treatment difference 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 
precuneus 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. 
Fig. 2 E-field precuneus modeling 

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4.0 
Study Population (Inclusion/Exclusion Criteria) 
 
Inclusion criteria:  
1. Between 18 and 40 years of age 
2. Within 10.5 years (10 years, 6 months) 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)44 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 
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 
 
 
 
 
 

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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 Form45. During the baseline 
assessment, questions are in relation to lifetime experiences and all subsequent questioning is 
in relation to the last assessment. 
 
 
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 
populations46. 
 
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 diagnoses44.  
 
Clinical Global Impressions Severity Scale (CGI-S)  
The CGI-S is used for repeated evaluations of global psychopathology47. 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)47. 
 
Abnormal Involuntary Movement Scale (AIMS) 
The AIMS is a 12-item scale designed to record the occurrence of dyskinetic movements48. 
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 
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. First, we will conduct a high-resolution 3D magnetization 

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prepared rapid gradient echo (MPRAGE) scan for individual anatomical reference, comprised of 
160 sagittal slices with 1.0x1.0x1.2 mm voxel dimension. Subjects will practice tasks on a 
personal computer during Visit 1 and prior to the scan at subsequent visits. An MRI-compatible 
response box will be utilized for tasks, recording reaction time and accuracy. Functional scans 
will be acquired using T2*-weighted gradient spin echo-planar imaging (EPI) sequence with 
TR/TE 1200/29 ms for 54 axial slices and voxel size of 2.5x2.5x2.5 mm. fMRI will employ scene 
encoding and recognition EM paradigms, shown by our group and others to demonstrate 
reliable precuneus activation during cognitive functions of interest49-59. We have successfully 
implemented all tasks in multiple studies of patients with psychosis. A task-free resting state 
fMRI scan will also be acquired to measure functional connectivity between precuneus and 
associated structures and circuits. 
 
Scene Encoding and Recognition Tasks: 
These tasks utilize stimuli and a task design 
modified from that used by Detre et al. in EM 
studies in temporal lobe epilepsy49,50,55. We will 
be using methods identical those in our 
previous work7. During encoding task, subjects 
view complex scenes one at a time and are 
instructed to remember each for later 
recognition testing (Fig. 3). Images are shown 
in a block design with interleaved 36-s image and control blocks. Image blocks consist of nine 
consecutive images, each displayed for 3.5 s, with an inter-stimulus interval (ISI) of 500 ms. A 
total of 36 scene images are shown. Control blocks consist of a retiled image, repeatedly 
displayed at the same rate. Subjects do not press buttons during the encoding phase. The 
recognition task is a separate event-related fMRI paradigm administered immediately after the 
encoding phase. During the recognition task, subjects are shown the 36 scenes from the 
encoding phase intermixed with 36 new scenes. These images will be displayed consecutively 
in a pseudorandomized manner, each for 3.5 s with an ISI of 500 ms. Subjects are instructed to 
indicate, via button press, whether each displayed image was previously seen (target) or new 
(foil). Button-press responses are recorded to assess reaction time and accuracy. Task length 
for each trial is 5:15. Different versions of the scene encoding and recognition EM tasks will be 
utilized, with order of administration randomized, to mitigate the potential impact of learning 
effects. 
 
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. 
 
 
 
 
 
Figure 3. Scene Encoding and Recognition EM Task 
 

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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. 
 
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. During the course of the study, subjects with an interruption of stimulation administration  
2. Subjects unwilling or unable to complete study assessments or procedures 
3. Subjects who experience seizure occurrence at any point during study participation 
4. Subjects who require a change in dose of antipsychotic medication or the addition of a 
new antipsychotic medication 

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5. 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 
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 precuneus directed rTMS on EM 
performance or neurocircuitry, there are no known calculations with EPP patients. We plan to 
enroll 30 subjects and anticipate a 20% drop out rate, thus yielding 24 completers. This is 
consistent with our previous clinical trial efforts in early phase psychosis populations, including a 
study of adjunct rTMS for cognitive impairment and negative symptoms37,43. For all planned 
analyses, a total of 24 subjects in a cross-over design will result in 0.8 power to detect an 
assumed treatment difference 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 previous precuneus rTMS pilot 
study was available, this standardized effect size of 0.6 is considered to a conservative estimate 
to detect the significant results. 
 
Statistical Analyses 
 
Intent-to-treat (ITT) analysis will be conducted, and thus all randomized subjects will be 
included. ITT is the most conservative approach for detecting a treatment effect, because the 
inclusion of subjects who do not complete the intervention will serve to underestimate rather 
than overestimate any treatment effect. Sensitivity analyses including a subset analysis using a 
“completers only” analysis will be performed to test the robustness of the findings. Statistical 
tests will be performed based on two-sided test at the 5% level of significance. 

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Descriptive characteristics at baseline will be summarized for the whole sample. For continuous 
variables, the mean and standard deviation will be presented. For categorical variables, the 
number and percent will be reported.  
 
Primary analyses: For each subject, change scores in activation of the precuneus (aim 1), 
functional connectivity (aim 2), and EM performance (aim 3) will be calculated at each treatment 
by using (post - baseline). We will employ a mixed model for repeated measures ANCOVA, of 
the general form for each measure: 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑖𝑖𝑖𝑖𝑖𝑖= 𝜇𝜇+ 𝛼𝛼𝑖𝑖+ 𝑏𝑏𝑖𝑖𝑖𝑖+ 𝛾𝛾𝑘𝑘+ 𝛽𝛽𝑋𝑋𝑖𝑖𝑖𝑖𝑘𝑘+ 𝜏𝜏𝑑𝑑(𝑖𝑖, 𝑘𝑘) + 𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖, 
where 𝜇𝜇 is overall mean; 𝛼𝛼𝑖𝑖 is the effect of the 𝑖𝑖th treatment sequence (𝑖𝑖= 1, 2, ⋯, 6); 𝑏𝑏𝑖𝑖𝑖𝑖 is the 
random effect with variance 𝜎𝜎𝑏𝑏
2 for the 𝑗𝑗th subject (𝑗𝑗= 1, 2, ⋯, 24) of the 𝑖𝑖th treatment sequence; 
𝛾𝛾𝑘𝑘 is the period effect (𝑘𝑘= 1, 2, 3); 𝛽𝛽𝛽𝛽 is the baseline value; 𝜏𝜏𝑑𝑑(𝑖𝑖, 𝑘𝑘) is the direct effect of the 
treatment administered in period 𝑘𝑘 of sequence group 𝑖𝑖;  and 𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 is the random error with 
variance 𝜎𝜎2 for the subject in period 𝑘𝑘. Based on this model, we will compare the treatment 
difference in change score between 1 Hz and Sham as well as 20 Hz and Sham. Under the 
assumption of missing at random, this mixed effect model will provide the unbiased estimates60. 
Secondary analyses:  We expect two mediation relations: (1) the treatment affects the 
connectivity through the activation of the precuneus; and (2) the treatment affects the EM 
performance through the activation of the precuneus.  We use the first mediation as an 
example. The following 3 equations proposed by Baron and Kenny will be analyzed in order to 
establish mediation61: 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑖𝑖𝑖𝑖𝑖𝑖= 𝜇𝜇+ 𝛼𝛼𝑖𝑖+ 𝑏𝑏𝑖𝑖𝑖𝑖+ 𝛾𝛾𝑘𝑘+ 𝛽𝛽𝑋𝑋𝑖𝑖𝑖𝑖𝑖𝑖+ 𝜏𝜏𝑑𝑑(𝑖𝑖, 𝑘𝑘) + 𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 (1); 𝑐𝑐ℎ𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑖𝑖𝑖𝑖𝑖𝑖=
𝜇𝜇+ 𝛼𝛼𝑖𝑖+ 𝑏𝑏𝑖𝑖𝑖𝑖+ 𝛾𝛾𝑘𝑘+ 𝛽𝛽𝑋𝑋𝑖𝑖𝑖𝑖𝑖𝑖+ 𝛾𝛾𝑀𝑀𝑖𝑖𝑖𝑖𝑖𝑖+ 𝜏𝜏𝑑𝑑(𝑖𝑖, 𝑘𝑘) + 𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 (2); and 𝑀𝑀𝑖𝑖𝑖𝑖𝑖𝑖= 𝜇𝜇+ 𝛼𝛼𝑖𝑖+ 𝑏𝑏𝑖𝑖𝑖𝑖+ 𝛾𝛾𝑘𝑘+ 𝛽𝛽𝑋𝑋𝑖𝑖𝑖𝑖𝑖𝑖+
𝜏𝜏𝑑𝑑(𝑖𝑖, 𝑘𝑘) + 𝑒𝑒𝑖𝑖𝑖𝑖𝑖𝑖 (3). Four steps are to be evaluated. First, a significant relation of treatment to the 
change in connectivity is required in (1). Second, a significant relation of treatment to the 
change in activation of the precuneus is required in (3). Third, mediator, the change in the 
activation of the precuneus, must be significantly associated with change in connectivity when 
both treatment and mediator are controlled as covariates. Fourth, the coefficients of treatment in 
(1) must be larger (in absolute value) than the coefficients of treatments in (2)62. If four steps are 
met, we will consider that the change in activation of the precuneus is mediator of the 
relationship between treatment and change in connectivity.  
 
 
 
 
Treatment 
Mediator: change in 
activation of the 
precuneus 
Change in Connectivity 
a 
b 
c’ 

Repetitive Transcranial Magnetic Stimulation as a Probe of Episodic Memory Neurocircuitry in Schizophrenia 
 
v.03.15.22 (D) 
 
 
 
Brain Imaging Analyses: Aim 1. Data analysis of the blood-oxygen level-dependent (BOLD) 
time series will utilize standard preprocessing through the AFNI software package. Standard 
preprocessing includes motion correction, despiking, detrending, smoothing, and exclusion of 
signal and motion outlier time points. Each condition’s timing will be convolved with a 
hemodynamic response function to model an ideal response for that condition. General linear 
modeling will provide a regression coefficient estimate (beta) of the BOLD response to each 
condition (Target correct; Foil correct; Target incorrect; Foil incorrect). We will also include 
regressors of no interest for motion and motion derivatives to reduce noise. For our primary 
analysis, we will create a region of interest (ROI) as a 10-mm radius sphere around our rTMS 
target in the precuneus. fMRI Contrast: Each event type will be modeled separately. Brain 
activity will be examined by contrasting the estimated beta coefficients for correct trials only 
(Target correct vs. Foil correct). We will extract the mean response from this contrast from 
our precuneus ROI and evaluate the aim via a mixed model for repeated measures. Aim 2. 
Beyond standard preprocessing, time-series data will be filtered to extract low frequency (< 0.08 
hz) BOLD data. The ANATICOR approach (within AFNI) will be used63 to reduce noise from 
physiological or hardware sources. ANATICOR utilizes tissue segmentation to control for 
spatially coherent fluctuations emanating from non-gray matter. Structural regions of interest 
(ROIs) will be defined on each side with Talairach-based atlases available via AFNI software for 
the ACC and bilateral middle frontal gyrus, in addition to the spherical precuneus ROI. Visual 
inspection of ROIs will ensure their correct position. The mean preprocessed time series will be 
extracted from each ROI, and time-series correlations between ROIs will be calculated. These 
correlations will be used as the dependent variable in a mixed model for repeated measures 
ANCOVA, with post-hoc tests as necessary. Supplementary analyses will examine connectivity 
differences of the precuneus ROI across the entire brain (corrected p < .05). 
 
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 
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.  
 
Treatment 
Mediator: change in 
activation of the precuneus  
Change in EM performance 

Repetitive Transcranial Magnetic Stimulation as a Probe of Episodic Memory Neurocircuitry in Schizophrenia 
 
v.03.15.22 (D) 
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. 
 
 
 

Repetitive Transcranial Magnetic Stimulation as a Probe of Episodic Memory Neurocircuitry in Schizophrenia 
 
v.03.15.22 (D) 
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v.03.15.22 (D) 
 
ATTACHMENT 1: Study Procedures Table 
 
Visit Number 
1c 
2 
3 
4 
5d 
Dayb 
 
0 
7 
14 
28 
Informed Consent 
X 
 
 
 
 
Screening (Demographics, Inc/Exc, 
Medical & Psychiatric History of Self and 
Family) 
X 
 
 
 
 
SCID Va 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
 
CGI-S 
X 
X 
X 
X 
 
CGI-I 
 
X 
X 
X 
 
Vitals 
X 
X 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
Pregnancy Test 
X 
X 
X 
X 
 
Motor Threshold Determination 
X 
 
 
 
 
MRI – Baseline & Baseline EM Task 
X 
 
 
 
 
Randomization (Order of Study 
Intervention) 
 
X 
 
 
 
Neuro Navigation 
 
X 
X 
X 
 
rTMS/sham Administration  
 
X 
X 
X 
 
Post Stimulation MRI-EM Task  
 
X 
X 
X 
 
PANSS 
X 
 
 
 
 
AIMS 
X 
X 
X 
X 
 
C-SSRS 
X 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
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 each Monday of three consecutive weeks. A 
total of 3 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 5 may occur by phone and ideally will occur 14 days after Visit 4. Visit window 
deviations will be granted at the discretion of the PI and will not be a protocol violation. 
 

Repetitive Transcranial Magnetic Stimulation as a Probe of Episodic Memory Neurocircuitry in Schizophrenia 
 
v.03.15.22 (D) 
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