A Pilot Open-label Trial of Individualized Repetitive Transcranial Magnetic Stimulation for Patients With Auditory Verbal Hallucinations
Phase: NA
Conditions: Schizophrenia and Related Disorders
Sponsor: Columbia University

 
 
 
 
 
 
A pilot open-label trial of individualized repetitive 
transcranial magnetic stimulation for patients with 
auditory verbal hallucinations 
 
 
NCT05319080 
 
December 21, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Lay Summary  
 
The large majority of patients with schizophrenia (Sz) experience auditory verbal hallucinations 
(AVH) as a core feature of their disorder. Treatment-resistant auditory verbal hallucinations 
(AVH) affect a third of patients with schizophrenia and can cause increased aggression, distress, 
suicide, and social dysfunction. The current standard of care is antipsychotic medication which 
can cause metabolic syndrome, sedation, orthostatic hypotension, extrapyramidal symptoms, and 
tardive dyskinesia among other adverse effects. Transcranial magnetic stimulation (TMS) emits a 
rapidly changing magnetic field over the scalp which induces current flow in underling brain 
tissue, either enhancing or disrupting function depending on the frequency of stimulation. It is 
generally well tolerated and repetitive TMS (rTMS) is currently FDA approved for treatment of 
depression. rTMS carries potential as an alternative treatment for schizophrenia patients with 
AVH who either do not respond to or do not tolerate medication. Inhibitory (1-Hz) standard TMS 
approaches, which use scalp-based targeting of speech perception areas such as left 
temperoparietal junction (TPJ) have yielded mixed results in reducing AVH, possibly due to 
variability of underlying brain anatomy between individual subjects. The influence of anatomical 
variability could be eliminated by individually positioning the TMS coil according to each 
patient’s structural brain MRI. The proposed pilot project will investigate the 
clinical efficacy of open-label individualized MRI-guided TMS applied to the left TPJ in ten 
patients with schizophrenia or schizoaffective disorder. If the results of the pilot study show 
promising reductions in AVH, it will set up the foundation for a larger sham-controlled clinical 
trial. 
 
Background, Significance, and Rationale  
 
A significant presenting symptom for approximately 70% of schizophrenia (Sz) patients is the 
experience of auditory verbal hallucinations (AVH), which are the only Sz symptom 
independently correlated with “patient distress” (Takeuchi et al., 2016). Moreover, chronic AVH 
are a strong predictor of suicide (Birchwood et.al, 2000, Howes et al., 2014), low socioeconomic 
status, and poor social function (Howes et al., 2014). The only approved medications for AVH in 
Sz are antipsychotics, which fail in ~30% of individuals (Hasan et.al, 2012, Kane et.al, 1998). 
Transcranial magnetic stimulation (TMS) offers an alternative and safe approach for Sz patients 
suffering from AVH who either do not respond to medication or cannot tolerate medication side 
effects.  
 
Transcranial magnetic stimulation (TMS) is a noninvasive method by which a rapidly changing 
magnetic field can be used to focally influence brain activity. TMS has been shown to be 
effective in both disrupting and facilitating ongoing cognitive processing. With TMS, a magnetic 
coil is positioned over a particular scalp region. A TMS device emits brief pulses of current 
through a stimulating coil held over and near the scalp. The current flow lasts less than a 
millisecond, and it produces a rapidly changing magnetic field around the coil. This magnetic 
field in turn induces current flow in cortical tissue near the surface of the head, stimulating 
neurons in a focal region, generating a brief modulation of neural activity (Luber et al., 2007). 
The magnetic field exponentially decreases in strength with distance as it passes unobstructed 

through the skull, effectively depolarizing neurons up to two centimeters into the brain. The 
effects are not entirely local, as the depolarized neurons transmit their activity transsynaptically 
to connected subcortical and transcortical regions within functional networks. The actual 
neurobiological effects depend on the intensity of the magnetic field, the coil shape and its 
orientation, and the geometry of the underlying cortex in relation to the field. The neural effects 
of TMS also depend on the frequency of stimulation when applied repetitively in a pulse train 
(rTMS). While rTMS is FDA approved for the treatment of depression, it is also proposed as a 
novel treatment for schizophrenia patients with treatment-resistant AVH when applied using 
inhibitory frequencies over left language-receptive areas. rTMS is generally well tolerated and 
safe but see “Risks and inconveniences” section for a detailed discussion of potential adverse 
effects. Current studies of 1-Hz (inhibitory) rTMS targeting speech perception areas such as left 
TPJ/Wernicke’s area have yielded mixed results in reducing AVH. However, most of these 
studies use scalp-based targeting approaches that don’t account for individual variability in 
underlying brain anatomy (Briend et al. 2020, Schiz Res. 
https://doi.org/10.1016/j.schres.2020.09.001). Here we propose to pilot an individualized MR-
guided rTMS approach of a left TPJ target to establish feasibility and potential efficacy using an 
open-label design in ten participants with schizophrenia or schizoaffective disorders with 
persistent AVH. In addition to assessing pre/post treatment changes in AVH severity and 
characteristics using established clinical scales, we will also assess pre/post changes in 
etiologically-relevant fMRI and neurophysiological (EEG) biomarkers. 
 
Specific Aims and Hypotheses  
 
Specific Aim 1: To evaluate the efficacy of individualized MR-guided inhibitory rTMS in 
reducing AVH symptoms in Sz. We hypothesize that TMS targeting an area of left TPJ involved 
in receptive language processing will reduce AVH severity. 
 
Specific Aim 2: To evaluate the utility of etiologically relevant MRI tasks and EEG biomarkers 
in tracking treatment response. We hypothesize that pre/post treatment changes in AVH severity 
will correlate with normalization of previously established deficits in MRI and EEG measures 
associated with AVH. 
 
Description of Subject Population 
 
Population: Adults with schizophrenia and schizoaffective disorder 
Number of completers required to accomplish study aims: 10 
Projected number of subjects who will be enrolled to obtain required number of completers: 12 
Age range of subject population: 22-55 
 
Gender, Racial and Ethnic Breakdown 
 
Based on prior studies of schizophrenia at NYSPI/Columbia: 
 
60% male; 40% female 
1/3 Hispanic; 2/3 non-Hispanic 
50% Caucasian; 30% African-American; 10% Asian-American; 10% Mixed Race or Other 

 
We will not exclude any subjects based on gender or ethnicity/race. Females of childbearing 
potential will be permitted to participate as long as they remain on adequate birth control. The 
proportions of ethnic groups in our study population reflect the demographics of schizophrenia 
patients within our catchment areas, and a significant proportion of Hispanic and African-
American subjects are included in our studies. Prior trials conducted by our group have 
consistently obtained a demographic mix that is representative of schizophrenia within the New 
York City and Rockland County populations, particularly our neighborhood of Washington 
Heights, which has a large percentage of African American and Hispanic residents. 
 
The demographics of schizophrenia in the United States are ~ 1% of the population of each 
ethnicity, with the exception of more men (ratio 1.4:1) and a 2 to 3 fold increased rate in African 
Americans (Regier et al, Acta Psychiatr Scand 1993, Bresnahan et al, Int. J. Epidemiol, 2007). 
The literature supports that the demographics of schizophrenia in any specific area, such as New 
York City in general, and Washington Heights specifically should reflect the demographics of 
the area (Reiger 1993). For example, Washington Heights (the neighborhood in which the New 
York State Psychiatric Institute is located) has a large percentage of Hispanic people with 
schizophrenia because of the relatively large number of Hispanic people in Washington Heights. 
 
Because we will be recruiting a portion of the participants from the study (protocol # 7114) 
within our division, we have used composite demographics from SZ patients in the study (which 
are representative of schizophrenia patients within the New York City and Rockland County 
areas) for the breakdown above. 
 
Description of subject population 
Subjects will be patients diagnosed with Schizophrenia or Schizoaffective Disorder, who suffer 
from AVH. Inclusion/exclusion criteria were based on previous studies. 
 
Suicide Risk Management Plan 
 
The rater who will be conducting C-SSRS has a master's degree in clinical psychology and has 
many years of experience working with vulnerable clinical patients. The rater has been 
administering C- SSRS under other protocols for the past two years. The C-SSRS will be 
conducted every week of the four-week study. In addition, the study PI (MD/PhD) will conduct a 
rigorous assessment with participants prior to the start of treatment, including asking if they have 
suicidal thoughts and plans, which will be recorded on the evaluation note form in the redcap. 
After the screening session, the study PI and the rater will go through the inclusion/exclusion 
criteria together to determine the patient's eligibility. On each day of the 10-day treatment, a 
covering MD will ask a series of questions about the patient's symptoms, mood, suicidal 
thoughts and medication use before starting the session. These will be recorded in the progress 
note form on the redcap after each day of treatment. All research members involved in the study 
have completed all necessary CITI training courses to ensure the safety and welfare of 
participants. 
 
The rater will gather lifetime history of suicidality as well as any recent suicidal ideation and 

behavior. The Suicidal Ideation section of C-SSRS contains 5 questions, which are 5 types of 
ideation of increasing severity. The Suicidal Behavior section will help us understand each type 
of suicidal behavior the patient has had or recently had. If a patient endorses items 4 or 5 of the 
Suicidal Ideation section, or they had suicidal behavior within the past 6 months as indicated in 
the Suicidal Behavior Section, they will be determined to be at risk of suicide. The study PI will 
be informed immediately and then he will communicate directly with the patient to further 
determine the patient's suicide risk level. During this time a more detailed and thorough medical 
assessment will be completed and other safety strategies will be initiated. If the patient already 
has a qualified mental health provider, that provider will be informed immediately of the 
situation and asked to meet with the patient as soon as possible for clinical management. If the 
patient doesn’t already have a qualified mental health provider or that provider cannot meet with 
them in a time frame that the study PI thinks is safe, we will initiate the referral process to help 
locate and contact a qualified mental health provider who can offer an appointment within a safe 
time frame. A referral list will be developed for those who are at intermediate and low acute risk. 
The referral resources included in the list will vary based on the individual patient's situation 
(e.g., insurance status) and the availability of mental health providers to see patients. We will 
continue to be responsible for the patient’s safety until we confirm with the provider that the 
patient will be seen in a timely manner and is now a patient of the provider. This active referral 
process and confirmation of follow-up will be documented in REDCap. In extreme 
circumstances, if a patient is judged to meet the criteria as an “immediate danger to self,” he/she 
will be asked to come to the ER. The study PI will speak with the responsible ER physician to 
provide all relevant information and request follow-up on disposition. In the event of emergent 
imminent risk in which the participant is unable to get to an emergency room on their own, the 
covering MD may call upon community resources such as 911. In individual cases where the 
study PI doesn’t believe that the patient ‘s presentation warrants active referral, a referral list 
with names and telephone nu e rationale for this will be documented in REDCap. 
 
Recruitment Procedures  
 
Recruitment of adults with schizophrenia or schizoaffective disorder from the study "Study of 
Early Cortical Processing in Schizophrenia”(Protocol #7114) within the Division of 
Experimental Therapeutics at NYSPI. 
Potential participants will also be recruited through flyers and online advertisements posted on 
Craigslist, Facebook, and RecruitMe. 
 
Research staff from the "Study of Early Cortical Processing in Schizophrenia” (Protocol #7114) 
will tell adult patients with schizophrenia or schizoaffective disorder about the study and ask if 
they would like to meet with investigators or research staff of this "A pilot open-label trial of 
individualized repetitive transcranial magnetic stimulation for patients with auditory verbal 
hallucinations" to learn more about the study and have any questions answered. For patients who 
express willingness to be contacted, the investigators and/or coordinators of the "Study of Early 
Cortical Processing in Schizophrenia” (Protocol #7114) will pass contact information along to 
appropriate research staff of the present protocol. A member of our research staff will send a 
targeted recruitment email and/or call the participants who express interest. Patients will also be 
recruited through flyers, Craigslist and online postings to recruitment websites. 
 

 
 
Inclusion/Exclusion Criteria  
 
Our criteria for the subject population are based on previously approved protocols of HD-tDCS 
on schizophrenia and schizoaffective patients led by Dr. Michael Avissar (IRB # 7882), previous 
trials on TMS in treating AVH (Auditory Verbal Hallucinations) in patients with schizophrenia 
(Hoffman et al., 2005; Thomas et al., 2019), and the FDA guidance on TMS 
(https://www.fda.gov/medical-devices/guidance-d-radiation-emitting-products/repetitive-
transcranial-magnetic-stimulation-rtms-systems-class-ii-special-controls-guidance).  
Inclusion 
Criterion 
Method of Ascertainment 
1. Age between 22-55  
Self-report 
2. DSM-V diagnosis of schizophrenia or 
schizoaffective disorder 
Structured Clinical Interview for DSM-5 
3. Capacity and willingness to provide 
informed consent 
Independent assessment of capacity 
4. Mean AHRS item score of greater or 
equal to 2. 
Auditory Hallucinations Rating Scale 
(AHRS) 
5. If female and not infertile, must agree 
to use one of the following forms of 
contraception for the duration of study 
participation: systemic hormonal 
treatment, an IUD which was 
implanted at least 2 months prior to 
screening, or “double-barrier” 
contraception. Women of child 
bearing potential must have a 
negative pregnancy test at screening. 
Self-report, urine pregnancy test 
6. Right handed 
Edinburgh Handedness Inventory 
7. Normal hearing 
Mean audiometry ≤25 dB above age corrected 
norms 
8. Taking an antipsychotic medication at 
a stable dose for at least 4 weeks. All 
oral and depot antipsychotics are 
allowable. 
Self report 
 
Exclusion  
 
Criterion 
Method of Ascertainment 
1. Substance use disorder (excluding 
SCID and self report 

nicotine) within last 90 days, or positive 
toxicology screen for any 
substance of abuse 
2. Pregnancy 
Urine pregnancy test at screening 
3. Participation in study of 
investigational medication/device 
within 4 weeks 
Self report 
4. History of seizure, epilepsy and 
neurologic conditions with structural 
cerebral damage, including stroke, 
multiple sclerosis, traumatic brain 
injury, Alzheimer’s and other 
neurodegenerative diseases, 
meningoencephalitis or intracerebral 
abscess, parenchymal or 
leptomeningeal cancers, dementia, 
developmental disability, 
cerebrovascular disease, increased 
intracranial pressure, or central 
nervous system (CNS) tumors, brain 
surgery, head injury with loss of 
consciousness >1 hour or clear 
cognitive sequelae, intracranial metal 
implants, known structural brain 
lesion 
Physician evaluation/Medical history/TASS 
5. Subjects with devices that may be 
affected by TMS (pacemaker, 
cardioverter defibrillator, medication 
pump, intracardiac line, cochlear 
implant, implanted brain 
stimulator/neurostimulator) 
Physician evaluation/Medical history/TASS 
6. Subjects with suicidal ideation with 
intent or plan (indicated by 
affirmative answers to items 4 or 5 of 
the Suicidal Ideation section of the 
baseline C-SSRS) in the 6 months 
prior to screening or subjects who 
represent a significant risk of suicide 
in the opinion of the investigator 
Columbia Suicide Severity Rating Scale 
(CSSRS) 
7. Frequent and persistent migraines 
Physician evaluation/Medical history 
8. Clinically significant skin disease 
Physician evaluation/Medical history 
9. Presence of unstable medical 
disorders, including those that are previously 
undiagnosed, untreated, inadequately treated, 
or active to an extent which might make 
participation hazardous. For 
Physician exam with vital signs/Medical 
history 

example, hypertension, previous 
stroke, brain lesions, or heart disease. 
10. History of prior clinically significant, 
adverse response to 
neurostimulation 
Self report/TASS 
11. Current treatment with ototoxic 
medications (amino- glycosides, 
cisplatin) 
Self report 
12. MRI incompatible implants 
Physician evaluation/Medical history/NYSPI 
MRI safety metal screening questionnaire 
13. Claustrophobia 
NYSPI MRI safety metal screening 
questionnaire 
 
Consent Procedures 
 
The screen is straightforward and some patients will be referred from the approved study 
(protocol #7114), such that diagnosis has already been established, and inclusion/exclusion 
criteria will have been reviewed. However, when potential participants are told about the study, 
they will also be told of the eligibility criteria for the study. They can review whether they 
believe they meet these criteria (without our asking them for Personal Health Information) and if 
so, and if interested in participation, they can provide written informed consent. Eligibility 
criteria will be more rigorously assessed after provision of written informed consent (i.e. using 
the SCID and the MRI questionnaire, and urine test for women of childbearing age). 
Consent procedures will be conducted by MDs only. During the consent process, an MD will 
discuss alternative treatments for hallucinations with potential participants and with their 
permission, the MD will attempt to reach out to their psychiatrist or equivalent provider to 
discuss clinical suitability of enrolling in the study. All individuals involved in screening and 
consent procedures have undergone HIPAA and CITI training and are familiar with study 
procedures of this protocol. 
 
The risks of travel for in-person visits during covid-19 will be discussed during the consent 
discussion. We will ask participants to exercise caution when traveling in public and follow 
public health guidelines, such as wearing masks in public and avoiding crowds. It is important 
for them to stay informed about public health recommendations and guidelines regarding 
COVID-19, such as those issued by the Centers for Disease Control (CDC.gov) and local 
government guidelines and directives. 
 
To minimize face to face interaction, we plan on conducting the bulk of the consent process, 
including a thorough explanation of the study and subject questions over the phone or on WebEx 
on site with the investigator and subject in separate rooms. This will allow for minimizing the 
face to contact to the actual physical signature when the consent is done in person. When the 
study MD is not onsite, we will utilize REDCap for consent, with an e-signature or use a digital 
signature on the PDF consent prior to printing for the patient. In all cases, the subject will be 
provided ample time to review the consent prior to signing. 
 

The consent discussion process will include discussion of the technology HIPAA-compliant 
platforms to be used. If the subject is on site at NYSPI, the subject will be in a private office 
when consented, which meets the requirements for the subject to have adequate wifi or privacy 
for the consent process. 
 
Study MDs obtaining informed consent will fully disclose and explain the risks and benefits of 
the study procedures to the participant, as well as answer any questions about the study and the 
material presented in the informed consent form that he/she may have. The consent form 
describes the nature of the procedures and time requirements, potential risks, the confidentiality 
of information, and the rights of research subjects, including their right to withdraw from the 
research at any time without loss of benefits to which they are otherwise entitled. Alternatives to 
study participation will be discussed, and the voluntary nature of participation in the study will 
be emphasized. This consent discussion will be documented in a consent note placed in the 
subject’s chart. 
 
Independent Assessment of Capacity  
 
An independent MD, PhD, or licensed professional will assess capacity to provide informed 
consent. If a patient has difficulty understanding any study elements during the consent process, 
the procedures will be explained by a member of the research team. If there is still doubt about 
the subject's understanding of the key elements of the study and ability to provide informed 
consent, the subject will not be enrolled in the 
study. 
 
Study Procedures 
 
We will recruit participants from NYSPl # 7114 (Study of Early Cortical Processing in 
Schizophrenia). In order to better understand the burden to participants who enroll in both 
protocol #7114 and the current protocol, we are summarizing the study procedures in # 7114: 
After providing informed consent, participants undergo a 2 hours phone screen (such as the 
SCID) to confirm diagnosis and assess comorbidity. Participants then partake in a 9-hour in 
person behavioral session (across two visits) that involves IQ tests, neurophysiological 
evaluation, collection of speech samples, and behavioral tests such as basic sensory, emotion 
recognition and reading tasks. Participants then undergo EEG sessions (8 hours), which can be 
done across 1-2 visits as best accommodates participants’ schedules. There are also 2 hours of 
MRI acquisition. Before going into the MRI scanner, all participants are screened using the 
NYSPI MRI safety questionnaire re metal implants. Women have urine pregnancy tests. #7114 is 
a cross-sectional study of deficits in early cortical or basic sensory processing, across stages of 
schizophrenia and related psychotic disorders and autism spectrum disorder (ASD). Participants 
in the protocol #7114 include patients (schizophrenia, recent-onset psychosis, clinical high risk 
and autism spectrum disorder) and for comparison, healthy volunteers similar in demographics. 
We will only recruit schizophrenia patients from the protocol #7114. 
 
The total participation period for each subject in this pilot study is 4 weeks, starting at week 0 
and ending at week 3. 

 
Screening/Informed Consent: 
Informed consent will be obtained before any study procedures are initiated. After providing 
informed consent, subjects will undergo medical screening (medical history, physical 
examination, vital signs, urine pregnancy test for women of childbearing potential, psychiatric 
screening (i.e. Structured Clinical Interview for DSM 5 (SCID) (Dunn et al., 2002), Auditory 
Hallucination Rating Scale (AHRS) (Hoffman et.al, 2003), Columbia Suicide Severity Scale (C-
SSRS) (Posner et al., 2007), Transcranial Magnetic Stimulation Adult Safety Screen (TASS) 
(Keel et.al., 2001) and audiometry to confirm eligibility. Screening procedures (except for 
physical exam) may be conducted by an RA trained by the Principal Investigator; consent 
procedures must be conducted by an MD. A study MD (Michael Avissar, MD/PhD or Daniel 
Javitt, MD/PhD) will be available to answer questions, if a subject wishes to speak to a doctor 
about the risks/benefits of TMS. 
 
Evaluation and motor threshold assessment 
Clinical and medical screening includes a physical exam and history, vital signs, review of 
inclusion and exclusion criteria, and urine pregnancy test (for women). Participants will then 
have an assessment of resting motor threshold (RMT; 1 minutes). This procedure is described, in 
detail, below. This session will last about 1 hour. 
EEG sessions: 
 
EEG tasks related to AVH will be compared pre/post treatment. There are ~5 hours of EEG 
recording, which will be done across 2 visits at baseline and post treatment. Each EEG session is 
expected to last 2.5 hours (1 hour of setup + 1.5 hours of tasks). EEG will be acquired on a 64-
channel, active-electrode Brainvision system, digitized at 500 Hz. RAs with EEG data collection 
experience will conduct this session. All tasks involve listening to sounds via headphones or 
speakers and some tasks require behavioral responses via button presses or mouse clicks. In 
some cases subjects are also instructed to view a fixation cross on a monitor or perform a basic 
visual task while listening to sounds. 
 
MRI (structural MRI, task-related and resting-state functional MRI): 
There are ~4 hours of MRI acquisition, which will be done across 2 visits at baseline and post 
treatment. Each MRI session will include anatomical scans, resting-state fMRI, and an auditory 
fMRI task. The participant will be placed in a supine position on the table. A head-holder will be 
used to decrease head movement during the scan. Participants will be given a squeeze ball which 

they can squeezed if they don't feel well or if there is any problem during scanning. The 
participants will wear earplugs or headphones to reduce the noise of the MRI . Before going into 
the MRI scanner, all participants will be screened using the NYSPI MRI safety questionnaire re 
metal implants. Women will have urine pregnancy tests. 
Audiometry: 
 
The audiometry test is performed in a quiet room. Participants will wear headphones connected 
to a device that sends a series of sounds of different volumes and frequencies to one ear at a time. 
Participants will be asked to respond by pressing a button on the joy stick each time they hear a 
sound. 
 
Standard audiometry will be performed before and after the full treatment at week 0 and week 3 
to assess for any changes in hearing thresholds. This is a precautionary measure given the 
theoretical risk of hearing loss from the noise-inducing damage, as the magnet generates a series 
of sound clicks during operation. Participants and providers will wear earplugs during operation 
of the TMS device. 
 
Assessments: 
 
Clinical assessments include Auditory Hallucination Rating Scale (AHRS), the Psychotic 
Symptom Rating Scales (PSYRATS), the Scale for the Assessment of Positive Symptoms 
(SAPS), the Positive and Negative Symptoms Scale (PANSS) and the Cardiff Anomalous 
Perceptions Scale (CAPS). These clinical assessments involve answering questions about 
psychiatric symptoms. The total assessment time will take up to 1 hour 40 minutes. There will be 
baseline (week 0) and post-treatment (week 3) assessments. These assessments will be conducted 
by RAs who have completed training for each measure used. The Clinical Global Impression 
Scale (CGI-S and CGI-I) will be completed by Dr. Avissar or other clinically trained personnel 
before each treatment session to quantify and track participant progress and treatment response 
over time, based on the above measures and general clinical impressions. AHRS assessment will 
be audiotaped. The second clinical rater will listen to an audiotaped session, blind to subject 
identity and session number. In addition, Dr. Avissar or other clinically trained personnel will 
ask participants questions using the Systematic Assessment for Treatment of Emergent Events 
(SAFTEE), and this will be done once on each treatment day. The Columbia Suicide Severity 
Rating Scale (C-SSRS) will be conducted by a qualified clinician (e.g., physician, licensed 
clinical psychologist, psychiatric nurse practitioner, licensed clinical social worker, or other 
qualified mental health clinicians). 
Participants will be administered the C-SSRS weekly to ensure that they meet the study 
safety/eligibility requirements. The study PI will be informed and will assess the participant for 
suicidality and safety. The PI will contact the participant’s primary mental health provider to 
inform them of patient’s current level of suicidality. If the PI determines that the participant is an 
immediate risk/danger to themselves or others, or feels that an emergency evaluation is clinically 
indicated, the patient will be referred the emergency room at CUMC/NYP-Columbia. 
 
TMS Sessions: 

All procedures will be administered in the TMS core of the NYSPI. The rTMS will be delivered 
by the PI, a study physician, or by research staff trained in the delivery of rTMS and approved 
by our local IRB. Stimulation will be delivered using a Magstim TMS device, including the 
Magstim Super Rapid2 Plus1 stimulator, and Magstim figure-8 coil (Magstim Active D70 
AirFilm air-cooled figure-8 coil). Participants will initially undergo an assessment of resting 
motor threshold (RMT; 15 minutes, see below). The precise positioning and orientation of the 
coil will be tailored to the individual’s MRI scan and monitored and adjusted in real-time using 
a state-of-the-art, gold-standard Neuronavigation system (Brainsight) at each session. The 
Brainsight system offers real-time three-dimensional display of cortical localization as the TMS 
coil is moved across the scalp. Optimization of target locations for TMS stimulation will be 
identified using Brainsight by applying an overlay of structural MRI and the previously 
identified TPJ target region. All subjects will be instructed to wear earplugs to protect hearing 
during each rTMS session and will be monitored by research staff throughout the entirety of 
each rTMS session. Dr. Michael Avissar, Dr. Daniel Javitt, Yadi Chen and other core approved 
providers will be delivering the TMS. They will receive the TMS training TMS Core of the 
NYSPI. Training on the use of the neuronavigation equipment is also provided. 
The staff members who will administer the rTMS will be required to meet all of the following: 
• 
Practical demonstration of ability to perform several determinations of the resting motor 
threshold, under supervision of a trained investigator or TMS consultant experienced in 
rTMS. 
• 
Performing at least the first two rTMS study sessions under the supervision of a trained 
investigator or rTMS consultant experienced in rTMS. 
• 
Working knowledge of the principles and practices of rTMS and the rTMS device being 
used in the study, including common side-effects and how to recognize them. Knowledge 
will be based on completed tutorial sessions with the investigators or rTMS consultant 
experienced in rTMS. 
• 
Knowledge of how to contact the covering physician available in the building. 
• 
Certification in basic adult life support (e.g. Cardiopulmonary Resuscitation (CPR). 
• 
Knowledge of seizure first aid, the location of the emergency equipment and medication, 
how to engage the emergency response system. 
• 
Bachelor’s degree or higher. 
 
TMS procedures 
 
Resting motor threshold determination 
The increasing popularity of TMS indicates the necessity for safe and effective application of 
brain stimulation. This means that an appropriate level of induced electric current should be used 
within a target region. Over-stimulation increases the risk of known adverse effects (Rossi et al., 
2009) and reduces the focality of the induced excitation (Thielscher and Kammer, 2004), while 
under-stimulation may reduce the efficacy of treatment (Mosimann et al., 2002). Motor threshold 
(MT) is the standard in the field for determining the intensity of the TMS for each individual, as 
recommended by safety guidelines, to maximize stimulation efficiency while minimizing risk of 
seizure. MT is defined as the minimum TMS intensity, applied to the scalp zone overlying motor 
cortex, sufficient to produce an overt motor response in the contralateral hand muscle (Kozel et 
al., McConnell et al., 2001, Stokes et al., 2007). The participant will be seated in a chair, and the 

resting motor threshold (RMT) will be determined by applying TMS over the motor cortex to 
elicit a twitch in the contralateral (right) hand muscle starting with 40% of the machine output. 
The coil will be adjusted until each pulse results in isolated movement of the right thumb 
(abductor pollicis brevis), and adjusted for the lowest intensity that reliably produced thumb or 
hand movement. The RMT will be defined as the lowest output that produces thumb movement 
50% of the time. 
 
Repetitive transcranial magnetic stimulation (rTMS) 
 
Transcranial Magnetic Stimulation (TMS) is a noninvasive tool for the study of the human brain 
that has been approved by the FDA for use in depression and is being investigated as a potential 
therapeutic agent in other areas of psychiatry and neurology. Contrary to single-pulse TMS, 
rTMS is able to change and modulate cortical activity that can last beyond the stimulation period, 
as a potential method for the treatment of neuropsychiatric conditions such as AVHs. We will 
deliver rTMS at a low frequency (1 Hz) to produce inhibitory effects that may be required to 
reduce the severity of AVHs. In our protocol, all participants will receive a 20-min once-daily 
rTMS sessions over a period of 2 weeks (weekends off), and therefore accrue a total of 10 rTMS 
stimulation sessions. The rTMS parameters that will be used are a frequency of 1 Hz (1 pulse per 
second) at an intensity of 90% of the motor threshold (MT). Therefore, we will deliver 1200 
continuous pulses per session/day which adds up to 12,000 pulses in total for the whole 
treatment. These parameters are well within established safety guidelines. Although the goal is to 
deliver 10 sessions over 10 days of rTMS treatment, the treatment will still be considered 
complete if the participant misses at most two days of treatment over the two week period. 
 
Localization of brain regions for stimulation 
 
Localization of brain regions is done by establishing skull landmarks for each individual and 
matching these against an MRI of each participant's brain using Brainsight's camera/computer 
system for coregistration of each participant to his or her MRI. Each individual subject’s 
structural MRI with overlay of the left TPJ target will be used to localize placement of the rTMS 
coil with frameless stereotaxy (Brainsight, Rouge Research, Inc., Montreal, Canada). 
 
Criteria for Early Discontinuation 
 
Subjects with a Clinical Global Impression-I (CGI-I) worsening of 2 or greater for two 
consecutive days, or a Clinical Global Impression-S (CGI-S) of 6 or 7 will trigger a clinical 
evaluation as to whether the patient should be discontinued. This will be documented in the 
clinical chart. Subjects who are unable to cooperate with study procedures (e.g., TMS, EEG, 
MRI) will be discontinued from the study. 
Blood and other Biological Samples 
 
Urine samples will be collected for purposes of pregnancy testing. Approximately 30 mL will be 
collected, tested, and immediately discarded. Test results will be documented and kept on file 
under the subject number (no identifying information will be used in the documentation). 
 
 

Clinical Treatment Alternatives 
 
 
Standard-of-care treatment for persistent auditory hallucinations consists of use of antipsychotic 
medications. Cognitive behavioral therapy for voices is sometimes used as adjunctive treatment 
for coping with AVH.  
 
Risks/Discomforts/Inconveniences  
 
Risks Associated with COVID-19: 
Going out in public and traveling involves some risk of infection with COVID-19. There is risk 
of COVID-19 infection during in-office visits and during travel for research purposes. 
 
Risks Associated with Medical Screening: 
Medical screening can be associated with minor psychological distress (answering emotionally 
difficult screening questions). Study personnel are trained at monitoring patient comfort and 
providing reassurance in the advent of psychological discomforts. Being informed of clinically 
significant findings may also cause psychological distress. Dr. Avissar (PI), who is a licensed 
physician (NY State) and certified by ABPN in Psychiatry will discuss any such results with 
subjects to minimize distress and provide referral. Dr. Javitt (collaborator), who is also licensed 
and board certified, will serve as a back-up in cases when Dr. Avissar is unavailable. 
 
Risks Associated with Clinical Assessments: 
Distress can be experienced from thoughts or discussion about psychiatric symptoms. Some 
subjects may experience distress or anxiety related to participating in these procedures, and they 
will be encouraged to report any concerns. A psychiatrist will be available to assist the subject if 
needed, and subjects will be removed from the protocol if their distress of anxiety becomes 
intolerable. Also, each study participant will be provided with a 24-hour emergency contact 
number. Risks of an audiotaped AHRS assessment include boredom and fatigue, as well as risks 
to confidentiality and the protection of personal health and identifying information. 
 
 
Risks Associated with TMS: 
The pulses at TMS session per day will be 1200, as described in Study Procedures. This number 
is far below what is considered safe. For example, Anderson et.al. (2006) describe safely 
administering 12,960 pulses per day to 63 healthy young men (ages 18-45) without adverse 
effect. To date, no clear guidelines exist regarding the maximal number of pulses to be delivered 
per session. No studies since 2007 investigating inhibitory rTMS for treatment of AVH deliver 
more than 1200 pulses per session to our knowledge (Tranulis et al., 2008; Freitas et al., 2009; 
Slotema et al., 2010; Demeulemeester et al., 2012; Otani et al., 2015; He et al., 2017; Slotema et 
al., 2012; Slotema et al., 2014; Zhang et al., 2013). In the above mentioned studies, only mild 
side effects such as transient headache and scalp discomfort were reported. No significant 
adverse event was observed. 
 
TMS safety was reviewed at meetings in 2008 and 2018 promoted and supported by the 
International Federation of Clinical Neurophysiology (IFCN), The report of these meetings 
(Rossi et al., 2009; Rossi et al., 2020) addressed the safety and ethics of TMS administration, 

including subject-based risk, and questions about how, where, and by whom TMS should be 
delivered. Since the introduction and development of standard international safety guidelines, 
TMS is generally considered a safe treatment method. 
 
Seizures 
Rossi and his colleagues (2020) provided an update on TMS/rTMS-induced seizures, which 
remains the most severe adverse event of this technique, although by now it is certain that such a 
risk is very low. The published papers up to February 2020 were searched for reports of seizures 
and 41 were identified (Chou et al., 2020). Of 41, 28 case reports were of seizures occurring in 
subjects who have neurological or psychiatric conditions. There were 19 with high frequency 
rTMS and 1 with low frequency. Even though several cases of seizures induced by TMS or 
rTMS have been reported to date, most of them happened prior to the definition of safety limits. 
Moreover, some of these cases may not have been seizures at all, and may have been 
respectively pseudoseizure (normal EEG and neurological exam) and convulsive syncope. 
Considering the large number of participants who have undergone TMS/rTMS since 1998 and 
the small number of seizures, we can assert that the chance of having a seizure during 
TMS/rTMS is extremely low. 
 
According to Rossi et al. (2020), single/paired and low frequency stimulation accounted for 16 
TMS induced seizures in over 200,000 sessions (16/200,000) across high and low-risk 
participants, while repetitive and high frequency stimulation accounted for 8 seizures 
(8/200,000). Evidently, high frequency rTMS delivered within the 2009 published guidelines to 
participants was less likely to cause seizures than low frequency and single/paired–pulse TMS. 
Moreover, low frequency rTMS seems even less likely to have seizures as a side effect than high 
frequency rTMS possibily because of its inhibitory effects. This study uses low frequency TMS 
is defined as TMS given at 1 Hz or below. TMS at this frequency has been repeatedly shown to 
be of minimal risk. 
 
 
Heating 
TMS can produce currents in skin electrodes (and jewelry, glasses, and watches) and implants 
that can heat them. Metallic brain implants could heat up as well. Heating of brain tissue over 43 
degree Celsius can result in irreversible damage (Matsumi et al., 1994). However, the observed 
heating risk in rTMS subjects is extremely low overall. No significant heating was detected in ex 
vivo studies with rTMS applied over implantable electrodes (Phielipp et al., 2017; Shimojima et 
al., 2010). Moreover, rTMS applied over vascular stents placed in gelled saline found 
temperature increase less than 1 degree Celsius that is considered safe (Varnerin et al., 2017). In 
conclusion, the rTMS induced heating is estimated to be very small and this should not pose any 
safety risk. Exclusion criteria include having any implants whatsoever, and individuals must 
remove all jewelry and watches during study procedures.  
 
Induced voltages 
Likewise, wires, electronic devices, and brain implants (i.e. VNS devices, cochlear implants, 
aneurysm clips, skull plates, stimulation electrodes) can have a voltage induced by a magnetic 
pulse. While TMS has been safely done with individuals with these devices, to err on the side of 

caution, exclusion criteria for this study include having any implants whatsoever, and as 
mentioned, individuals must remove all jewelry and watches during study procedures. 
 
 
Exposure to magnetic fields 
According to Rossi et al., 2009, adverse events from magnetic field exposure have not occurred 
even in situations where patients have received cumulative doses of 72,000 pulses, 156,000 
pulses, and even 420,000 pulses. Also, chronic exposure to electromagnetic fields appears safe at 
levels even greater than what is possible with TMS (Rossi et al., 2009). In the current protocol, 
participants receive 1,200 pulses each day for 10 treatment days, for a total of 12,000 pulses, far 
below the cumulative doses listed above. 
 
Hearing 
Per Rossi et al., 2009, “rapid mechanical deformation of the TMS stimulating coil when it is 
energized produces an intense, broadband acoustic artifact that may exceed 140 dB of sound 
pressure”, which they note exceeds recommended OSHA safety levels for the auditory system. 
After exposure to TMS, a small proportion of adult humans have experienced transient increases 
in auditory thresholds, and a permanent threshold shift was observed in one person who did not 
wear ear plugs, and who was being stimulated with a rather loud “H-coil”. Most studies in which 
hearing protection was used reported no change in hearing after TMS (Rossi et al., 2009). While 
not applicable here in this study of adults, a pediatric study showed that 18 children who had 
TMS without hearing protection had no change in hearing. Given the risk of increasing auditory 
threshold in adults with TMS, especially when hearing protection is not utilized, all participants 
will wear earplugs or headsets during TMS procedures. Audiometry is conducted at baseline and 
post-treatment. Any change in hearing will prompt a referral to a specialist and reporting as an 
adverse event. 
 
Local pain, headache, discomfort 
Headache is the most common side effect of TMS. This headache is typically of a muscle-
tension type. It usually develops during or immediately after the stimulation and may last for 
minutes to hours following the end of the stimulation. It is typically limited to the day of 
stimulation, and usually responds promptly to single doses of over the counter pain medications. 
TMS can also stimulate scalp muscles and produce a twitch in the scalp or upper face that can be 
uncomfortable for some, painful for others. Neck pain can occur related to head immobilization, 
and trigeminal stimulation can also lead to a sense of discomfort. Scalp pain may also occur. 
Migraine has not been reported with TMS. Pain, headache and discomfort, while uncomfortable, 
do not indicate any problems with safety, and are easily managed with over-the-counter 
analgesics. 
 
According to Rossi et al., 2009, in therapeutic TMS, 28% of patients experience headache and 
39% experience pain or discomfort (vs. 16% and 15% respectively with sham TMS). In prior 
clinical studies at NYSPI of daily therapeutic TMS for up to 10 days in depressed patients, the 
frequency of headache with active TMS did not differ from sham (also ~28%). In clinical trials, 
<2% of patients discontinue TMS because of pain. 
 

In the majority of cases, any pain related to TMS rapidly vanishes with the cessation of TMS, 
though headaches may occasionally persist, such that an oral analgesic is indicated. 
 
Cognitive changes 
In general, the effects of TMS on cognition are relatively low, in both healthy and patient 
populations. Fitzgerald et al. (2005) reported the effects of low frequency rTMS in patients with 
treatment-resistant auditory hallucinations, without significant deterioration in any cognitive test. 
Per Rossi et al., 2020, to date no reliable evidence has indicated longer lasting side effects of 
TMS on cognition. 
 
 
Acute psychiatric changes 
In general, psychiatric adverse events induced by rTMS were transient and relatively minor in 
severity, occurring at a rate between 1 and 5% (Rossi et al., 2020). Per Najib & Horvath (2014), 
acute mania occurrence during rTMS over the left prefrontal cortex in patients with uni- and 
bipolar depression has been documented. But the prevalence of this emergence seems to be 
below natural change rates of bipolar patients taking mood stabilizers. Although cases of rTMS 
induced psychotic symptoms, agitation, anxiety, insomnia and suicidal ideation have been 
reported in psychiatric patient populations, it is still unknown if such side effects occur at a 
higher rate than during the natural course of each disease state (Rossi et al., 2020). 
 
 
Endocrine effects, effects on immune system 
None, per Rossi et al., 2009 
 
Autonomic function 
TMS can induce a short lasting increase in heart rate and blood pressure, and can briefly alter 
cerebral hemodynamics, which is of import in individuals with medical illnesses such as acute 
stroke. Therefore, all participants will be screened for medical illness and also have vital signs 
obtained. 
 
Pregnancy 
The effect of TMS on pregnancy and the unborn fetus are unknown and pregnant women are 
excluded from the study. Women of child bearing potential must use a medically acceptable birth 
control method during the study. All negative pregnancy tests have to have been obtained within 
the prior 5 days for women of childbearing potential to have any TMS procedures. Likewise, 
women who are breastfeeding cannot participate in the study. 
 
Ineffective therapy 
The efficacy of TMS on schizophrenia patients has not been established, though rTMS has been 
proposed as a promising treatment for people with schizophrenia, especially those who 
experience auditory hallucinations. In addition, there is no definitive answer to how long the 
effects of TMS treatment will last. 
 
 
Risks associated with EEG: 

Each EEG session length, including the application and removal of the electrode cap and any 
required breaks, will be approximately 2.5 hours. Based on our prior experience, we expect this 
session length to be tolerable for patients. Subjects may experience scalp itching/irritation due to 
the recording procedures. Otherwise

there are no explicit risks to the subject by participating in EEG. The EEG recording is 
performed with the patient in an enclosed, sound-proofed room, which may cause mild anxiety, 
but they are monitored with a closed-circuit camera, told to wave at the camera if they need to 
get the technician’s attention, and the door is frequently opened between task blocks to check in. 
In our experience, these measures have been sufficient to mitigate any initial anxiety about the 
recording room. 
 
 
Risks Associated with MRI: 
Some participants may experience sensations during the MRI scan, which are caused by changes 
in the magnetic field that can stimulate nerves in the body. Subjects will be instructed to report 
any tingling, muscle twitching, or painful sensations (very rarely) that might occur during 
scanning. 
 
Some participants may find it uncomfortable to remain still and may experience minor distress 
by the confined and noisy conditions in the MRI scanner (i.e. claustrophobia) - they can come 
immediately out of the MRI scanner if this develops. Of note, both the FDA and the NYSPI IRB 
have deemed MRI Scanning on the GE 3Tesla MRI Scanner at the New York State Psychiatric 
Institute to be classified as a non-significant risk. 
 
For MRI, the long-term effects of being placed in a magnet of this strength (3 Tesla) are 
unknown, but there have been no reports of any long-term ill effects caused by magnets of the 
same or even higher strength, either here or elsewhere. However, although there are no known 
risks associated with pregnancy, pregnancy tests will be conducted before each MRI session, and 
subjects testing positive will be excluded from further participation. 
 
 
Procedures in Place to Minimize Risk: 
 
 
Informed Consent: 
Written informed consent, approved by the NYSPI IRB will be obtained from each participant 
prior to entering the study. The informed consent document will explain in simple terms, before 
the patient is entered into the study, the risks and benefits to the patient. The informed consent 
document will contain a statement that the consent is freely given, that the patient is aware of the 
risks and benefits of entering the study, that the patient is free to withdraw from the study at any 
time, and that withdrawal from the study will not affect any aspect of the delivery of their current 
care. The nature of the procedures and the alternatives to study participation will be discussed 
with each subject prior to obtaining written informed consent. A multidisciplinary team 
including at least one psychiatrist not associated with the study will review the eligibility of the 
patients, with special attention to the ability of the patient to understand and evaluate the risks 
associated with the study (capacity evaluation). The evaluation of the psychiatrist not involved in 
the study is documented in the chart. Subjects will be informed that the information they provide 
will be kept confidential except within the research team and how that confidentiality will be 
assured. They will be told that their records are filed by a number, not by name, and that all 
records are kept in locked files accessible only to research personnel. Consent will be obtained 

after a thorough explanation of the study and an opportunity for the participant to ask questions 
about the study. The consent form will be signed and dated by the subject and study personnel.  
 
It will be the responsibility of the PI to ensure that an informed consent form is obtained from 
each participant and that the appropriate signatures and dates on the informed consent document 
are obtained prior to the performance of any protocol procedures and in accordance with current 
state and federal regulations. 
The signed informed consent document will be retained with study records. Each participant will 
be given a copy of his or her signed informed consent. 
 
 
Protections Against Risk: 
As described above, subjects are safeguarded from undue risk by procedures to obtain informed 
consent, insure confidentiality, and minimize possible risks associated with the study. Described 
below are general safeguards that will be used to minimize risks. These include exclusion of 
subjects at highest risk, the monitoring of any side effects, and the termination of subjects from 
research participation if it is believed that such participation endangers their welfare. 
 
1. Careful medical and psychiatric screening will identify patients whose risk for potential 
adverse effects would be elevated with study procedures. Such patients will be excluded from 
the study. As an example, an actively suicidal patient would be excluded from study 
participation and referred for appropriate treatment. In addition, pregnant subjects will be 
excluded. 
 
2. Careful monitoring of patients during the assessment and study period will be performed. 
Psychiatrists in the inpatient units at NYSPI are available for clinical emergencies. 
 
3. Patients who begin the study and experience adverse effects sufficient to require removal from 
the study will be referred for appropriate clinical care. The exact nature of “appropriate 
clinical care” will be determined by the judgment of clinicians familiar with the specific 
patient and may include medication, cognitive-behavioral therapy, or other modalities. 
 
4. As in any type of research, patients’ confidentiality must be carefully guarded and respected. 
All data with identifying information will be stored in locked file cabinets or password-
protected computer files. Data being analyzed will be identified by subject codes and 
identifying information will be removed. The identity of patients will not be revealed in the 
presentation or publication of any results from the project. All individuals working on the 
project will be educated about the importance of strictly respecting patients’ rights to 
confidentiality. 
 
5. TMS: Routine safety procedures are in place to ensure only authorized personnel have access 
to the stimulation suite, which is locked and only accessible to study personnel. All TMS 
device settings are checked by two trained operators before initiation of any stimulation 
protocol to ensure correct stimulation duration and current intensity settings. Once set, 
parameters will not be changed during the stimulation protocol outside of aborting treatment 
in case of an adverse event. Subjects are encouraged to report discomfort or adverse events 

and are informed that they may ask for stimulation to be aborted at any time. Furthermore, 
stimulation will be aborted for any concerning and/or unexpected adverse reaction at the 
discretion of the research physician. We will be monitoring the potential for adverse events in 
this study. All adverse events are documented in the treatment notes and reported. Data on the 
severity and duration of each adverse event will be collected, including information on any 
interventions performed to address the adverse event and whether the event was resolved. 
 
One of the most common risks of rTMS is the possibility of having a headache after the sessions. 
To try to reduce the risk of headache we will assure participants’ comfort before and during the 
procedures. If needed, participants can contact the study doctor to discuss their symptoms and 
receive over the counter pain medicines such as ibuprofen or acetaminophen. 
 
To minimize risk of rTMS, individuals who have a history of seizures or have been diagnosed 
with epilepsy or current use of medications known to lower seizure threshold will be excluded 
from this research study. An MD will be present for the first three sessions in the building and 
immediately available during all rTMS sessions. In the event of a seizure, our staff will make 
sure that the participant is on the floor (cannot fall) and will clear the area of all objects. Most 
seizures will end spontaneously at 1 to 2 minutes. In the event that the seizure has not ended in 
two minutes, the hospital emergency team will be called and Lorazepam (which is stored in the 
room) will be administered IM (4mg). If seizures continue or recur after a ten to twelve minute 
observation period, an additional intravenous dose of 4 mg may be administered until the acute 
care medical team arrives. The New York State Psychiatric Institute has emergency response 
procedures for situations which would include a seizure. The emergency team has a “crash cart” 
that they bring to emergencies and is notified via building wide loud speaker and mobile phone. 
911 would also be called and the subject would be transferred to the Emergency Department at 
New York Presbyterian, the hospital for the Columbia University Medical Center, which is 
within the same medical campus. Any seizure that may occur should not deny the participant of 
employability, motor vehicle licensure, of insurability. If desired, participants may receive a 
letter to state this. 
 
 
6. COVID-19: (1) All in-person procedures will be done in accordance to standard NYC and 
NYS DOH COVID precautions for healthcare workers interacting with patients, which 
currently include wearing a mask, PPE and eye protection at all times for staff members; (2) 
The components of the TMS device will be wiped down and disinfected before and after each 
session; (3) We have also minimized in office visits to lessen this risk. We may also be able to 
arrange alternative transportation for subjects to avoid the subway and the bus; (4) We will 
keep subjects informed about current public health recommendations, such as federal and 
local government guidelines and directives. 
 
Audiotaping 
Audiotapes will be converted into computer files that adheres to HIPAA regulations, which will 
be stored on a secure room at NYSPI for up to five years, and then will be erased. 
 
EEG 

These studies entail the recording of EEG from the scalp employing standard sensors and 
amplification methods. These procedures are well standardized and there are few known risks. 
These are principally due to equipment malfunction. The recording equipment used in these 
studies meet the current design criteria for subject safety, including isolation from potential 
electrical hazards. 
 
 
MRI 
There are no significant risks associated with MRI and fMRI. It is possible that some participants 
might experience minor distress from the confined and noisy conditions in the scanner. This 
possibility will be minimized by the use of earplugs, and experienced technicians will monitor all 
participants for any signs of distress. In the event that a participant becomes anxious during a 
scan, the study will be halted. Participants will be able to communicate with the investigators at 
all times using the intercom system should they wish to request that the study be terminated or if 
they have concerns or questions during the procedure. The participant is in full view of the 
operator at all times. Participants cannot have an MRI if they have any metallic implants or metal 
on their person, of if they are pregnant. 
 
The probability of an incidental finding that might lead to the diagnosis of an unknown 
abnormality is greater than zero. All participants will be alerted to this possibility during the 
consent process. In that event, participants or their designated physician will be provided copies 
of their anatomical scans and advised to seek further evaluation if they have concerns. 
 
Measures taken to minimize risks and discomforts related to MRI include: a) a questionnaire 
used for screening for metallic devices, implants, and other contraindications to scanning; b) 
exclusion for pregnancy using a pregnancy test prior to scanning; c) exclusion of those unlikely 
to tolerate the sense of confinement during scanning; d) providing adequate medical, safety 
monitoring and observation during scanning as appropriate; e) reducing scanning time to that 
necessary to accomplish the scientific aims of the study; f) enhancing the subjects' physical and 
emotional comfort during the scan (i.e. ear plugs or headphones for the loud noise produced by 
the scanner). 
 
All precautions and protections are given to the participant to ensure that they are as safe and as 
comfortable as possible. For participants’ comfort within the scanner, they lie on a padded table 
with a pillow to rest their heads on. A blanket is also provided to keep participants warm during 
the procedure. If the participant appears nervous or anxious, a trained member of the research 
staff remains with them inside the scanning suite for the duration of the scan. The participant is 
given a button box to terminate the scan at any time. If he/she pushes the button, he/she will be 
removed from the scanner immediately. Participants may end the MRI scans at any time. 
 
 
Methods to Protect Confidentiality  
 
All data (written and electronic) will be coded by number. Personal identifying information will 
be stored in an electronically secure database at NYSPI. A master list matching subjects with 
codes will be kept under lock and key, separate from any research records or the computer 

database, with access restricted to research staff, to the extent permitted by law. Only staff 
directly involved in this project will have access to the master list linking subject names to code 
numbers. All paper records will be kept in a locked office. Computerized data including MRI 
data will be kept on encrypted computers that are password protected. Any files that contain 
identifying information will be kept electronically in folders on a computer that is password 
protected. 
 
In the informed consent form, subjects are told that the information they provide and all findings 
of testing will be kept strictly confidential, with access limited to the research staff, and possibly 
state or federal regulatory personnel. All staff members involved in this project are required to 
receive training in the protection of human subjects. This includes both Good Clinical Practices 
at Columbia University (entitled Health Sciences: Protection of Human Research Participants 
[GCP] for Patient-Oriented Clinical Investigators) and the Collaborative Institutional Training 
Initiative (CITI) at NYSPI. 
 
For remote visits, we will use HIPAA-compliant videoconferencing, phone and web-based 
platforms. 
 
De-identified data may also be shared with other investigators at NYSPI for the purposes of 
substitution in the case of failure of data collection. For instance, if the subject participates in 
another MRI protocol at NYSPI, and during those sessions the investigators fail to collect all of 
the needed anatomical and functional MRI sequences, we may share our data with them if we 
have collected the same types of MRI sequences for our protocol. The inverse may happen as 
well; we may receive data from another NYSPI protocol if because of a technical failure we are 
unable to collect all of the necessary MRI sequences. 
 
Direct Benefits to Subjects 
 
Participants may not experience any direct benefits from their involvement in this study. 
 
The proposed project is a clinical trial of TMS for treatment of AVH and an experimental 
intervention. Therefore, we do not consider AVH treatment a definite benefit of participation. 
Nevertheless, participants are informed of the purpose of the trial and may in fact experience a 
reduction in AVH. 
 
MRI findings and clinical assessments are unlikely to be of direct benefit to participants, but 
subjects will be informed of any clinically significant findings from the MRI and clinical 
assessments.  
 
Compensation and/or Reimbursement  
 
Subjects will be compensated as follows: 
• Pre-treatment session (screening, clinical assessment, EEG and MRI): $185 
• Treatment day: $100 
• Post-treatment session (clinical assessment, EEG and MRI): $160 

In this study, each subject will undergo 1 pre-treatment session, 1 post-treatment session and 10 
treatment days. Total compensation for all sessions is $1345. 
 
Statistical Analysis Plan  
 
We will use a repeated measures t-test to analyze changes in the Auditory Hallucination Rating 
Scale (AHRS). This involves comparing scores before and after TMS treatment in participants 
who completed all study procedures. The goal of this analysis is to determine if there are 
improvements in symptoms of auditory verbal hallucination. Additionally, similar analyses will 
be performed for secondary outcome measures such as PANSS, investigating if there is a 
significant decrease in PANSS P3 scores for participants after the TMS treatment sessions. 
Furthermore, the study will explore potential associations between the intensity of TMS 
treatment and the extent of AHRS improvement. This will involve conducting Pearson's 
correlation analysis to assess whether higher treatment intensity is linked to a more favorable 
treatment response. 
The study also aims to assess the utility of EEG biomarkers that are relevant to the condition's 
etiology in tracking treatment response. Specifically, changes in EEG biomarkers related to 
hallucinations will be examined. Moreover, the investigation will extend to evaluating functional 
connectivity using fMRI. 
 
References  
Andreasen, N. C. (1984). Scale for the assessment of positive symptoms. Group, 17(2), 173-180. 
 
Bell, V., Halligan, P. W., & Ellis, H. D. (2006). The Cardiff Anomalous Perceptions Scale 
(CAPS): a new validated measure of anomalous perceptual experience. Schizophrenia bulletin, 
32(2), 366-377. 
 
Briend, F., Nathou, C., Delcroix, N., Dollfus, S., & Etard, O. (2020). A new toolbox to compare 
target localizations for non-invasive brain stimulation: An application of rTMS treatment for 
auditory hallucinations in schizophrenia. Schizophrenia Research. 
 
Birchwood, M., Meaden, A., Trower, P., Gilbert, P., & Plaistow, J. (2000). The power and 
omnipotence of voices: Subordination and entrapment by voices and significant others. 
Psychological medicine, 30(2), 337-344. 
 
Freitas, C., Fregni, F., & Pascual-Leone, A. (2009). Meta-analysis of the effects of repetitive 
transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia. 
Schizophrenia research, 108(1-3), 11-24. 
 
Demeulemeester, M., Amad, A., Bubrovszky, M., Pins, D., Thomas, P., & Jardri, R. (2012). 
What is the real effect of 1-Hz repetitive transcranial magnetic stimulation on hallucinations? 
Controlling for publication bias in neuromodulation trials. Biological psychiatry, 71(6), e15-e16. 

 
Dunn, L. M., & Dunn, D. M. (2007). PPVT-4: Peabody picture vocabulary test.First, MB, 
Spitzer, RL, Gibbon M, and Williams, JBW: Structured Clinical Interview for DSM-IV-TRAxis 
I Disorders, Research Version, Patient Edition With Psychotic Screen (SCID-I/P W/ PSY 
SCREEN) New York: Biometrics Research, New York State Psychiatric Institute, November 
2002. 
 
Fitzgerald, P. B., Benitez, J., Daskalakis, J. Z., Brown, T. L., Marston, N. A., de Castella, A., & 
Kulkarni, J. (2005). A double-blind sham-controlled trial of repetitive transcranial magnetic 
stimulation in the treatment of refractory auditory hallucinations. Journal of Clinical 
Psychopharmacology, 25(4), 358-362. 
 
Grunze, H., Kasper, S., Goodwin, G., Bowden, C., Baldwin, D., Licht, R., ... & WFSBP Task 
Force on Treatment Guidelines for Bipolar Disorders. (2002). World Federation of Societies of 
Biological Psychiatry (WFSBP) guidelines for biological treatment of bipolar disorders, part I: 
treatment of bipolar depression. The World Journal of Biological Psychiatry, 3(3), 115-124. 
 
Glasser, M. F., Coalson, T. S., Robinson, E. C., Hacker, C. D., Harwell, J., Yacoub, E., ... & 
Smith, S. M. (2016). A multi-modal parcellation of human cerebral cortex. Nature, 536(7615), 
171-178. 
 
Haddock, G., McCarron, J., Tarrier, N., & Faragher, E. B. (1999). Scales to measure dimensions 
of hallucinations and delusions: the psychotic symptom rating scales (PSYRATS). Psychological 
medicine, 29(4), 879-889. 
 
He, H., Lu, J., Yang, L., Zheng, J., Gao, F., Zhai, Y., ... & Ma, X. (2017). Repetitive transcranial 
magnetic stimulation for treating the symptoms of schizophrenia: a PRISMA compliant meta-
analysis. Clinical Neurophysiology, 128(5), 716-724. 
 
Howes, O. D., & Murray, R. M. (2014). Schizophrenia: an integrated sociodevelopmental-
cognitive model. The Lancet, 383(9929), 1677-1687. 
 
Hoffman, R. E., Hawkins, K. A., Gueorguieva, R., Boutros, N. N., Rachid, F., Carroll, K., & 
Krystal, J. H. (2003). Transcranial magnetic stimulation of left temporoparietal cortex and 
medication-resistant auditory hallucinations. Archives of general psychiatry, 60(1), 49-56. 
 
Hoffman, R. E., Gueorguieva, R., Hawkins, K. A., Varanko, M., Boutros, N. N., Carroll, K., & 
Krystal, J. H. (2005). Temporoparietal transcranial magnetic stimulation for auditory 
hallucinations: safety, efficacy and moderators in a fifty patient sample. Biological psychiatry, 
58(2), 97-104. 
 
Kay, S. R., Fiszbein, A., & Opler, L. A. (1987). The positive and negative syndrome scale 
(PANSS) for schizophrenia. Schizophrenia bulletin, 13(2), 261-276. 
 

Kane, J., Honigfeld, G., Singer, J., & Meltzer, H. (1988). Clozapine for the treatment-resistant 
schizophrenic: a double-blind comparison with chlorpromazine. Archives of general psychiatry, 
45(9), 789-796. 
 
Kozel, F. A., Nahas, Z., Debrux, C., Molloy, M., Lorberbaum, J. P., Bohning, D., ... & George, 
M. S. (2000). How coil–cortex distance relates to age, motor threshold, and antidepressant 
response to repetitive transcranial magnetic stimulation. The Journal of neuropsychiatry and 
clinical neurosciences, 12(3), 376-384. 
 
Luber, B., Stanford, A. D., Malaspina, D., & Lisanby, S. H. (2007). Revisiting the backward 
masking deficit in schizophrenia: individual differences in performance and modeling with 
transcranial magnetic 
stimulation. Biological psychiatry, 62(7), 793-799. 
 
McConnell, K. A., Nahas, Z., Shastri, A., Lorberbaum, J. P., Kozel, F. A., Bohning, D. E., & 
George, M. S. (2001). The transcranial magnetic stimulation motor threshold depends on the 
distance from coil to underlying cortex: a replication in healthy adults comparing two methods of 
assessing the distance to cortex. Biological psychiatry, 49(5), 454-459. 
 
Mosimann, U. P., Marré, S. C., Werlen, S., Schmitt, W., Hess, C. W., Fisch, H. U., & Schlaepfer, 
T. E. (2002). Antidepressant effects of repetitive transcranial magnetic stimulation in the elderly: 
correlation between effect size and coil-cortex distance. Archives of General Psychiatry, 59(6), 
560-561. 
 
Najib, U., & Horvath, J. C. (2014). Transcranial magnetic stimulation (TMS) safety 
considerations and recommendations. In Transcranial magnetic stimulation (pp. 15-30). Humana 
Press, New York, NY 
 
Otani, V. H. O., Shiozawa, P., Cordeiro, Q., & Uchida, R. R. (2015). A systematic review and 
meta-analysis of the use of repetitive transcranial magnetic stimulation for auditory 
hallucinations treatment in refractory schizophrenic patients. International journal of psychiatry 
in clinical practice, 19(4), 228-232. 
 
Phielipp, N. M., Saha, U., Sankar, T., Yugeta, A., & Chen, R. (2017). Safety of repetitive 
transcranial magnetic stimulation in patients with implanted cortical electrodes. An ex-vivo study 
and report of a case. Clinical Neurophysiology, 128(6), 1109-1115. 
 
Posner, K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., ... & 
Mann, J. J. (2011). The Columbia–Suicide Severity Rating Scale: initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. American journal 
of psychiatry, 168(12), 1266-1277. 
 
Rossi, S., Hallett, M., Rossini, P. M., Pascual-Leone, A., & Safety of TMS Consensus Group. 
(2009). Safety, ethical considerations, and application guidelines for the use of transcranial 
magnetic stimulation in clinical practice and research. Clinical neurophysiology, 120(12), 2008-
2039. 

 
Rossi, S., Antal, A., Bestmann, S., Bikson, M., Brewer, C., Brockmöller, J., ... & Hallett, M. 
(2020). Safety and recommendations for TMS use in healthy subjects and patient populations, 
with updates on training, ethical and regulatory issues: expert guidelines. 
 
Shimojima, Y., Morita, H., Nishikawa, N., Kodaira, M., Hashimoto, T., & Ikeda, S. I. (2010). 
The safety of transcranial magnetic stimulation with deep brain stimulation instruments. 
Parkinsonism & related disorders, 16(2), 127-131. 
 
Slotema, C. W., Blom, J. D., Hoek, H. W., & Sommer, I. E. (2010). Should we expand the 
toolbox of psychiatric treatment methods to include Repetitive Transcranial Magnetic 
Stimulation (rTMS)? A meta- analysis of the efficacy of rTMS in psychiatric disorders. The 
Journal of clinical psychiatry, 71(7), 873-884. 
 
Slotema, C. W., Aleman, A., Daskalakis, Z. J., & Sommer, I. E. (2012). Meta-analysis of 
repetitive transcranial magnetic stimulation in the treatment of auditory verbal hallucinations: 
update and effects after one 
month. Schizophrenia research, 142(1-3), 40-45. 
 
Slotema, C. W., Blom, J. D., van Lutterveld, R., Hoek, H. W., & Sommer, I. E. (2014). Review 
of the efficacy of transcranial magnetic stimulation for auditory verbal hallucinations. Biological 
psychiatry, 76(2), 101-110. 
 
Stokes, M. G., Chambers, C. D., Gould, I. C., English, T., McNaught, E., McDonald, O., & 
Mattingley, J. B. (2007). Distance-adjusted motor threshold for transcranial magnetic 
stimulation. Clinical 
Neurophysiology, 118(7), 1617-1625. 
 
Transcraniel Magnetic Stimulation Core. (2021). Guidelines for human research within the TMS 
core (TMSC). 
 
Thomas, F., Bouaziz, N., Gallea, C., Andrianisaina, P. S. K., Durand, F., Bolloré, O., ... & 
Valero-Cabré, A. (2019). Structural and functional brain biomarkers of clinical response to 
rTMS of medication-resistant auditory hallucinations in schizophrenia patients: study protocol 
for a randomized sham-controlled double- blind clinical trial. Trials, 20(1), 1-15. 
 
Thielscher, A., & Kammer, T. (2004). Electric field properties of two commercial figure-8 coils 
in TMS: calculation of focality and efficiency. Clinical neurophysiology, 115(7), 1697-1708. 
Tranulis, C., Sepehry, A. A., Galinowski, A., & Stip, E. (2008). Should we treat auditory 
hallucinations with repetitive transcranial magnetic stimulation? A metaanalysis. The Canadian 
Journal of Psychiatry, 53(9), 577- 586. 
 
Takeuchi, H., Fervaha, G., Lee, J., & Remington, G. (2016). What symptom domains are 
associated with patient distress in schizophrenia?. Schizophrenia research, 176(2-3), 329. 
Varnerin, N., Mirando, D., Potter-Baker, K. A., Cardenas, J., Cunningham, D. A., 
Sankarasubramanian, V., ... & Plow, E. B. (2017). Assessment of vascular stent heating with 

repetitive transcranial magnetic stimulation. Journal of Stroke and Cerebrovascular Diseases, 
26(5), 1121-1127. 
 
Zhang, Y., Liang, W., Yang, S., Dai, P., Shen, L., & Wang, C. (2013). Repetitive transcranial 
magnetic stimulation for hallucination in schizophrenia spectrum disorders: a meta-analysis. 
Neural regeneration research, 8(28), 2666.