The Effects of Repetitive Transcranial Magnetic Stimulation Prefrontal Target Location on Outcomes for Major Depressive Disorder
Phase: NA
Conditions: Major Depressive Disorder, Depression
Sponsor: Nicholas Trapp

 
 
 
 
 
 
 
 
 
 
 
Title: The Effects of Repetitive Transcranial Magnetic Stimulation Prefrontal Target Location on 
Outcomes for Major Depressive Disorder 
ID: 201709834 
Date: 08/22/2019 
 
 

Study Procedure Timeline and Protocol 
Eligible patients will be identified during clinical transcranial magnetic stimulation intakes, which occur 
weekly in the psychiatry clinic (2JPP clinic).  Interviews are conducted by physicians who are members of 
the research team.  If a patient is identified as eligible for the study, he or she will be asked if they are 
interested in participating in the research study.  If they answer yes, a study physician will set aside time 
at the end of the appointment to discuss the details, or will obtain information and permission to 
contact the patient over the phone after the appointment to provide details.   
After detailed description of the study, if patient is willing to participate and meets study criteria, 
consent form will be signed.  This will occur on the day the patient presents for initial testing as part of 
the research study.  Once expressing interest, the patient will work with the study physician or a 
research team member to set up a date and time for the patient to come in for cognitive, psychological, 
and neurobehavioral testing, and, in a subset of patients, an MRI scan.  If they choose not to participate, 
they will proceed with rTMS treatments as is standard clinical care. 
Participants who are interested in the study will present for their baseline testing prior to initiation of 
their rTMS treatment course.  The testing will occur in a designated research space, likely W264 or T212 
in General Hospital.  This is estimated to take 1-3 hours, depending on whether or not an MRI is 
included.  These assessments include NIH Toolbox cognitive and emotional batteries (30-45 minutes), 
Temperament and Character Inventory (30 minutes), MOCA, CGI, PHQ-9 and MADRS (20-30 minutes 
total), and neurobehavioral testing and neurologic exam (30-60 minutes).  Patients will have heart rate 
variability and facial movements monitored while viewing video clips or images, or hearing stories that 
may be emotionally charged or neutral (10-15 minutes).  EEG will be recorded at rest and during tasks 
(30 minutes).  Some patients may be given an actigraphy wristband to monitor their daily level of 
activity and their circadian rhythms.  Some of these assessments are already obtained as part of the 
initial work-up for rTMS patients and that data is available for review under a separate previously 
approved IRB.  The neuroimaging will include 21 minutes of resting state fMRI, T1rho, T1 MPRAGE, and 
DTI (<=60 minutes total).  A research team member will escort the patients receiving MRIs to the MRI 
scanner and back.  If a subject chooses to participate in the Vocal Pattern detection portion of the study, 
they will complete the procedures once weekly for the entirety of their TMS treatment course. The 
research team member will schedule this with the subject in advance so they are prepared for the 
length of the visit. Subjects will complete the PHQ9 questionnaire, if they have not already. Next, the 
recording part will begin with the reading the Grandfather Passage, and the Rainbow Passage. Finally, 
the subject will be asked some questions about your daily life and your interests. 
The course of TMS will occur as clinically determined by the TMS physicians providing the patient’s care.  
The only unique aspect is that patients in the study will be randomized to either receive rTMS at the F3 
location (determined using free software from clinicalresearcher.org) or the 5.5cm method, as is the 
current standard of clinical care at the University of Iowa for clinical rTMS treatments. Some early 
internal data has shown that these targets can vary anywhere from a few millimeters apart to a few 
centimeters, but all targets are within the prefrontal cortex on the left side and consistent with the FDA-
approved treatment region for major depressive disorder.  The nature of these targeting strategies 

should prevent any target from ever falling outside a clinically approved range, but if for some reason it 
appears that a target is outside of the FDA-approved target region, a study physician will be called to 
evaluate and confirm the targeting, and adjust if felt to be clinically inappropriate (e.g., not in the 
prefrontal cortex for that patient).    Noninvasive autonomic measures will be obtained during the 
course of treatment including blood pressure, heart rate, pupil size, and facial movements, although this 
should not interfere with or delay the administration of the TMS therapy.  Some of these measures are 
already intermittently obtained on patients undergoing TMS therapy. 
Treatment will then proceed as managed by the clinical rTMS service at University of Iowa.  Follow-up 
appointments will occur as clinically scheduled by the rTMS clinical service and the patient’s other 
providers as is standard of care.  The patient and raters will be blinded to the treatment target for each 
patient, which will be assigned randomly.  The treatment technician will be aware of the treatment site 
as needed for performing the appropriate measurements and targeting procedure during appointments. 
After a patient has either completed their rTMS course or the course has been terminated by the rTMS 
team for whatever reason, the patient will have the same testing performed as was performed at their 
initial study visit.  This may include an MRI if patient consented to this and a pre-treatment MRI was 
conducted on the patient.  For purposes of the study, the follow-up MRI could occur either at the very 
end of the treatment course or at some point during the treatment course, as determined by the study 
physicians and with patient approval/agreement.  They will then be asked to schedule a follow-up 
phone call 4-6 weeks after completion of the rTMS treatment course, and some questionnaires may be 
administered over the phone at that time, including a PHQ-9.  After this visit, they will no longer be a 
part of the study. 
Recruitment 
Patients will be recruited as described above.  Only patients who come for and complete a clinical rTMS 
intake will be asked to participate in the study. 
Determination of Treatment-Resistant Depression 
Treatment resistant depression will be identified based on clinical interview by a physician with special 
training in rTMS or psychiatry.  This will be a standard clinical interview that will confirm the diagnosis of 
major depressive disorder, rule out other causes of depression, and evaluate for previous failure of 
medication and psychotherapy trials.  This is standard of care for rTMS treatment as determination of 
whether it is indicated for use for major depressive disorder, and thus occurs as part of every rTMS 
evaluation.  After this appointment, further questioning may occur by the research study team if needed 
to confirm that patient meets study criteria or to clarify any information obtained during the clinical 
interview. 
Inclusion Criteria 
As per the IRB: 

Inclusion:  
-Diagnosis of major depressive disorder  
-Age greater than or equal to 18 years  
-Able to consent for treatment and research participation  
-English-speaking  
-Have been evaluated by a psychiatrist or neurologist with expertise in TMS and felt to be 
an appropriate candidate to undergo TMS treatments 
Exclusion Criteria 
As per the IRB: 
Exclusion:  
-Age less than 18 years  
-Patients that are excluded during TMS assessment including:  
-Patients with epilepsy or seizure disorder  
-Patients with implanted ferromagnetic equipment in their face or skull near the stimulation 
target  
 
MRI Exclusion criteria:  
-Implanted device including pacemaker, coronary stent, defibrillator, or neurostimulation 
device that is not MRI-compatible  
-Metal in body including bullets, shrapnel, metal slivers  
-Claustrophobia  
-Uncontrolled high blood pressure  
-History of atrial fibrillation  
-History of significant heart disease  
-Hemodynamic instability  
-History of kidney disease  
-Pregnant 
MRI 
The MRI scan will occur as described in the study protocol.  Only a small subset of all patients enrolled in 
the study will receive an MRI scan before and after the treatment course.  These scans will be scheduled 
to coincide with the other parts of the study evaluation if possible.  Patients who are asked to 
participate in the MRI portion of the study can choose to refuse to participate in the MRI portion and 
still participate in the other portions of the study, or can refuse all portions and receive rTMS as is the 
clinical standard of care.  In a small subset of patients (n=25 approximately), a repeat neuroimaging or 
neurobehavioral assessment session may be completed partway through the TMS course to look for 
biomarker or imaging changes during the course of TMS.  This will be arranged with the patient several 
days ahead of time with their consent, and they will have the option to decline to participate. If subjects 
take part in this MRI midway through treatment subjects will undergo a single session of TMS in a 
research area in close proximity to the research MRI scanners. We will be using the same protocol and 
parameters as the patients' clinically determined TMS sessions, and the same device (albeit a replica 
device purchased for research purposes). The purpose of this MRI and single session occurring in close 

proximity to the scanners will be to allow for rapid post-treatment MRI to detect short-term function 
and metabolic brain changes.  
Scales/Testing 
All of the scales and testing involved in the study are as described above.  The neurobehavioral testing 
that is discussed above is composed primarily of neuropsychological testing and emotional scales, as 
well as a neurologic exam (some portions of this, again, are already conducted as part of the standard 
work-up for the rTMS clinical service). 
Targeting 
Targeting either the F3 left prefrontal cortex location or the 5.5cm target location will occur as described 
above.  Targeting the F3 location requires taking measurements of the head circumference, tragus-to-
tragus distance, and nasion-to-inion distance, and using computer software to calculate the correct 
prefrontal target using head landmarks.  The 5.5cm target location is determined by measuring 5.5cm 
anterior to the primary motor cortex of the brain, which is identified using a TMS procedure called 
motor threshold testing, all of which is done as part of the standard of care in clinical rTMS and will not 
be altered for this study.  Targets will be marked onto a swim cap which the patient will wear during 
treatments, to ensure that the same target can be stimulated from treatment-to-treatment reliably, 
again, as is standard practice in rTMS treatments. 
Treatment as Usual (Parameters) 
Treatment parameters other than stimulation location will be as per clinical standard of care, including 
3000 total pulses at a frequency of 10Hz, with 4-second train duration, 26-second off time, for 75 total 
trains.  All treatments will be targeted at the left prefrontal cortex as is FDA-approved for major 
depressive disorder, and all treatment targets will fall within this region. 
Safety 
All treatments will follow the standard of care safety procedures for clinical rTMS.  An rTMS-trained 
technician will be present with each patient during the entirety of their treatment, with a study 
physician immediately available if needed for emergent response (such as for induced seizure).  There is 
no evidence to suggest the risk of seizure is higher with stimulation at either target being investigated in 
this study.  Management of seizure will occur as is standard practice for clinical rTMS.  If a patient were 
to indicate suicidal thoughts during the course of their work-up and evaluation for this study, it would be 
managed as per standard of care for the clinical rTMS service, which involves a thorough safety risk 
assessment by a team physician, appropriate safety planning, and transfer to a higher level of care as 
clinically indicated.  This may involve anything from providing additional resources for crisis 
intervention, discussion with the patient’s primary psychiatrist or family (if patient provides consent to 
do so), or transfer to an emergency room for further evaluation.  As a study physician will be either 
conducting all portions of the study evaluation or immediately available, and all study physicians 

involved are also involved in standard clinical rTMS care, this should not be onerous and should be well 
within the scope of the team’s clinical abilities.