Enhancing Cortical-hippocampal Functional Connectivity as a Novel Means for Relieving Chronic Low Back Pain
Phase: NA
Conditions: Chronic Pain, Back Pain, Pain
Sponsor: Northwestern University

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PROTOCOL TITLE: Enhancing cortical-hippocampal functional connectivity as a novel means 
for relieving chronic low back pain 
PRINCIPAL INVESTIGATOR: 
Vania Apkarian, PhD 
Department of Physiology 312-503-0404 
a-apkarian@northwestern.edu 
 
VERSION DATE: 02 Jun 2021 
(Include the version date here and in the footer.) 
 
STUDY SUMMARY: 
 
Investigational Agent(s) 
(Drugs or Devices) 
NA 
IND / IDE / HDE # NA 
Indicate 
Special Population(s) 
Children 
Children who are wards of the state 
Adults Unable to Consent 
Cognitively Impaired Adults 
Neonates of Uncertain Viability 
Pregnant Women 
Prisoners (or other detained/paroled individuals) 
Students/Employees 
Sample Size 16 
Funding Source NIDA 
Indicate the type of consent 
to be obtained 
Written 
Verbal/Waiver of Documentation of Informed Consent 
Waiver of HIPAA Authorization 
Waiver/Alteration of Consent Process 
Site 
Lead Site ( For A Multiple Site Research Study) 
Data Coordinating Center (DCC) 
Research Related 
Radiation Exposure 
Yes 
No 
DSMB / DMC / IDMC 
Yes 
No 

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LIST OF ABBREVIATIONS 
 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
BDI 
Back Depression Inventory 
BDI-II 
Back Depression Inventory, Second Version 
BP 
Brain Properties 
CBP 
Chronic Back Pain 
CESM 
Cognitive Emotional Sensory Motor 
CNS 
Central Nervous System 
CTA 
Chicago Transit Authority 
dMRI 
diffusion Magnetic Resonance Imaging 
EDW 
Enterprise Data Warehouse 
FC 
Functional Connectivity 
GMV 
Gray matter volume 
HIPAA 
Health Insurance Portability and Accountability Act 
Hipp 
Hippocampus 
Hz 
Hertz 
MQSIII 
Medication Quantification Scale, third version 
MRI 
Magnetic Resonance Imaging 
NAc 
Nucleus Accumbens 
NIH 
National Institutes of Health 
NMG 
Northwestern Medical Group 
NMH 
Northwestern Memorial Hospital 
NRS 
Numeric Rating Scale 
NU 
Northwestern University 
PAG 
Periaqueductal Gray 
PDQ 
Pain Detect Questionnaire 
PHH 
Personal Health History 
PHI 
Protected Health Information 
PIDs 
Participation identification numbers 
REDCap 
Research Electronic Data Capture 
rsfMRI 
Resting State Functional Magnetic Resonance Imaging 
rTMS 
Repetitive Transcranial Magnetic Stimulation 
SC 
Central Sensitization 
SEM 
Structural Equation Modeling 
TJS 
Thomas Jack Schnitzer 
TMS 
Transcranial Magnetic Stimulation 
VBM 
Voxel-based morphometry 

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KEY ROLES AND CONTACT INFORMATION 
Principal Investigator: 
Apkar Vania Apkarian, PhD 
Professor 
Department of Physiology 
300 E. Superior Street, Room 7-705 
Chicago, Illinois 60611 
Phone: (312) 503-0404 
Fax: (312) 503-5101 
Email: a-apkarian@northwestern.edu 
Co-Investigators: 
Joel Voss, Ph.D. 
Department of Medical Social Sciences 
Northwestern University Feinberg School of Medicine 
303 E Chicago Ave 19th Floor 
Chicago, IL 60611 
312-503-5619 
joel-voss@northwestern.edu 
 
Clinical Site 
Investigator: 
Thomas J. Schnitzer, MD, PhD, Professor 
Department of Physical Medicine and Rehabilitation 
710 N. Lake Shore Drive, Room 1020 
Chicago, IL 60611 
Phone: (312) 503-2315 Fax: (312) 503-1505 
Email: tjs@northwestern.edu 
 
Institutions: 
Northwestern University 
Chicago, IL 60611 
Other Key Personnel 
Data Analyst: 
James W. Griffith, PhD 
Northwestern University 
633 N. St. Clair, 19th floor 
Phone: (312) 503-5345 
Fax: (312) 503-4800 
Email: j-griffith@northwestern.edu 

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OBJECTIVES: 
(Describe the purpose, specific aims, or objectives. State the hypotheses to be tested.) 
 
 
Chronic back pain (CBP) can last from months to a lifetime, severely impacting patients’ quality 
of life. Based on our human brain imaging studies and preclinical findings, the hippocampus and 
its network are associated with pain and pain experience in patients with chronic pain. In this 
study we aim to test whether a non-invasive enhancement of dorsal hippocampus activity leads 
to networks alteration that can modulate pain in CBP patients. 
 
Aim 1: To investigate whether a novel target, dorsal hippocampus, indirectly stimulated using 
high frequency rTMS, will lead to an increase in hippocampal network connectivity that can 
modulate pain, as compared a sham control rTMS, in CBP patients. 
 
We hypothesize that changes in pain from baseline to post-stimulation will be superior for 
hippocampal-target than for control stimulation (sham). Pain is primarily assessed by daily 
ratings on our phone app; additional questionnaires will be used as secondary exploratory 
outcomes. 
BACKGROUND: 
Pain is the primary reason why people seek healthcare. Everyday millions of Americans are 
either partially or totally disabled due to pain. If untreated, this pain can lead to depression, 
insomnia, depressed immune function, changes in eating patterns, impaired cognitive function, 
and other long-term deleterious effects commonly associated with chronic pain1–3 . Chronic back 
pain constitutes the major form of chronic pain, with a prevalence as high as 70-85% in adults 
at some time in their lives 4. In the US, low back pain is the most common cause of activity 
limitation in adults younger than 45 years of age and the second most frequent reason for 
physician visits1,5. Estimates from other countries support the fact that low back pain is one of 
the major - if not the major - cause of work absence, and therefore results in a significant burden 
to both the economy and health care system. 
Current treatments for CBP involve the use of nonsteroidal anti-inflammatory drugs, 
antidepressants, and/or anticonvulsants or opioids. These carry relatively high risks yet show 
limited success rates6, leading investigators to explore non-invasive interventions that in 
combination with conventional treatments, may produce greater pain relief in CBP 7,8. 
Chronic back pain is associated with many negative affective mood disorders 9, and cumulative 
evidence suggests an association of hippocampal networks and chronic pain. Previous research 
performed by our group has shown the hippocampal circuitry being involved in the transition 
from acute to chronic pain, and hippocampal mechanisms such as diminished hippocampal 
neurogenesis 10. Moreover, abnormal glutamatergic activity was previously described in animal 
chronic pain models and bilateral hippocampal deactivation during innocuous stimulation in 
neuropathic patients 11,12. Therefore, our group conducted an animal study using chemogenetics 
or direct GLU injection to increase dorsal hippocampal glutamatergic activity and modulate pain. 
This demonstrated the analgesic effects of hippocampal stimulation; since increases in 
excitability of dorsal hippocampal neurons altered resting state connectivity (rsfMRI) within 
hippocampal networks that are specifically related to neuropathic behavior (tactile allodynia), 
thus indicating the potential for hippocampal stimulation in the management of chronic pain 13. 
Considering the previously established role of the hippocampus in pain perception, and its 

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morphological changes in chronic pain, there is now impetus for investigating hippocampal 
excitation in chronic pain relief. With this in mind, we reason that in humans, by modulating local 
hippocampal circuits, we can directly target chronic pain. 
In this pilot study, we aim to indirectly stimulate the dorsal hippocampus to increase 
hippocampal connectivity and modulate pain. We will use rTMS to stimulate an area of the 
parietal cortex with high functional connectivity to the hippocampus, using seed-based 
connectivity analysis of rsfMRI data, in order to modulate hippocampal-mediated networks. It is 
notable that targeting hippocampal excitability using rTMS is an approach that we have 
pioneered. The hippocampus is not directly accessible to rTMS. We use cortical “access 
windows”, which are stimulation-accessible areas of the cortex that have high connectivity with 
the hippocampus and therefore stimulation applied to these areas can indirectly influence the 
hippocampus. In several experiments. We have shown that this method increases excitability 
and rsfMRI connectivity of dorsal hippocampus, leading to long-lasting improvements in 
hippocampal-dependent function14–17. We hypothesize that dorsal hippocampal stimulation will 
lead to analgesic effects in CBP. 
In line with the promising preclinical results we report, in this study we will collect preliminary 
data to systematically test whether the modulation of hippocampal network changes the 
experience of pain in CBP patients. 
STUDY ENDPOINTS 
This is a mechanistic study; therefore, the main study aim is to show that the hippocampal 
stimulation leads to functional connectivity changes across series of hippocampal networks and 
how these connectivity changes are correlated with pain decrease. 
The secondary outcome will be changes in pain ratings. The effects of the brain stimulation will 
be measured by daily pain ratings (painApp) and questionnaires, using our in-house pain app. 
As we collect these outcomes repeatedly, we will have changes in pain immediately after the 
stimulation session and also over the next 2-weeks.We will test immediate and 2-weeks 
changes in painApp ratings relative to baseline. Questionnaire analyses, and other time course 
analyses of painApp data will be treated as exploratory in nature. 
 
STUDY INTERVENTION(S) / INVESTIGATIONAL AGENT(S): 
Brain Stimulation 
For the brain stimulation we will use Repetitive Transcranial Magnetic stimulation (rTMS) The 
sessions will be performed at either the CTI or the LHN. Repetitive TMS parameters are 
determined based on the allowable dosage of rTMS delivery, calculated based on published 
standards for experimental rTMS protocols, and in accordance with standard operating 
procedures for rTMS 18,19. Previous studies have shown that four or more rTMS sessions are 
needed to induce changes in the hippocampal network conectivity20. 
The brain stimulation can be delivery using different devices; in this project we will use a 
MagPro X100 stimulator connected to a MagPro Cool-B65 liquid-cooled butterfly coil 
(MagVenture A/S, Farum, Denmark). Resting motor threshold (M1-rTMS) will be determined 
during the visit 1 or visit 2 and used along the 10 visits. Single TMS pulses are delivered to the 
thumb-control area of the brain’s primary motor cortex and the pulse intensity required to 
reliably evoke movement of the thumb is determined. This value is used as each individual 
subject’s “motor threshold”, and stimulation is delivered at a proportion of the motor threshold. 

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The rTMS pulse sequences and intensities used are all within the published safety guidelines 
21,22. 
As different stimulation conditions (hippocampal, M1 or sham) will be delivered in each of the 
three rounds of stimulation, participants will be told that stimulations can feel and sound 
different. All participants will receive all the 3 modalities of stimulation following specific order 
(see details below). 
• 
Stimulation Modality 1- Hippocampus-stimulation: 
Repetitive TMS will be applied at 100% resting motor threshold intensity to a region of interest 
located in the parietal cortex, that will be determined based on its connectivity with the 
hippocampus. This stimulation consists of a series of 1,600 pulses administered as 2-second 
periods of 20 Hz pulse trains separated by 28-s inter-train intervals (~20 minutes for the entire 
daily stimulation session). The induced current field will be oriented perpendicular/anterior to the 
long axis of the gyrus encompassing the stimulation location. 
• 
Stimulation Modality 2-Sham-stimulation: 
Parameters will be identical to the hippocampus-stimulation, except that the coil will be flipped 
over to the sham side and a stimulating electrode will be attached to the skin near the parietal 
rTMS target location. This electrode will be used to deliver a small current mimicking real 
stimulation sensation, therefore participants cannot reliably discriminate physical sensations for 
real versus sham rTMS. 
A trained co-investigator on the study will administer the rTMS. Prior to performing any study 
procedures, the study staff member will be trained in the techniques of rTMS as well as all 
aspects of the evaluations. This study staff member will then be evaluated by the PI of the 
study. The PI will then give confirmation that the co-investigator is qualified to administer the 
stimulation and the evaluations. Subjects are allowed to miss up to 1 stimulation visit in each 
treatment round, we will drop out subjects that miss more than 1 stim visit per round. 
 
Stimulation modality sequences: 
The order of the stimulation modalities will be different across subjects. Subjects will be 
randomly assigned to one of two possible groups/stimulation sequences (fig 1). Before 
enrollment starts, we will produce 18 envelopes containing the stimulation sequence (see below 
possible combinations; we expect to use only 16). The stimulation sequence will be kept in 
sealed envelopes; therefore, subjects will get their assignment according to the order of 
entrance in the study. The study coordinator will retain the original sequence list which will be 
kept in a locked place. The study staff who provides the stimulation TMS session will be the only 
un-ed personnel. 

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2x a DAY PAIN APP RATINGS~ 100 measures 
 
 
 
~7 days  
 
 
Consent 
fMRI 
Questionnaires 
Figure 1: Study design and stimulation sequence. The subjects will be allocated to 1 envelop 
according to the entrance in the study. All participants will receive all the 2modalities of 
stimulation. Each round is composed by 5 daily session of stimulation, participants will not know 
which round is active and which is sham. Participants randomized to group 1 will have a second 
MRI at visit 6; and participants randomized to group 2 at visit 11. 
 
PROCEDURES INVOLVED: 
General Overview 
Participants will be enrolled after meeting all inclusion/exclusion criteria including an NRS (0-10 
pain score) >4/10 for back pain and no contra-indications to the rTMS stimulation and MRI 
exam. 
Detailed Study Outline 
• 
Pre-screening Procedures: 
During the pre-screening process, the subject will contact a study staff (or vice-versa) usually 
via phone call or email. During this call, the co-investigator will discuss in greater depth the 
details of the study, explain the study procedures and encourage the subject to ask questions. 
In the privacy of the laboratory, the co-investigator will ask the subject questions from the 
following: 
 
o Phone screening questionnaire 
• 
Visit 1 - (Approx. Time: 2-3 hours) 
Screening Procedures: 
At Screening the PI and the co-investigators will conduct a review of inclusion/exclusion criteria 
to determine the subject’s eligibility for enrollment. Study procedures will be reviewed with the 
subject, and documentation of informed consent will be obtained. 
At Visit 1 the following procedures will be completed: 
o Discuss study-specific procedures with the subject; 
o Review inclusion and exclusion criteria, including list of current medications; 
o Obtain a signed and dated consent form; 
o Demographic Data; 
o Review the subject medical history with the study coordinator. 
 
Baseline 
 2 
 1 
 1 
fMRI 
Round 2 fMRI 
Randomization 
~2 weeks 
~2 weeks 
~2 weeks 
~2 weeks 

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o Measure blood pressure, heart rate and respiratory rates will be measured. 
o Measure height and weight 
o Urine sample for illicit drugs test and pregnancy exam (if applicable); 
o Fill out a screening form to make sure it is safe for the subject to have a brain 
scan and stimulation sessions. It is important that the subjects inform the study 
coordinator if they have any history of: 
 
Metal fragments in their eyes or face. 
 
Implantation of any electronic devices such as (but not limited to) cardiac 
pacemakers, cardiac defibrillators, cochlea implants or nerve stimulators. 
 
Surgery on the blood vessels of their brain or the valves of the heart 
 
Claustrophobia (fear of enclosed places) 
 
Body piercing or tattoos 
o Smartphone pain app rating*; 
o 
A 15-minute MRI scan; 
o Personal Health History (PHH) 
o Complete questionnaires about general health and pain 
o Safety questionnaires for the TMS procedures. 
o PainDetect; 
o Short-form Montreal Pain Questionnaires (sfMPQ); 
o BDI 
o Pain Catastrophizing scale 
o PROMIS 57 
* PainApp: participants will be instructed to use our smartphone-based app to report pain 
intensity (NRS, where 0 is no pain and 10 is worst imaginable pain), mobility (minimum, 
average, maximum), mood (NRS, where -10 is sad and +10 is happy), and medication use, 
collected twice daily from Visit 1 until the end of participation (~100 ratings). 
MRI Scan: 
Subjects will undergo MRI scanning at the Northwestern University, Department of Radiology 
Center for Translational Imaging (CTI). All procedures are standard in our laboratory and have 
been approved in multiple previous IRB protocols. 
More specifically, we will conduct a MRI scan (Siemens Trio, 3T, 64-channel head coil) with 
both structural (T1 scan, 5 minutes) and rsfMRI (EPI scan, 8 minutes) protocols. No contrast will 
be used in the MRI. 
The structural scan will allow us to use the built-in neuronavigation TMS system, for optimal 
localization of the stimulation sites. Resting-state fMRI will be used to identify the functional 
localization for indirect stimulation of the hippocampus. To do so, we will follow a well- 
established in-house processing pipeline, replicating the methods used in our previous 
experiments using this method 14–17. Briefly, whole-brain seed-based correlation will be 
performed, using the left dorsal hippocampus as a seed region. This will allow us to identify, at a 
single-subject level, the exact parietal target that has maximal connectivity to the dorsal 
hippocampus. By stimulating this parietal target, modulation of the hippocampus connectivity 
can be achieved non-invasively 14,23 and with long-lasting effects in brain connectivity after three 
stimulation sessions 24. 
In this same visit, participants will further complete questionnaires regarding pain ratings and 
the characteristics of their pain (see below for detail information). 
Participants will be assigned to one of the six possible stimulation sequences and trained on our 
pain app (a smartphone-based tool used to rate pain and mood on NRS scales, as well as 
indicate rescue medication use, twice a day). They will be asked to use the pain app for the next 
7-10 days prior to the first round of intervention and during all the study duration. 

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There will be 2 MRI visits: one at baseline (visit 1), the second MRI will depend on participants 
allocation: participants randomized to group 1 will have a second MRI at visit 6; and participants 
randomized to group 2 at visit 11. 
• 
Visit 2 – 11 (Approx Time: 1 hour) 
Intervention visits: These visits will be scheduled ~1 week after the visit 1 measurements are 
done. 
At visit 2, the stimulation protocol will start, and participants will receive a total of 10 sessions: 5 
consecutive daily sessions of each stimulation round following the prior stimulation sequence 
order, interleaved by 2 weeks of wash out period. All subjects will undergo sessions of sham, 
and hippocampal-stimulation, in a crossover manner. As different stimulation conditions 
(hippocampal, M1 or sham) will be delivered in each of the two rounds of stimulation, 
participants will be told that stimulations can feel and sound different. 
Before stimulation, the subjects will complete the following assessments: 
o NRS for back pain 
After each session, subjects will complete the following assessments: 
o Side Effects Questionnaire for rTMS 
o NRS for back pain 
o At visits 6 and 11 participants will also complete the following questionnaires: 
o PainDetect; 
o Short-form Montreal Pain Questionnaires (sfMPQ); 
o BDI 
Global impression of changeAfter the end of Round 1 or Round 2: 
o MRI 
Sources of materials 
Research materials to be obtained from participants: 
Urine specimens will be collected at the screening visit to check for illicit drug use. In addition, 
women of childbearing potential will be required to have a urine pregnancy test at screening visit 
ensure a negative result (testing required by our MR unit; these tests will be disposed of at the 
visit). 
Research data collected from participants: 
There are several types of data that we will be collecting: brain images; self-report questionnaire 
measures; and physical, psychological, and physiological parameters. In addition, clinical and 
demographic data will be obtained, including: complete information regarding descriptors of the 
participants’ back pain (duration, frequency and magnitude of pain, etc) as well as a general 
medical history including surgical and treatment history, disability status, drinking and drug use, 
demographics, smoking status, height and weight. For all participants, the smartphone app will 
be used to monitor medication use, ratings of back pain intensity (NRS), mood and mobility, 
twice daily until the end of the study participation 
Questionnaires used for assessing characteristics of cohorts: 
• 
Personal Health History (PHH): This general questionnaire will assess demographic 
information (gender, age, marital/relationship status, race/ethnicity, and education), pain history 
(descriptions, diagnostic testing history, and treatment history), general health history (other 
medical/surgical history, concurrent medications, health behaviors, a general symptom 

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checklist, and health-care utilization), and work history. The entire questionnaire will be 
completed at the visit 1. Subjects will be asked about any changes to concurrent medications at 
subsequent visits. History and physical examination will be done to confirm diagnosis, inclusion 
and exclusion criteria and assess overall safety. 
• 
Vitals measurements: blood pressure, heart rate, respiration rate, height and weight 
will be measured. 
• 
PainDETECT (PD-Q): A 12-item self-report instrument that assesses neuropathic pain 
properties and was originally developed in a sample of 8,000 low back pain suffers in Germany. 
The PD-Q demonstrates high sensitivity (80%) and specificity (85%) and has since been 
validated in other clinical pain populations. Although this instrument has not been validated in 
OA populations, it has been widely used in numerous OA studies25. 
• 
Beck Depression Inventory, second version (BDI-II): A 21-item self-report instrument 
for measuring the severity of depression in adults. It is well validated in pain populations and 
has been extensively used in pharmacological research26. 
• 
Short-form Montreal Pain Questionnaires (sfMPQ): A well-validated pain measure, 
which permits separation of sensory and affective components of pain, as well as a total pain 
score. It also includes a numeric/descriptor scale, a visual analog pain scale (VAS), and a body 
map to localize the pain27. This instrument is very well validated and often used in 
pharmacological research. However, its affective subscale is thought to be relatively 
rudimentary. It will be used to track development or continuation of pain, as well as post-surgical 
pain. 
• 
Numerical Rating Scale (NRS): is an 11-point numerical rating scale used to measure 
pain intensity, where 0 corresponds to no pain and 10 indicates worst possible pain28. The 
timeframe in question is concerned with the average pain experienced at the moment, in the 
past 24hrs, or average over past week. This questionnaire has been extensively used across 
pain management studies. 
• 
NIH PROMIS-57 Profile: This 57-item questionnaire contains brief scales for anxiety, 
depression, fatigue, pain interference, pain intensity, physical function, sleep disturbance, and 
the ability to participate in social roles. Each scale was created using PROMIS methodology and 
calibrated using item response theory. 
• Pain Catastrophizing Scale (PCS): The PCS is a 13-item instrument derived from definitions 
of catastrophizing described in the literature as well as items from the catastrophizing 
subscale of the CSQ. The PCS instructions ask participants to reflect on past painful 
experiences, and to indicate the degree to which they experienced each of 13 thoughts or 
feelings when experiencing pain, on 5-point scales with the end points (0) not at all and (4) all 
the time. The PCS yields a total score and three subscale scores assessing rumination, 
magnification and helplessness. The PCS has been shown to have adequate to excellent 
internal consistency (coefficient alphas: total PCS = .87, rumination = .87, magnification = .66, 
and helplessness = .78). 
• 
Global impression of change (PGIC): this questionnaire reflects a patient's belief about 
the efficacy of treatment. Although widely used in chronic pain clinical trials, PGIC's validity has 
not been formally assessed. PGIC is a 7 point scale depicting a patient's rating of overall 
improvement. 

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• 
Description of smartphone PainApp: All participants will also use a smartphone app 
to log their back-pain intensity, their mood, their mobility and medication use and other 
information that they may wish to report. The smartphone data are entered every day during the 
study and after termination of treatment until the final study visit. Smartphone entries are 
immediately transmitted through Wi-Fi to a secure web site, downloaded daily to assess 
compliance, and stored in a second secure server (we have been using such apps for about 6 
months and they have been very effective). 
 
 
Procedures 
Visit 1 
Visit 2,3,4 
5,7,8,9,10 
Visits 6 and 
11 
Informed consent process 
X 
Inclusion/exclusion criteria 
X 
Demographic survey and patient 
information criteria 
X 
Pregnancy test (if applicable)1 
X 
X1 
Drug urine test 
X 
Vitals measurements 
X 
Personal Health History (PHH) 
X 
General physical exam 
X 
BDI 
X 
MRI 
X 
X2 
Pain Detect Questionnaire (Pdq) 
X 
X 
Short-form Montreal Pain Questionnaires 
(sfMPQ) 
X 
X 
Pain Catastrophizing Scale (PCS) 
X 
NIH PROMIS-57 Profile 
X 
Randomization 
X 
rTMS stimulation 
X 
X 
NRS before/after stimulation 
X 
X 
NRS average pain 
X 
Adverse events questionnaire 
X 
X 
PainApp (During all the study)3 
X 
X 
X 
Approximate visit duration 
2-3 hrs 
1-2 hrs 
1-2 hrs 
 
Table 1: Related Procedures and Study Schema. Visits 1 through 10 will be completed according 
to the presented schema. 1.There is no specific recommendation for or against pregnancy, 
however, since this study will be utilizing Repetitive TMS as a mode of intervention, we will take 
the conservative approach and exclude pregnancy. Female subjects of childbearing potential will 
be asked to take a pregnancy test. If the pregnancy test is positive, the subject may not enroll in 
the study. Pregnancy test will be repeated in visits 2 and 8 (every ~ 2 weeks). 

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2. Visit 6 and 11: These visits will be separated in two parts: part 1: last day of stimulation 
(stimulation + questionnaires) and part 2: MRI (at least 24hrs after part 1). For group1, only visit 
6 will have 2 parts and for group 2 only visit 11 (see Figure 1 for details). 
3. PainApp: participants will be instructed to use our smartphone-based app to report pain 
intensity (NRS, where 0 is no pain and 10 is worst imaginable pain), mobility (minimum, average, 
maximum), mood (NRS, where -10 is sad and +10 is happy), and medication use, collected twice 
daily from Visit 1 until the end of participation). 
 
DATA AND SPECIMEN BANKING 
Data will initially be entered onto case report forms and then into the Research Electronic Data 
Capture (REDCap) database. All questionnaires will be electronic (created or copied into 
REDCap) and completed by the participant via links sent to his/her email address. Once 
completed, the questionnaire data are stored in the REDCap database and cannot be altered by 
any team members. This process will be designed so that the system automatically sends the 
correct questionnaires at defined intervals and tracks participants over the follow-up, informing 
research staff either when participants have completed the battery or when they have gone 
outside the allotted time window and must be called. Thus, REDCap will aid in the promotion of 
scheduled and diligent contact between participants and the research team. All remaining data 
will be collected by the designated clinical manager as well as by the MRI research team. 
Scanning data will all be digital and is burned onto DVDs, sent to a Northwestern University 
archive system, and stored in the lab’s secure servers. Likewise, data collected with our 
smartphone app will be digitally stored in the lab’s secure server. Only subjects’ participation 
identification numbers (PIDs) will be included in any of these materials; a master study list will 
be maintained by the lead clinical investigator (TJS). Access to this list will be limited to the site 
investigators, clinical coordinator, and other study personnel directly involved with data 
collection on an as needed basis. All the data will be collected specifically for this study and not 
in the course of usual clinical care. All non-digital data (e.g., consent forms) will be stored in a 
locked cabinet in a locked room. Any digital information will be pass-word protected and if any of 
this has identifying information on it, it will be encrypted. 
Access to PHI: 
All data collected will be linked to participants by their unique study participation identification 
numbers (PIDs), provided at the time of screening. A master study list linking participants’ 
names to study identification numbers will be the only means of linking data to specific 
individuals. This list will be kept on an encrypted personal computer residing in the Apkarian lab, 
not connected to the internet, and with password protection. Only Apkarian and Schnitzer will 
have access to this file, and it will only be used in case of an unforeseen emergency need. 
SHARING RESULTS WITH PARTICIPANTS 
Screening laboratory tests may be shared with the participants and/or their physicians at their 
request. The results of the questionnaires and brain scans will not be provided to the 
participants. 
STUDY TIMELINES 
Participants may be involved for approximately 7 weeks; for a total of 11 visits. Each treatment 
period will consist of five consecutive days of stimulation sessions followed by two weeks wash 

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out period. It is anticipated that enrollment will require approximately 8 months. The primary 
analyses will be completed 6 months later. 
 
INCLUSION AND EXCLUSION CRITERIA 
Pre-screening of participants will occur by phone or email. We will discuss the study aims and 
objectives, the procedures that will need to be followed, and the risks and potential benefits with 
all individuals during pre-screening procedure. A written consent form will be provided to each 
subject prior to any procedures being carried out; this will be read by the potential subject and 
any and all questions answered by the coordinator and/or site investigator. Subject will sign two 
copies of the consent form; one will be given to the subject and one will be kept in the subject’s 
file. 
 Inclusion Criteria: 
• 
≥ 6 months of back pain on a daily basis; 
• 
male or female with no racial or ethnic restrictions; 
• 
18 to 75 years old; 
• 
average back pain intensity > 4/10 at study entry; 
• 
must be able to read, understand, and sign consent form; 
• 
generally healthy. 
Exclusion Criteria: 
• 
back pain with fever, chills, rheumatoid arthritis, ankylosing spondylitis, acute 
vertebral fractures, 
• 
history of tumor in the back; 
• 
back surgery within the past 6 months; 
• 
Chronic neurologic conditions, e.g., Parkinson’s 
• 
involvement in litigation regarding back pain; 
• 
other severe medical diseases; 
• 
pregnancy; 
• 
positive urinary screen for any recreational drugs, 
• 
opioids use; 
• 
use of anticoagulants (low dose ASA allowed); 
• 
history of gastric ulcer; renal insufficiency or congestive heart failure, 
• 
contraindication to MRI, 
• 
contraindication to TMS; including history of seizure/epilepsy* 
• 
Any medical condition that in the investigator’s judgment may prevent the 
individual from completing the study or put the individual at undue risk; 
• 
In the judgment of the investigator, unable or unwilling to follow protocol and 
instructions; 
• 
Diagnosis of major depression; 
• 
Intra-axial implants (e.g. spinal cord stimulators or pumps) 
* contraindication to TMS such as: history of seizures, unexplained loss of consciousness, any 
metal implants in the head, frequent or severe headaches or neck pain, any other electronic 
implanted medical devices such as pacemakers, defibrillators, or implant medication pump. 
 
VULNERABLE POPULATIONS: NONE 
PARTICIPANT POPULATION(S) 
Accrual 
Number: 
Category/Group: 
(Adults/Children 
Consented: 
Maximum Number to be 
Enrolled: 
Number to Complete 

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Special/Vulnerable 
Populations) 
Consented or 
Reviewed/Collected/Screened 
the Study or Needed 
to Address the 
Research Question 
Local 
16 
16 
16 
Study-wide 
16 
16 
16 
Total: 
16 
16 
16 
 
RECRUITMENT METHODS 
Potential patients will be screened via a database maintained by one of the co—investigators 
(TJS), the registry is approved under the IRB (STU00007522 - Protocol title: Physical Medicine 
& Rehabilitation Registry). We will also extend recruitment through community and partnerships 
with medical institutions (Northwestern Medicine, Shirley Ryan AbilityLab), through online 
advertisement, and by flyer-based methods including ads. 
Materials that will be used to recruit subjects will be uploaded in the IRB application, and only 
used once they have been approved. They include ads, brochures, and letters. Contact 
information on the fliers/ads and other subject facing recruitment materials will be updated as 
needed without IRB approval. No other content on the subject facing recruitment materials will 
be changed without IRB approval, only contact information. 
 
COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES 
Participants will not be paid at the time of prescreening. For the screening visit, participants will 
receive $75 ($25 for questionnaires + $40 for the MRI) for travel and their involvement. For 
visits after the screening period (V2-V11) participant will receive $20/stimulation session; $100 
dollars will be reloaded at the PNC card after each stimulation round (5 visits). Participants will 
receive $40 dollars for each MRI completed. Participants will receive $0.25 per eDiary entry 
recorded throughout the study, ratings are capped at a max of 2/day and as the study lasts 
approximately 7 weeks. In addition, participants will receive an extra $20 if complete all the 
study visits and bonus of $20 dollars if they complete more than 90% of the pain diary ratings 
(90% is approximately 90 rates). In all visits, participants can opt to receive a parking voucher. If 
a parking voucher is required for one of the Northwestern Parking garages, $6 will be deducted 
from total visit payment. Payment may be prorated based on visit completion. All compensation 
will be made using a Stored Value Card (VISA). 
Visit 
Number of 
Visits 
Amount per visit 
Total 
Amount 
Payment 
Type 
Screening/MRI completion 
1 
$75 
$75 
PNC card 
V2-V11 
10 
$20 
$200 + $201 
PNC card 
Second MRI completion 
1 
$40 
$40 
PNC card 
PainApp ratings 
100 
$0.25 
dollar/response, 2 
times per day 
maximum + $202 
$25 + $202 
PNC card 

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1 Participants will receive an extra $20 if complete all the study visits, including 10 stimulation visits. 
2If participants complete 90%of all pain diaries entries (around 90 entries) they will receive an additional 
$20 dollars at the of the study. 
WITHDRAWAL OF PARTICIPANTS 
Participants may be withdrawn from the study if they are not able to undergo brain MR imaging 
or if they do not provide regular pain data with the cellphone app. Participants will be notified 
that they will have to discontinue the study if those circumstances occur. 
If a participant withdraws early, payment will be made for the portion of the research study that 
has been completed (prorated to the nearest 1-hour increment). Incomplete data sets obtained 
from participants (due to early withdrawal) will be excluded from the primary analysis and 
included in an exploratory full dataset analysis. 
RISKS TO PARTICIPANTS 
Taking part in this study may involve the following risks: 
The most common side effects of rTMS can include mild headaches or discomfort at the 
stimulation site. This occurs in approximately 5% of subjects. The subject is allowed to stop the 
stimulation at any time if they feel uncomfortable. These effects generally wear off shortly after 
the session and can be treated via over-the-counter analgesics. If subjects experience 
discomfort at a stimulation location, research staff will attempt to move the stimulator to a 
location that minimizes this discomfort. Research staff will be in constant contact with the 
subject during the rTMS procedure and will discontinue the protocol if discomfort cannot be 
successfully reduced. Vital signs will be collected and used to exclude subjects from rTMS if 
outside of normal established ranges (see above). With the permission of the subject, the 
primary care physician will be contacted by the research team to arrange follow-up care if vital 
signs are outside of the normal range. 
Although extremely rare, undergoing rTMS may induce a seizure. The risk of seizure due to 
rTMS is extremely rare with the rTMS procedures that will be used under this protocol. The 
screening procedures and rTMS stimulation protocol used here is in accordance with 
recommendations by the safety of TMS consensus group and by the international workshop on 
the safety of repetitive TMS, and the proposed rTMS procedures are classified as very low in 
risk based on these recommendations. The risk of seizure for our rTMS parameters among 
individuals meeting our safety requirements (including no history of seizure/epilepsy, among 
other exclusionary criteria) is quantified in two publications: Rossi et al. (2009)18 and Oberman 
et al. (2011)22. Rossi et al. Identified one instance of seizure among all studies conducted from 
1998-2008 among subjects with no history of seizure meeting our inclusion/exclusion criteria. 
There were additional instances of seizure reported among subjects who would be excluded 
from our studies because of psychiatric diagnoses, current use of anti-psychotic drugs, and 
neurological diagnosis, all of which are exclusionary for our studies. The risk estimate quantified 
from Rossi et al., 2009, for subjects meeting our criteria is 0.01% likelihood of seizure during a 
rTMS session. Oberman, 2011, reviewed studies using the same inclusion/exclusion criteria as 
in our studies and report a risk of 0.02% likelihood of seizure during a rTMS session. The risk of 
seizure for an individual with no seizure history and meeting our other inclusion/exclusion 
criteria is therefore approximately 0.01-0.02% (~1 to 2 in 10,000). 
Despite the very low risk of seizure for these procedures, trained clinical staff (nurse, doctor, 
nurse practitioner or a physician assistant) will be present for all rTMS sessions. Trained clinical 

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staff will be available for all sessions, however they will stay in an adjacent room observing with 
no direct unnecessary contact with the subjects. This is a mechanism study and only subjects 
will be blinded to the stimulation sequence. This will not compromise blinding. The clinical staff 
will monitor subjects for any signs of seizure, especially tonic-clonic muscle contractions 
associated with grand mal seizure. In the case of a seizure, rTMS procedures will be 
immediately terminated and an emergency response unit (911) will be called. The trained 
clinical staff will perform standard medical intervention for seizure. We will follow standard in- 
house safety protocol required by CTI. In the rare event that a seizure the attending neurologist 
collaborating with the study - Dr. Vanhaerents will be notified as soon as possible, and subjects 
will be released to emergency medical care upon their arrival. 
With MRI, there is risk of claustrophobia and anxiety involved with the scanning procedure, 
which involves the potentially uncomfortable experience of lying in a relatively confined space 
with minimal head and body movements for up to 15 minutes at a time. In this time period, their 
pain (if they have any) may become worse. Over the last 20 years of doing brain scans in 
various populations (healthy and not), the main limiting factor has been claustrophobia. 
Participants also may feel anxious in the scanner and simply cannot tolerate it. 
With regard to the questionnaires, although the majority of participants will find these to be 
harmless, mundane, or possibly interesting, there is always a possibility that some of the 
questions may be sensitive in nature and may make them uncomfortable (particularly those 
asking about mood or personality). All questionnaires have the option of being marked as “will 
not answer”. Any task that subjects are not comfortable with will be skipped. These tasks are 
administered by trained personnel and they are well aware of such potential limitations and take 
full care not to expose volunteers to undoable tasks. 
There is no known fetal risk from MRI scanning during pregnancy; however, the absolute safety 
has not yet been established. Therefore, any patient who is pregnant or states that there is a 
possibility of being pregnant will not be excluded from the study. 
 
POTENTIAL BENEFITS TO PARTICIPANTS 
We cannot promise any benefits; however, possible benefits include a decrease in pain as a 
result of the stimulation sessions. We are not able to estimate at this time the probability, 
magnitude or duration of benefit. We hope to define these parameters with the results of this 
study. 
DATA MANAGEMENT AND CONFIDENTIALITY 
Data will initially be entered onto case report forms and then into the Research Electronic Data 
Capture (REDCap) database. All questionnaires will be electronic (created or copied into 
REDCap) and completed by the participant via links sent to his/her email address. Once 
completed, the questionnaire data are stored in the REDCap database and cannot be altered by 
any team members. This process will be designed so that the system automatically sends the 
correct questionnaires at defined intervals and tracks participants over the follow-up, informing 
research staff either when participants have completed the battery or when they have gone 
outside the allotted time window and must be called. Thus, REDCap will aid in the promotion of 
scheduled and diligent contact between participants and the research team. All remaining data 
will be collected by the designated clinical manager as well as by the MRI research team. 
Scanning data will all be digital and is burned onto DVDs, sent to a Northwestern University 
archive system, and stored in the lab’s secure servers. Likewise, data collected with our 
smartphone app will be digitally stored in the lab’s secure server. Only subjects’ participation 

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identification numbers (PIDs) will be included in any of these materials; a master study list will be 
maintained by the lead clinical investigator (TJS). Access to this list will be limited to the site 
investigators, clinical coordinator, and other study personnel directly involved with data collection 
on an as needed basis. All the data will be collected specifically for this study and not in the course 
of usual clinical care. All non-digital data (e.g., consent forms) will be stored in a locked cabinet 
in a locked room. Any digital information will be pass-word protected and if any of this has 
identifying information on it, it will be encrypted. 
Data Analysis Plan 
MRI data will be analyzed using the FSL software library [30]. Briefly, structural data will be skull- 
stripped and normalized to MNI space through nonlinear transformation. Functional data will be 
motion corrected and smoothed with a 4 mm smoothing kernel. Data will be further denoised by 
performing motion-censoring and regressing out the motion parameters. Finally, data will be 
band-pass filtered (0.01 to 0.1 Hz). Functional connectivity analyses will be carried on by 
performing Pearson correlations between the BOLD time series of a hippocampal seed and all 
other voxels in the brain. The maximal statistically significant cluster near a predetermined 
coordinate in the parietal cortex (see Wang et al. 2014) will be extracted, spatially warped to the 
subject native space, and fed into the TMS neuronavigation system for stimulation. 
Statistical analyses will be performed using the software R. We use repeated-measures within- 
subject analysis of variance for dependent variables 1) change in painApp immediately after rTMS 
relative to baseline, and 2) for change in painApp in the long term (average over the second week 
after rTMS) relative to baseline, with independent factors being hippocampus-rTMS and sham- 
rTMS; with Bonferroni post-hoc comparisons. If the ANOVAs are significant and post-hoc 
comparisons indicate superiority of hippocampus-rTMS, we declare that the approach is a 
clinically important means of pain control in CBP, and newer larger studies should be launched. 
Power Calculation 
This study aims to collect preliminary data in humans to test whether a manipulation of the 
hippocampal network can lead to changes in pain experience in CBP participants. With this in 
mind, we will aim for a final sample size of 12 subjects. Due to possible dropouts over the course 
of the study, we will recruit a total of 16 subjects. If this study shows indication that the 
hippocampal stimulation leads to higher connectivity increase across series of hippocampal 
networks that modulates pain, the results of this study will be used to perform a power calculation 
in order to perform a future study aiming to treat chronic back pain. 
 
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS 
The primary protection will be careful recruitment, thereby limiting enrollment only to eligible 
subjects, i.e., subjects meeting all inclusion and exclusion criteria. 
MR Imaging 
Individuals who cannot tolerate the confinement of an MRI scanner and those who may not be 
able to be scanned because of implanted metal devices will be excluded. Claustrophobia is the 
main limiting factor; we attempt to identify people at risk by having people lie in the simulation 
scanner (a fake scanner made to look and feel like the real one) to assess their comfort levels. 
There is a standard checklist of additional exclusionary items for MR scanning (e.g., implanted 
devices, exposure to metallic fragments at work, etc) that will be utilized prior to entering 
participants into the study and again prior to each imaging session. Personnel continuously query 
the subject in the scanner as to their overall well-being during scans and will discontinue the scan 

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and relieve the subject from the discomfort at any time requested. It is possible that the anatomical 
scans may uncover a brain abnormality of which the participant was not aware. In such cases, 
the subject is removed from the study and given appropriate medical advice (TJS); his/her scans 
are sent to a radiologist for an opinion and this person then consults with TJS. The likelihood of 
this happening is low (less than 1%). Over the last 20 years of doing brain scans in various 
populations (healthy and not), participants often are surprised at how anxious they feel in the 
scanner and simply cannot tolerate it. Otherwise, subjects are usually enthusiastic in participating 
in trials that may lead to new discoveries that either pertain to their conditions or help other people. 
TMS 
Individuals who cannot tolerate TMS stimulation or those who may not receive stimulation will be 
excluded. To minimize risk and protect participants, a trained clinical staff will be present for all 
the rTMS sessions (a trained clinical staff will also be present on “sham” sessions, even though 
in these sessions the intensity of stimulation is adjusted to a low value that cannot influence the 
brain). Study staff personnel continuously query the subject regarding their overall well-being 
during the stimulation protocols and will discontinue and relieve the subject from the discomfort 
at any time requested. 
Questionnaire Risks 
To deal with the possibility that some questions may be sensitive in nature or make people feel 
uncomfortable, individuals will be told that they need not complete any items of entire 
questionnaires if they feel that doing so will cause discomfort. Because we are measuring 
depression, anxiety, and other mental health constructs in these questionnaires, Dr. Griffith, a 
licensed clinical psychologist, will be available to consult about any concerns that patients have 
about their mental health, including referrals to appropriate providers. All such participants will be 
given a list of referral sources in case they wish to seek mental healthcare, and participants will 
be invited to contact the research team with any questions about getting connected with 
appropriate healthcare. 
 
PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS 
Privacy and confidentiality will be maintained using allocation numbers (also called participant 
IDs, PIDS) throughout the study with the master study list being maintained by the PI and study 
coordinator with availability limited to those study personnel who have a documented need for 
this information. All electronic information will be pass-word protected and stored on a secure 
server; when necessary, it will also be encrypted for extra protection. 
To deal with the possibility that some questions may be sensitive in nature or make people feel 
uncomfortable, individuals will be told that they need not complete any items of entire 
questionnaires if they feel that doing so will cause discomfort. Because we are measuring 
depression, anxiety, and other mental health constructs in these questionnaires, Dr. Griffith, a 
licensed clinical psychologist, will be available to consult about any concerns that patients have 
about their mental health, including referrals to appropriate providers. All such participants will be 
given a list of referral sources in case they wish to seek mental healthcare, and participants will 
be invited to contact the research team with any questions about getting connected with 
appropriate healthcare. 
COMPENSATION FOR RESEARCH-RELATED INJURY 

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If a subject is injured as a result of this study (medications, or procedures), they should seek 
medical treatment through their primary care physician or treatment center of choice. They will be 
instructed during the consent process to promptly tell the study doctor about any illness or injury. 
The hospital [university, researchers] will not pay for medical care required because of a bad 
outcome resulting from participation in this research study. 
ECONOMIC BURDEN TO PARTICIPANTS 
Participants will not be responsible for any study-related costs because of participation in the 
research. 
 
CONSENT PROCESS 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the 
study and continues throughout study participation. We will be obtaining informed consent for all 
subjects in this study. We do not plan to enroll non-English speaking subjects, cognitive 
impaired individuals, individuals under 18 years of age, and or adults who are unable to 
consent. 
The following outlines the informed consent process: 
After passing the pre-screening over the phone, the participant will be scheduled for a screening 
visit. If possible, a copy of the IRB-approved consent form will be emailed or mailed to the 
subject prior to the scheduled visit. 
The consent process will take place in Abbott Hall on the 10th floor clinical research exam 
space in a private exam room or in the CTI in a private room. The consent form will be 
explained to the participant (the participant will read along with staff): each section of the form 
will be discussed, taking time to highlight the purpose of the study, procedures, risks, 
confidentiality measures taken to protect the participant, and how to revoke/withdraw consent, if 
desired, and to answer any questions the participate may have. If staff cannot answer the 
question or if the participant has concerns to discuss, the study physician or PI will be contacted 
to speak to the participant. Subjects will be given as much time as they need to make their 
decision whether or not to participate. There will be a waiting period available to the participant; 
they will have an opportunity to take the consent document home to discuss with family, friends, 
and/or their physician prior to signing the document. Once the document is signed, the subject 
will sign and date two copies. One copy to take home and one copy to keep with the subject’s 
source documents. The consent process will also be documented in the subject’s source 
documents. 
All participants will be re-consented should a new ICF be approved by the IRB with updated 
information. In cases where participants may need to be notified of new information before an 
ICF is approved by the IRB, subjects will be notified by phone about updated information. 
This study will follow SOP: Informed Consent Process for Research (HRP-090) as well as 
“SOP: Written Documentation of Consent (HRP-091).” 
 
NON-ENGLISH-SPEAKING PARTICIPANTS 

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Only English-speaking participants will be enrolled. 
 
PROTECTED HEALTH INFORMATION (PHI AND HIPAA) 
We are committed to respect participant privacy and to keep personal information confidential. 
When choosing to take part in this study, participants are giving us the permission to use their 
PHI that includes health information in their medical records and information that can identify 
them. For example, PHI may include name, address, phone number or social security number. 
Health information that we may collect and use for this research includes: 
• 
Results of physical examinations 
• 
Medical history including back pain history and family history of back pain 
• 
Lab tests, or certain health information indicating or relating to a particular condition 
as well as information collected by cellphone apps 
• 
Records about study medication or drugs 
• 
Records about MRI scans 
• 
Substance abuse information: current recreational drug use or history of alcohol or 
drug abuse 
The following groups of people may give the researchers information about research 
participants: All current and previous health care providers, including but not limited to the NMH. 
Once we have the health information listed above, we may share some of this information with 
the following people. Please note that any research information shared with people outside of 
NU and its clinical partners (or affiliates) will not contain subject’s name, address, telephone or 
social security number or any other direct personal identifier unless disclosure of the direct 
identifier is required by law [except that such information may be viewed by the Study sponsor 
and its partners or contractors at the PI’s office] 
• 
Authorized members of the NU workforce, who may need to see information, such as 
administrative staff members from the Office for Research, Office for Research Integrity 
and members of the Institutional Review Board (a committee which is responsible for the 
ethical oversight of the study), 
• 
Clinical affiliates, including but not limited the NMH. Individuals’ participation in this 
clinical trial will be tracked in an electronic database and may be seen by investigators 
running other trials and by other healthcare providers having access to this database. 
• 
Other University research centers and University contractors who are also working on 
the study, 
The informed consent document will include a HIPAA authorization as well. 
The results of this study may also be used for teaching, publications, or presentation at scientific 
meetings. However, the individual’s name and personal information will not be used. 
QUALIFICATIONS TO CONDUCT RESEARCH AND RESOURCES AVAILABLE 
Northwestern University, primarily through the Feinberg School of Medicine, is one of the 
country’s premier centers in education, research, and clinical services. Interaction between 
scientists is supported and encouraged. The scientific environment is more than adequate to 
contribute to the success of the proposed research. 
Apkarian’s Lab center: The lab has a human and animal component of ~1800 square feet. 
The human brain-imaging lab has 3 post-doctoral fellows, PhD and undergraduate students. 

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The brain imaging data processing center of the lab was recently relocated at Northwestern 
University Data Center Facilities’ secure datacenter located in Evanston Campus, and is 
accessed via a remote interface. All necessary software for analysis of neuroimaging and 
behavioral data is available. 
Dr. Schnitzer has dedicated research space with 3 dedicated examination rooms, a 
phlebotomy room and clinical laboratory and 1400 square feet of office spaces for research 
staff. All clinical equipment required is available. 
Laboratory for Human Neuroscience (LHN): The laboratory Dr. Voss occupies ~2,400 ft2. 
There are three testing enclosures outfitted for cognitive neuroscience experiments with human 
subjects. The laboratory maintains a dedicated MagVenture X100 MRI-guided TMS system and 
a variety of physiological monitoring devices and electrical stimulus generators. Dr. Voss’s 
laboratory has easy access to all research spaces and is a Co-Investigator on this project. 
Center for Translational Imaging (CTI): Human imaging Human brain imaging is done Center 
for Translational Imaging (CTI), a core facility of Northwestern University. There are two 3.0 T 
MRI scanners, dedicated for research and shared between 15 NIH funded research groups, 
having led to >100 publications. We have access to the MRI facilities for the next 5 years. CTI is 
managed by the Radiology Department and is fully staffed and equipped. Besides that, the LHN 
maintains a TMS system that is identical to the system housed in the CTI. 
Research staff have all completed CITI training and have training in human subject’s protection. 
All personnel will be fully informed and trained regarding the protocol and follow the research 
clinic’s SOPs for undertaking clinical studies. For rTMS, research staff has completed at least 
20-hours of supervised hands-on experience operating the machine and interacting with 
participants. rTMS training is provided by Laboratory for Human Neuroscience. 
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