Use of Repetitive Transcranial Magnetic Stimulation to Augment Hypnotic Analgesia
Phase: NA
Conditions: Fibromyalgia
Sponsor: Stanford University

 
 Use of Repetitive Transcranial Magnetic Stimulation (rTMS) to 
Augment Hypnotic Analgesia 
Study Protocol and Statistical Analysis Plan 
NCT02969707 
 February 14, 2019 

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FULL PROTOCOL TITLE 
Use of Repetitive Transcranial Magnetic Stimulation (rTMS) to Augment Hypnotic Analgesia: 
 
A randomized, double-blind, sham-controlled, mechanistic clinical trial assessing the efficacy of 
rTMS in modulating the neural circuitry underlying hypnotizability, hypnosis, and hypnotic 
analgesia among participants with a diagnosis of Fibromyalgia Syndrome (FMS) and low-
moderate hypnotizability 
 
Principal Investigators:   
Nolan R. Williams, MD 
Stanford University 
Department of Psychiatry 
401 Quarry Rd 
Mail Code 5719 
Stanford, CA 94305 
Tel: (650) 723-1147 
Fax: 
 
Email: nolanw@stanford.edu 
 
David Spiegel, M.D. 
Stanford University 
Department of Psychiatry 
401 Quarry Rd 
Mail Code 5718 
Stanford, CA 94305 
Tel: (650) 723-6421 
Fax: 
 
Email: dspiegel@stanford.edu 
 
 
 
Supported by:  
 
The National Center for Complementary and Integrative Health  
1R33AT009305-01
 
 

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Tool Revision History 
 
Version Number: 1.1 
Version Date: 09/18/2016 
Summary of Revisions Made: per emailed request 
Version Number: 1.2 
Version Date: 10/18/16 
Summary of Revisions Made: per emailed request 
Version Number: 1.3 
Version Date: 03/14/2018 
Summary of Revisions Made:  
 
The assessments were updated: Sense of Agency, Tellegen’s Absorption Scale and the 
Ishihara Vision Test were added. ATHF was changed to ATRQ and the McGill Pain 
Questionnaire Long Form was changed to the Short Form Version.  
 
A targeting MRI scan was added as part of the screening process for the TMS 
administration. 
 
The assessments table was updated to reflect the schedule of events: hematology was 
removed, HIP/HIS were separated and administration of the HIP time points were 
updated, SOARS was added to the HIP, the online screening consent was added 
 
Vital signs were removed from the SOE. 
 
Urinalysis was updated to reflect that it is only assessed on TMS administration days. 
 
Due to the stability of trait hypnosis, enrollment time frame has been updated from 1-
month to be based upon individual subjects’ availability to schedule their study visits this 
is in response to subjects not being available to complete all required visits within a 1-
month period. 
Version Number: 1.4 
Version Date: 10/10/2018 
Summary of Revisions Made: 
 
Clarification was made under Section: Schedule and Type of Evaluations, that the 
target scan and first  study visit can be on the same day. 
 
Under 4.2, it was clarified that the high risk participants will be excluded if they are 
already taking opioids. 
 
Pain Numeric Rating Scale (PNRS) and Dissociative Experiences Scales were added to 
Section 6.2.1. 
 
Needle-like sensations and pain was added to Section 7.4 as an expected AE. 
 
 
 
 
 

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Version Number: 1.5 
Version Date: 02/14/2019 
Summary of Revisions Made: 
 
Under 6.2.2, spectroscopy language was added to the Baseline MRI Session for TMS 
targeting 
 
Under 6.2.5, optional MRI spectroscopy assessment is added. 
 
Under Secondary objectives, section F and G are added to include MRS secondary-
aims. 
 
Under 9.6.2,  section F and G are added to include MRS secondary outcome measures 
and analyses. 
 

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TABLE OF CONTENTS 
Page 
FULL PROTOCOL TITLE......................................................................................................1 
Tool Revision History .............................................................................................................2 
TABLE OF CONTENTS ..........................................................................................................4 
STUDY TEAM ROSTER .......................................................................................................7 
PARTICIPATING STUDY SITES..........................................................................................8 
PRÉCIS ...................................................................................................................................9 
1. STUDY OBJECTIVES ....................................................................................................... 11 
1.1 
Primary Objective ...................................................................................................... 11 
1.2 
Secondary Objectives ................................................................................................ 13 
2. BACKGROUND AND RATIONALE ................................................................................ 14 
2.1 
Background on Condition, Disease, or Other Primary Study Focus ............................ 14 
2.2 
Study Rationale ......................................................................................................... 14 
3. STUDY DESIGN ................................................................................................................. 19 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ............................................. 27 
4.1 
Inclusion Criteria ....................................................................................................... 27 
4.2 
Exclusion Criteria ...................................................................................................... 28 
4.3 
Study Enrollment Procedures ..................................................................................... 29 
5. STUDY INTERVENTIONS ............................................................................................... 31 
5.1 
Interventions, Administration, and Duration .............................................................. 31 
5.2 
Handling of Study Interventions ................................................................................ 33 
5.3 
Concomitant Interventions ......................................................................................... 34 
5.3.1 Allowed Interventions ............................................................................................ 34 
5.3.2 Required Interventions ........................................................................................... 34 
5.3.3 Prohibited Interventions ......................................................................................... 34 
5.4 
Adherence Assessment .............................................................................................. 34 
6. STUDY PROCEDURES ..................................................................................................... 34 
6.1 
Schedule of Evaluations ............................................................................................. 35 
6.2 
Description of Evaluations ......................................................................................... 36 
6.2.1 Screening Evaluation ............................................................................................. 36 
6.2.2 Enrollment, Baseline, and/or Randomization.......................................................... 38 

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6.2.3 Blinding ................................................................................................................. 42 
6.2.4 Followup Visits...................................................................................................... 43 
6.2.5 Completion/Final Evaluation ................................................................................. 44 
7. SAFETY ASSESSMENTS .................................................................................................. 44 
7.1 
Specification of Safety Parameters ............................................................................. 46 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ..... 46 
7.3 
Adverse Events and Serious Adverse Events .............................................................. 47 
7.4 
Reporting Procedures ................................................................................................. 49 
7.5 
Followup for Adverse Events ..................................................................................... 52 
7.6 
Safety Monitoring ...................................................................................................... 52 
8. INTERVENTION DISCONTINUATION ......................................................................... 54 
9. STATISTICAL CONSIDERATIONS ................................................................................ 54 
9.1 
General Design Issues ................................................................................................ 55 
9.2 
Sample Size and Randomization ................................................................................ 59 
9.3  Stimulation Group Assignment Procedures ................................................................. 61 
9.4  
Definition of Populations ........................................................................................... 64 
9.5 
Interim Analyses and Stopping Rules ......................................................................... 65 
9.6 
Outcomes .................................................................................................................. 65 
9.6.1 Primary Outcome ................................................................................................... 59 
9.6.2 Secondary Outcomes ............................................................................................. 60 
9.7 
Data Analyses ............................................................................................................ 73 
10. DATA COLLECTION AND QUALITY ASSURANCE ................................................. 76 
10.1 
Data Collection Forms ............................................................................................... 76 
10.2 
Data Management ...................................................................................................... 76 
10.3 
Quality Assurance...................................................................................................... 78 
10.3.1 
Training ............................................................................................................. 78 
10.3.2 
Quality Control Committee ................................................................................ 78 
10.3.3 
Metrics ............................................................................................................... 78 
10.3.4 
Protocol Deviations ............................................................................................ 79 
10.3.5 
Monitoring ......................................................................................................... 80 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY .................................................. 82 
11.1 
Institutional Review Board (IRB) Review .................................................................. 82 
11.2 
Informed Consent Forms ........................................................................................... 82 
11.3 
Participant Confidentiality ......................................................................................... 82 

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11.4 
Study Discontinuation................................................................................................ 83 
12. COMMITTEES ................................................................................................................. 84 
13. PUBLICATION OF RESEARCH FINDINGS ................................................................ 85 
14. REFERENCES .................................................................................................................. 78 
15. SUPPLEMENTAL MATERIAL ...................................................................................... 89 
I. Stanford IRB-Approved Informed Consent Form 
II. TMS Stimulation Manual 
III. TMS Blinding Manual 
IV. Hypnosis and Hypnotic Analgesia Manual 

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STUDY TEAM ROSTER  
 
Nolan Williams, M.D., Principal Investigator 
 
 
Stanford, CA 94305 
Tel: (650) 723-1147 
Fax: 
 
Email: nolanw@stanford.edu 
 
David Spiegel, M.D., Principal Investigator 
 
 
Stanford, CA 94305 
Tel: (650) 723-6421 
Fax: 
 
Email: dspiegel@stanford.edu 
 
Leanne Williams, Ph.D., Co-Investigator 
 
 
Palo Alto, CA  94305 
Phone:  
 
Fax: N/A 
Email: 
 
 
 
Dave Yeomans, Ph.D., Co-Investigator 
 
Stanford, CA 94305
 
Phone: 
 
Fax: 
 
Email: 
 
 
 
Booil Jo, Ph.D., Co-Investigator 
 
 
Stanford, CA 94305
 
Phone: 
 
 
Fax: 
 
Email: 
        
 

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PARTICIPATING STUDY SITES 
 
Nolan Williams, M.D. 
Principal Investigator 
 
Stanford University 
Department of Psychiatry 
 
 
Stanford, CA 94305 
Tel: (650) 723-1147 
Fax: 
 
Email: nolanw@stanford.edu 
 
 
David Spiegel, M.D. 
Principal Investigator 
 
Stanford University 
Department of Psychiatry 
 
Stanford, CA 94305 
Tel: (650) 723-6421 
Fax: 
 
Email: dspiegel@stanford.edu 
 
 

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PRÉCIS  
 
Title 
 
Use of Repetitive Transcranial Magnetic Stimulation (rTMS) to Augment Hypnotic Analgesia  
 
Objectives 
 
Primary Mechanistic Objective: To determine the effect of active, inhibitory rTMS 
(continuous theta-burst stimulation-cTBS) over left dorsolateral prefrontal cortex (L-
DLPFC) on modulating the neural network that underlies hypnotizability and hypnosis.  
Relevant Clinical Objective: To determine the effect of active, inhibitory rTMS (cTBS) over 
L-DLPFC on enhancing hypnotic analgesia (HA) as measured by change in pain 
thresholds. 
 
Secondary Objective A: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on modulating the neural network that underlies hypnotic intensity. 
Secondary Objective B: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on enhancing hypnotizability (as measured by the Hypnotic Induction Profile-HIP and Stroop 
Task) and hypnotic intensity (as measured by the Hypnotic Intensity Scale-HIS). 
Secondary Objective C: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network underlying the conflict regulation system as a surrogate of effective 
modulation of the neural circuitry that underlies hypnotizability.  
Secondary Objective D: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network that underlies the post-hypnotic Stroop Effect. 
Secondary Objective E: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on modulating the neural network that underlies hypnotic analgesia (HA). 
 
Design and Outcomes   
 
Study Design: This study is a double blind, placebo-controlled, mechanistic trial assessing rTMS 
as a strategy for the modulation of the neural circuitry underlying hypnotizability and hypnotic 
analgesia in participants with a diagnosis of Fibromyalgia Syndrome (FMS). 
 
Schedule and Type of Evaluations: There are four visits for this. The first visit is a screening 
visit where the participant will be consented to be screened for the study. The participant will then 
be screened to determine inclusion and exclusion criteria. If the participant meets criteria, the 
participant will be consented for the imaging and rTMS portions of the study. The participant will 
be assigned their randomization code and their counterbalanced imaging days. Up to three 
separate imaging visits will be conducted including a baseline MRI for TMS target identification 
(Visit #2) and two separate MRI-TMS sessions consisting of a hypnotic analgesia and hypnotic 
stroop procedures (Visits #3-4). Visit #2 and #3 can take place on the same day. During the TMS-

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MRI visits which include thermal pain and stroop MRI sessions, the participant will receive either 
sham or active rTMS (depending on randomization) in a non-crossover design.  
Study Overview Diagram: 
 
 
All participants will undergo the Hypnotic Stroop Scan Session Day. All participants will receive 
the identical pre-rTMS scan session. One-half (n=50) will receive active rTMS and one-half (n=50) 
will receive sham rTMS (two arm, double-blind, sham-controlled). All participants will receive the 
identical post-rTMS scan session. Changes in resting state functional connectivity between L-
DLPFC and dACC in the active rTMS versus the sham rTMS conditions will be assessed. This 
primary endpoint is a between-group comparison. We will also measure the difference in brain 
activation during the hypnotic induction, and Stroop task (after post-hypnotic suggestion) between 
the active and sham rTMS. This will also be a between-groups comparison. Using the Hypnotic 
Induction Profile (HIP) and Hypnotic Intensity Scale (HIS), we will compare the change in 
hypnotizability and hypnotic intensity score between the active and sham rTMS groups.  
 
All participants will undergo the Hypnotic Analgesia Scan Session Day. All participants will 
complete identical pre- and post- rTMS scan session. One-half will receive active rTMS and one-
half will receive sham rTMS. Changes in resting state functional connectivity between L-DLPFC 
and dACC in the active rTMS versus the sham rTMS conditions will be assessed. This primary 
endpoint is a between-group comparison. This scan-session also addresses a secondary aim of 
determining the difference in functional connectivity within the hypnotic analgesia network 
between the active and the sham rTMS groups. This will be a between-groups comparison. We 
will also compare the activation within the hypnotic analgesia network between the active and 
sham rTMS groups. This will be a between-groups comparison. We will also utilize a perturbation 
technique to probe the hypnotic induction in an alternative way. Finally, we will compare the 
difference in pain thresholds between the active and sham rTMS groups.  
 
Interventions and Duration  
 
Intervention: We will compare active versus sham rTMS as a technique for modulating the neural 
Recruitment/Screening of Fibromyalgia Subjects (Visit #1)
(n=100)
Active rTMS Group (n=50)
Randomization
(n=25)
Hypnotic Stroop Session (Visit #3)
Counterbalancing
Sham rTMS Group (n=50)
Counterbalancing
TMS Target MRI Visit (Visit #2)
Hypnotic Analgesia Session (Visit #4)
MRI #1
rTMS
MRI #2
MRI #1
rTMS
MRI #2
(n=25)
Hypnotic Analgesia Session (Visit #3)
Hypnotic Stroop Session (Visit #4)
MRI #1
rTMS
MRI #2
MRI #1
rTMS
MRI #2
(n=25)
Hypnotic Stroop Session (Visit #3)
Hypnotic Analgesia Session (Visit #4)
MRI #1
rTMS
MRI #2
MRI #1
rTMS
MRI #2
(n=25)
Hypnotic Analgesia Session (Visit #3)
Hypnotic Stroop Session (Visit #4)
MRI #1
rTMS
MRI #2
MRI #1
rTMS
MRI #2

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circuitry underlying hypnotizability (Primary Mechanistic Outcome) in an effort to improve efficacy 
of hypnotic analgesia (Relevant Clinical Outcome). The total length of time that the participants 
will be four study visits. The study will involve one screening visit, three required scan session 
days (five required scan sessions including target identification scan, two pre-rTMS scan 
sessions, and two post-rTMS scan sessions).  
 
Sample Size and Population  
 
The target population is 18-70 year-old male and female participants who are low-moderately 
hypnotizable, have a confirmed diagnosis of fibromyalgia and have no contraindications to MRI 
or rTMS. We will enroll 100 pain medication-free (not taking opiates or anti-depressants on the 
day of rTMS) participants and employ a two-arm design with 50 subjects per arm. 
1. STUDY OBJECTIVES 
 
1.1 
Primary Mechanistic and Relevant Clinical Objectives 
 
Primary Mechanistic Objective: To determine the effect of active, inhibitory rTMS 
(continuous theta-burst stimulation-cTBS) over left dorsolateral prefrontal cortex (L-
DLPFC) on modulating the neural network that underlies hypnotizability and hypnosis. In 
other words, the Primary Outcome Measure is the change in functional connectivity 
between the L-DLPFC and the dACC in active versus sham rTMS and the effect of rTMS 
inhibition of activity in the DLPFC on activity in the dACC.  
 
Primary Mechanistic Hypothesis: Active, inhibitory rTMS (cTBS) over L-DLPFC will 
modulate the neural network that underlies hypnotizability by producing greater increases 
in functional connectivity between L-DLPFC and dACC as compared to sham rTMS (sham 
cTBS). We hypothesize that active, inhibitory rTMS (continuous theta-burst stimulation) 
will produce increases in functional connectivity between the L-DLPFC and the dACC, 
producing a transient phenotype appearing on neuroimaging like a high hypnotizable.  
This increase in functional connectivity, coupled with inhibition of activity in the DLPFC, 
would be hypothesized to reduce activity in the dACC as well, which is what we have shown to 
be associated with entry into the hypnotic state.  Thus rTMS-induced increase in functional 
connectivity should increase hypnotizability and, coupled with inhibited activity, enhance hypnotic 
intensity as well. 
 
Relevant Clinical Objective: To determine the effect of active, inhibitory rTMS (cTBS) over 
L-DLPFC on enhancing the efficacy of hypnotic analgesia (HA) as measured by change in 
pain thresholds. 
 

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Relevant Clinical Hypothesis: Active, inhibitory rTMS (cTBS) over L-DLPFC will enhance 
the efficacy of hypnotic analgesia (HA) as compared to sham rTMS (sham cTBS). 
 
 
 
 

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1.2 
Secondary Objectives 
 
Secondary Objective A: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on modulating the neural network that underlies hypnotic intensity. 
 
Secondary Hypothesis A: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies hypnotic intensity by decreasing activity in L-DLPFC and dACC as 
compared to sham rTMS (sham cTBS) as measured by BOLD fMRI and interleaved TMS-MRI. 
 
Secondary Objective B: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on enhancing hypnotizability (as measured by the Hypnotic Induction Profile-HIP and Stroop 
Task) and hypnotic intensity (as measured by the Hypnotic Intensity Scale-HIS). 
 
Secondary Hypothesis B: Active, inhibitory rTMS (cTBS) over L-DLPFC will increase the HIP 
and HIS scores as well as hypnotic reduction of the Stroop Effect as compared to sham rTMS 
(sham cTBS). 
 
Secondary Objective C: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network underlying the conflict regulation system as a surrogate of effective 
modulation of the neural circuitry that underlies hypnotizability.  
 
Secondary Hypothesis C: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies conflict regulation by producing greater increases in functional connectivity 
between the right inferior frontal gyrus (rIFG) and the default mode network (DMN) as compared 
to sham rTMS (sham cTBS). 
 
Secondary Objective D: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network that underlies the post-hypnotic Stroop Effect. 
 
Secondary Hypothesis D: Post-hypnotic instruction of word blindness after active, inhibitory 
rTMS (cTBS) over L-DLPFC will reduce dACC activity during the Stroop task (similar to high 
hypnotizables) as compared to sham rTMS (sham cTBS). 
 
Secondary Objective E: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on modulating the neural network that underlies hypnotic analgesia (HA). 
 
Secondary Hypothesis E: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies HA by producing a decrease in activity and an increase functional 
connectivity among the anterior cingulate, dorsolateral, insular, and somatosensory cortices 
(hypnotic analgesia network) as compared to sham rTMS (sham cTBS). 
 

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2. BACKGROUND AND RATIONALE 
 
 
2.1 
Background on Fibromyalgia Syndrome (FMS) 
 
 
Fibromyalgia syndrome (FMS) is a poorly understood disorder characterized clinically as 
widespread pain lasting three months or more which is not explainable by any other 
disease/disorder (1). Traditional treatments have limited benefit (2), and long-term use of opioid 
medications is problematic in these patients (2) due to demonstrated reduced opiate binding 
potential in FMS (3). Hypnotherapy as an intervention has been demonstrated to be quite 
successful in the treatment of FMS (4). It appears that the type of suggestion utilized is of primary 
importance to the efficacy of the hypnotherapy intervention for FMS (5). Hypnotic analgesia for 
FMS has been demonstrated to have effects on the orbitofrontal, cingulate cortices, and thalamus 
(6, 7). There have been numerous studies looking at rTMS for the modulation of pain syndromes 
(8, 9) as well as for the assessment of anti-nociception properties of rTMS through experimentally 
induced pain in normal healthy controls (10). L-DLPFC rTMS both have demonstrated efficacy in 
modulating the pain experienced in fibromyalgia (8, 11).  
 
 
2.2 
Study Rationale 
 
 
Neural Circuitry Underlying Regulation of Cognition: Theories of cognitive regulation suggest 
that there is a central neural network with two necessary components, which regulate cognition 
and control conflict in the human brain. The first component is the dorsolateral prefrontal cortex 
(DLPFC), which initiates and implements a cascade of control (12). The second, the dorsal 
anterior cingulate cortex (dACC), monitors performance and signals when adjustments in control 
are needed(12, 13). The DLPFC and dACC predictably interact together during conflict tasks such 
as the Stroop task(13) and the flanker task(14). 
 
 
Transcranial Magnetic Stimulation: A Technique for Probing and Manipulating Neural 
Networks: Tools that selectively manipulate cognitive brain circuitry can effectively drive cognitive 
processes (15). Transcranial magnetic stimulation (TMS) noninvasively activates neuronal 
elements. In TMS, high-intensity magnetic field is produced by passing a brief electric current 
through a magnetic coil. The scalp and skull are crossed unimpeded, and a transient electric field 
is induced in underlying excitable neuronal tissue. Repetitive TMS produces periods of lasting 
activation or inhibition that persist after stimulation (16). In particular, inhibition generally results 
from stimulation at or below 1 Hz and excitation is produced from 5 Hz or higher.  

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Theta-Burst Stimulation: In 2005, a new rTMS approach, termed theta-burst stimulation (TBS), 
was developed (17). This TBS approach was modeled from earlier work in animal models of 
hippocampal slice physiology and LTP induction (18, 19). This approach is not only more efficient 
than traditional rTMS(20), but also much safer (21-24) and the after-effects of TBS have a much 
longer duration of effects then traditional rTMS(25). This is important because the currently 
utilized traditional rTMS approaches have very limited duration of effect in comparison(20, 26). 
While single applications of theta-burst have greater duration of effect than traditional rTMS, these 
single stimulations have a limited duration of effect in comparison to multiple, spaced stimulation 
sessions(20, 27). In order to produce a prolonged after-effect of stimulation that is capable of 
maintaining the after-effects for the entire duration of the planned scanner sessions, the 
application of two theta-burst stimulations with spacing of 10-20 min is necessary(27-30).  
 
 
The Neural Circuitry of Hypnotizability and Manipulated by Hypnotic Techniques: 
Hypnotizability is a measurable behavioral phenotype capable of reflecting differences in 
functional connectivity between the L-DLPFC and the dACC(31, 32), the two central brain regions 
that process conflict (13, 14). Consistent with this is the functional neuroimaging finding of 
reduced dACC activity upon entering the hypnotic state (33, 34). On functional neuroimaging, it 
has been observed that there is increased connectivity between the left dorsolateral prefrontal 
cortex (L-DLPFC) and the dorsal anterior cingulate cortex (dACC) in high hypnotizables compared 
with lows during rest(31). During conflict tasks, specific post-hypnotic instruction-induced changes 
in response latency correlate with changes on functional imaging in the dACC(32, 35, 36). There 
is also evidence of less dACC activity among highs than lows during a flanker task (32). During 
hypnosis and only among high hypnotizables there is reduced activity in the dorsal anterior 
cingulate cortex increased functional connectivity between the L-DLPFC (a node in the Central 
Executive Network-CEN) and the insular cortex (a node in the Salience Network-SN), and 
reduced connectivity between the L-DLPFC (CEN), medial frontal and posterior cingulate cortices 
(a node in the default mode network-DMN)  (33, 34). 
 
Hypnotic Analgesia Neural Network: Hypnotic analgesia (HA) involves a neural network 
including the prefrontal cortex (L-DLPFC), the anterior cingulate cortex (ACC), the insular cortex, 
and the somatosensory cortex(37). A proposed mechanism for hypnotic analgesia involves 
activity that links L-DLPFC with dACC and insula, thereby modulating activity in S2 and dorsal 
posterior insula. Other studies have indicated involvement of dACC and the insular cortex (IC) in 
hypnotic analgesia (7, 37-40). These and other brain regions have been identified in mixed effects 
analysis of pain-reducing properties of leading analgesic drugs during pain versus placebo 
stimulation as measured by fMRI and PET pain reports (41, 42). Other brain regions are involved 
in hypnotic analgesia including the sensory cortex (S1) (38, 39, 43), and periaqueductal grey (39). 
 
 
 
Hypnotic Analgesia Tool for the Modulation of Pain: Hypnotic analgesia utilizes targeted 
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system within the human brain(38, 44). The specific hypnotic instruction modulates the neural 
network involved with that instruction. The degree of pain experienced under the hypnotic 
suggestion of induced pain is positively correlated with L-DLPFC, dACC, and insular activity(45). 
Hypnotic analgesia reduces activity in the dACC (44).  
 
The Neural Circuitry Modulated by DLPFC rTMS: Like hypnosis, rTMS delivered over the L-
DLPFC is correlated with a reciprocal interaction of the L-DLPFC with the ACC. This reciprocal 
interaction is seen in normal healthy controls performing conflict tasks(15) as well as in individuals 
with depression(46). Over L-DLPFC, rTMS has been demonstrated to exert frequency dependent 
changes where inhibitory rTMS modulates the network in one direction and excitatory rTMS 
modulates the network in the opposite direction(47). This infers that changes in the targeted 
network occur predictably depending on the frequency selected(47). 
 
Hypnosis and rTMS as Tools for Modulating Brain Activity and Connectivity: Manipulations 
of brain circuitry can be measured through imaging techniques(47-49). BOLD fMRI is a technique 
that measures changes in blood flow are accompanied by lesser changes in oxygen 
consumption(50). Functional connectivity MRI (fcMRI) is a neuroimaging technique that measures 
connectivity between functionally connected brain regions(51). This technique captures both the 
brain processes at work in a variety of cognitive states(52) as well as the manipulation of these 
networks through targeted perturbations such as with rTMS(47) or hypnosis(31, 48). rTMS 
modulation of brain activity has behavioral outcomes that are correlated with change in functional 
connectivity(46). fcMRI and rTMS can be combined to image the resulting rTMS brain connectivity 
manipulations(53). One could consider rTMS as a tool for driving functional connectivity in a given 
direction for a predictable period of time. fcMRI has not only been demonstrated to underlie the 
propensity to experience hypnosis(31), but additionally to measure the effects of hypnosis as 
compared to the baseline scan(48). Therefore, fcMRI can measure the effect of rTMS-augmented 
hypnotherapy, as it has been demonstrated to have the sensitivity to capture the effects of each 
of these interventions in isolation(31, 48). 
 
Change in Functional Connectivity and Activity Modulated by rTMS (Primary Outcome 
Measure):  rTMS has been demonstrated to reliably change functional connectivity in a frequency 
dependent manner(54). There are numerous studies demonstrating rTMS-modulated increases 
in functional connectivity(46, 47, 53-58), suggesting that the rTMS modulation of L-DLPFC rTMS 
will 
cause 
a 
predictable 
increase 
in 
functional 
connectivity 
to 
the 
dACC(47). 
Hypnosis/hypnotizability will be increased with rTMS as has been demonstrated previously(26, 
59) which we believe will have a beneficial effect on the treatment outcome as has been previously 
demonstrated on attention measures(60, 61) and clinical populations(62).   This increase in 
functional connectivity, coupled with inhibition of activity in the L-DLPFC, would be 
hypothesized to reduce activity in the dACC as well, which is what we have shown to be 
associated with entry into the hypnotic state. Thus rTMS induced increase in functional 
connectivity should increase hypnotizability and, coupled with inhibited activity, enhance hypnotic 
intensity as well. 
Neural Networks Affected By Fibromyalgia and the Effect of HA on the FMS Networks: In 
addition to abnormalities in pain processing, there is aberrant processing of non-painful 

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somatosensory information in FMS, especially when somatic signals arise from the body within 
an aversive stimulus context (63). At the neural network level, FMS can be understood as a 
disorder involving a reduction in descending control, including suppression of descending 
inhibitory pathways and/or enhancement of descending facilitative pathways (64). Central 
mechanisms of pain processing in the frontal cortex and cingulate cortex appear to play an 
important role in pain pathophysiology in FMS (65). Hypnotic analgesia specifically for FMS has 
been demonstrated to have increased cerebral blood-flow in bilateral orbitofrontal and subcallosal 
cingulate cortices, the right thalamus, and the left inferior parietal cortex, and decreased bilaterally 
in the cingulate cortex(6).  
 
The Effects of DLPFC rTMS for Pain and the Neural Network Involved in FMS: There have 
been numerous studies looking at rTMS for the modulation of pain syndromes(8, 9) as well as for 
the assessment of anti-nociception properties of rTMS through experimentally induced pain in 
healthy controls(10). L-DLPFC rTMS has demonstrated efficacy in treating fibromyalgia(66). 
When compared to sham, active L-DLPFC rTMS reduces hot pain and hot allodynia(8). This 
analgesia has been associated with elevated blood oxygenation-level dependent (BOLD) signal 
in the L-DLPFC and diminished BOLD signal in the anterior cingulate, thalamus, midbrain, and 
medulla. Pretreatment with naloxone, a mu-opioid antagonist, abolishes the analgesic effects of 
real rTMS. In addition, naloxone reduces the rTMS-induced attenuation of BOLD signal response 
to painful stimuli throughout pain processing regions (67) (68). 
 
Functional Brain Basis of Differences in Hypnotizability: fMRI has been utilized to examine 
the role of three major resting state networks – the central executive (CEN), salience (SN) and 
default mode (DMN) networks - in the trait ability to experience hypnosis and the hypnotic 
state(33, 34, 69). There are identified differences in fMRI functional connectivity between 
individuals who are high and low in hypnotizability involving increased connectivity of the left 
anterior aspects of the DLPFC and the dACC in high hypnotizables compared with lows during 
rest (49). The degree of pain experienced during hypnotic suggestion is positively correlated with 
L-DLPFC, dACC, and insular activation (45). Conversely, hypnotic analgesia specifically directed 
at pain affect (‘the pain will not bother you’) associated with reduced activity in the dACC (44). 
These findings also suggest that dACC deactivation during hypnosis is task dependent, with 
decrements in activation related to decreased salience of negative affect. Hypnotizability has 
been correlated with performance on conflict tasks(70) along with neural strategies of response 
to those tasks(32). 
 
Brain Activity and Functional Connectivity Associated with the Hypnotic State: During 
hypnosis and only in among high hypnotizables, there is reduced activity in the dorsal anterior 
cingulate cortex as well as increased functional connectivity between the L-DLPFC (CEN) and 
the insular cortex (SN), and reduced connectivity between the L-DLPFC (CEN) and medial frontal 
and posterior cingulate cortices (DMN). These changes in neural activity underlie the focused 
attention and enhanced somatic control that characterizes hypnosis. 
Clinical Efficacy of Hypnotic Analgesia:  In a randomized trial among 241 adults undergoing 
invasive radiological procedures involving arterial cut-downs, those who received the assistance 

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of hypnosis utilized less medication, reported less pain and anxiety, experienced fewer procedural 
complications, and were able to complete their procedures in an average of 17 minutes less time 
(71-73). Hypnosis made their experience less uncomfortable, less anxiety provoking, and shorter. 
A similar randomized clinical trial has been conducted to evaluate whether hypnotic relaxation, 
when compared to routine care, could decrease children’s distress and the ease and duration of 
performing a voiding cystourethrogram (VCUG) (74). In that study, forty-four children scheduled 
for an upcoming VCUG were randomized to receive hypnosis (n = 21) or routine care (n = 23) 
while undergoing the procedure. In 4 of 5 outcomes (parent report, observational rating of the 
child, medical staff rating of the procedure, and total procedure time), effect sizes were moderate 
to large (.56-.86). Hypnosis is effective in reducing chronic cancer pain (75, 76).  A combination 
of weekly group psychotherapy and training in self-hypnosis reduced pain by 50% with the same 
low amount of analgesic medication among 86 women (75).  
 
Role of Endogenous Opiates in Hypnotic Analgesia and DLPFC rTMS: The mechanism of 
hypnotic analgesia has been demonstrated to be independent from the endogenous opiate 
system. In this study, all 6 participants were first determined to be able to achieve hypnotic pain 
reduction. Then in double blind fashion, these participants were injected with either saline or 10 
milligrams of naloxone. There was no difference in the extent of analgesia between the conditions, 
demonstrating that blockage of endogenous opiate receptors does not interfere with hypnotic 
analgesia (77). Conversely, excitatory L-DLPFC rTMS exerts its anti-nociception effects through 
endogenous opiate pain mechanisms. Administration of naloxone pretreatment has been 
demonstrated to abolish the efficacy of rTMS anti-nociception (67). Neuroimaging has been 
utilized to confirm that the administration of naloxone does in fact block the neural elements 
involved in the anti-nociception properties of active, excitatory L-DLPFC rTMS (68). 
 
Modulation of Pain in Fibromyalgia with rTMS at dACC and DLPFC: Several groups have 
investigated the analgesic effect rTMS in FMS related pain (11). In a recent study, sixteen FMS 
patients received 20 rTMS sessions over a 4-week period. The primary outcome measure was 
the Brief Pain Inventory (BPI) item 5 rating (“average pain rating in the last 24 hours” expressed 
on a 11-point numeric rating scale with “0” being “no pain” and “10” being “worst pain imaginable”) 
measured 4 weeks after the last modulation session. It was demonstrated that there was up to an 
84% decrease in pain ratings (average decrease 31%) after active TMS when stimulating at 10 
Hz compared to a control group which was stimulated with 1 Hz. L-DLPFC rTMS can be utilized 
in the modulation of fibromyalgia(78) with improvements in measures of pain (66). In these 
studies, the stimulation parameters were 10 Hz with a pulse train duration (on time) 5 seconds, 
power (intensity) level 120% of resting motor threshold, and an inter-train interval (off time) 10 
seconds (15 second cycle time). The primary outcome measure for this study was also the Brief 
Pain Inventory (BPI) item 5 rating. Excitatory L-DLPFC rTMS was shown to demonstrate a mean 
29% (statistically significant) reduction in pain symptoms in comparison to the FMS patient’s 
baseline pain. Sham rTMS participants had a 4% non-significant change in daily pain from their 
baseline pain(66).  Inhibitory rTMS over the dACC was demonstrated to not exert a clinically 
meaningful effect on pain, suggesting that outside of hypnosis, inhibitory rTMS alone should not 
exert an independent effect on pain(11). 
Intervention Regimen: We will employ a spaced continuous theta-burst technique that is capable 
of providing a change in neural activity, which will last for the entirety of each of the participant’s 

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post-rTMS scanner sessions(27-30, 79).  
 
Name and Justification: This study will utilize two applications of 800 pulses of continuous theta-
burst stimulation at 80% of the resting motor threshold as this has been demonstrated effective 
in producing a prolonged change in cortical excitability(30) as well as safe(17). The %rMT will be 
adjust based off of skull to cortex distance as previously reported. The spaced application of theta-
burst stimulation (TBS) was chosen as the stimulation strategy because this study will require 
more than an hour of change in the targeted neural network node of interest and the spaced 
approach has been demonstrated to have a much longer duration of effect than a single 800 pulse 
cTBS stimulation session(27, 28, 30, 79). The fifteen minute spacing is essential as it has been 
demonstrated that prolonged stimulation approaches without spacing in between can cause a 
reversal of intended effect(80). The spacing has been utilized in animal models of LTP/LTD 
induction(19). 
 
Route: The spaced TBS approach will be applied to the left dorsolateral prefrontal cortex (L-
DLPFC) in the region of the L-DLPFC that has the highest functional connectivity with the dorsal 
anterior cingulate (dACC). This sub-region of the L-DLPFC will be identified by utilizing 
neuronavigation hardware and coupling this with the latest in cutting-edge rTMS targeting 
methodology(81).  
 
Dosage: 80% of the resting motor threshold adjusted to target depth will be utilized as the dose 
of cTBS because this dose has been demonstrated effective in modulating the desired cortical 
target across several studies (27, 30). 800 pulses of continuous theta-burst with 30 Hz bursts at 
6 Hz will be utilized as this is the optimal approach for producing inhibition(82). This study 
approach will utilize two stimulation trains of 800 pulses with a 15 minute spacing in between each 
train of continuous theta-burst as has been previously described(27, 30). This stimulation 
approach will be applied in between the pre- and post- rTMS scanner sessions for both scanner 
session days (total of two stimulation sessions for each participant).  
 
Known and Potential Risks: There is no known risk of seizure with the currently stated 
parameters(17, 24). In order to have a seizure from rTMS or theta-burst stimulation, one must 
receive stimulation that is at or greater than 100% of the participant’s motor threshold (24). The 
motor threshold is reflective of stimulation output necessary to cause a neuronal depolarization 
(83). Without neuronal depolarization, seizure from rTMS has not been demonstrated to occur. 
The traditional rTMS parameters have resulted in seizure because these require 120% of the 
motor threshold (84). Theta-burst stimulation has been demonstrated to modulate the brain with 
less than 100% motor threshold (17). Only one case of theta-burst stimulation has resulted in 
seizure and this case was related to using 100% resting motor threshold (24, 85). Theta-burst 
stimulation has been utilized safely in children with no incidence of seizure (21, 22) and has been 
suggested to be similar risk to single and paired pulse TMS (21), which has been rated as minimal 
risk for children (23). 
3. STUDY DESIGN 
 

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This study is a double-blind, placebo-controlled, mechanistic trial assessing active rTMS as a 
strategy for the modulation of the neural circuitry underlying hypnotizability and hypnotic analgesia 
in participants with FMS (31). We will utilize the gold standard for blinded rTMS studies which 
utilizes a double-sided active/sham rTMS coil that allows for double blinding of the treater and the 
participant (Magventure Cool-B65 A/P Butterfly Coil)(86). All 100 participants will be randomized 
to one of the two stimulation arms (sham or active rTMS) and will go through both of the hypnotic 
stroop and hypnotic analgesia scan-session days. The only difference between these two groups 
is the application of active versus sham rTMS. Otherwise, all hypnosis interventions and MRI 
scans include the same structural and functional acquisitions.  
 
Figure 2: This is a double blind, sham-controlled, counterbalanced, mechanistic trial. There will 
be 100 participants with a confirmed diagnosis of FMS recruited, enrolled, and randomized to one 
of the two arms (active or sham rTMS). The scan sessions will be counterbalanced to control for 
order effects.  
 
Primary Mechanistic Objective: To determine the effect of active, inhibitory rTMS (continuous 
theta-burst stimulation-cTBS) over left dorsolateral prefrontal cortex (L-DLPFC) on modulating the 
neural network that underlies hypnotizability and hypnosis. In other words, the Primary 
Mechanistic Outcome Measure is the change in functional connectivity between the L-DLPFC 
and the dACC in active versus sham rTMS (cTBS), and the associated effect of inhibition of 
activity in the L-DLPFC on activity in the dACC.  
 
Primary Mechanistic Hypothesis: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate 
the neural network that underlies hypnotizability by producing greater increases in functional 
connectivity between L-DLPFC and dACC as compared to sham rTMS (sham cTBS). We 
hypothesize that active, inhibitory rTMS (continuous theta-burst stimulation) will produce 
increases in functional connectivity between the L-DLPFC and the dACC(47), producing a 
transient neural phenotype(30) which appears on neuroimaging like a high hypnotizable(31).  
This increase in functional connectivity, coupled with inhibition of activity in the L-DLPFC, 
would be hypothesized to reduce activity in the dACC as well, which is what we have shown to 
be associated with entry into the hypnotic state.  Thus rTMS induced increase in functional 
Recruitment/Screening of Fibromyalgia Subjects (Visit #1)
(n=100)
Active rTMS Group (n=50)
Randomization
(n=25)
Hypnotic Stroop Session (Visit #3)
Counterbalancing
Sham rTMS Group (n=50)
Counterbalancing
TMS Target MRI Visit (Visit #2)
Hypnotic Analgesia Session (Visit #4)
MRI #1
rTMS
MRI #2
MRI #1
rTMS
MRI #2
(n=25)
Hypnotic Analgesia Session (Visit #3)
Hypnotic Stroop Session (Visit #4)
MRI #1
rTMS
MRI #2
MRI #1
rTMS
MRI #2
(n=25)
Hypnotic Stroop Session (Visit #3)
Hypnotic Analgesia Session (Visit #4)
MRI #1
rTMS
MRI #2
MRI #1
rTMS
MRI #2
(n=25)
Hypnotic Analgesia Session (Visit #3)
Hypnotic Stroop Session (Visit #4)
MRI #1
rTMS
MRI #2
MRI #1
rTMS
MRI #2

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connectivity should increase hypnotizability and, coupled with inhibited activity, enhance hypnotic 
intensity as well. 
 
Relevant Clinical Objective: To determine the effect of active, inhibitory rTMS (cTBS) over L-
DLPFC on enhancing HA. 
 
Relevant Clinical Hypothesis: Active, inhibitory rTMS (cTBS) over L-DLPFC will enhance HA 
as compared to sham rTMS (sham cTBS). 
 
Secondary Objectives 
Secondary Objective A: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on modulating the neural network that underlies hypnotic intensity. 
Secondary Hypothesis A: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies hypnotic intensity by producing reduced activity in the dACC, increased 
functional connectivity between the L-DLPFC (CEN) and the insula (SN), and reduced 
connectivity between the L-DLPFC (CEN) and the posterior cingulate cortex (DMN) as compared 
to sham rTMS (sham cTBS) as measured by BOLD, interleaved TMS-BOLD, and functional 
connectivity MRI. 
 
Secondary Objective B: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on enhancing hypnotizability (as measured by the Hypnotic Induction Profile-HIP and Stroop 
Task) and hypnotic intensity (as measured by the Hypnotic Intensity Scale-HIS). 
Secondary Hypothesis B: Active, inhibitory rTMS (cTBS) over L-DLPFC will increase the HIP 
and HIS scores as well as Stroop Effect as compared to sham rTMS (sham cTBS). 
 
Secondary Objective C: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network underlying the conflict regulation system as a reflection of effective 
modulation of the neural circuitry underlying hypnotizability.  
Secondary Hypothesis C: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies conflict regulation by producing greater increases in functional connectivity 
between the right inferior frontal gyrus (rIFG) and the default mode network (DMN) as compared 
to sham rTMS (sham cTBS). 
 
Secondary Objective D: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network underlying post-hypnotic Stroop Effect. 
Secondary Hypothesis D: Post-hypnotic instruction of word blindness after active, inhibitory 
rTMS (cTBS) over L-DLPFC will reduce dACC activity during the Stroop task (similar to high 
hypnotizables) as compared to sham rTMS (sham cTBS). 
 
Secondary Objective E: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on modulating the neural network that underlies hypnotic analgesia (HA). 

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Secondary Hypothesis E: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies HA by producing a decrease in activity and an increase functional 
connectivity among the anterior cingulate, dorsolateral, insular, and somatosensory cortices 
(hypnotic analgesia network) as compared to sham rTMS (sham cTBS). 
Study Population: This study will enroll female and male participants between 18-65 years-old 
with a confirmed diagnosis of FMS(1), low-moderate hypnotizability (HIP=0-8)(87), the ability to 
safely receive rTMS(88) and MRI(89), as well as the willingness to participate in two scanner 
session days and receive rTMS stimulation during both of those days. 
 
Groups/Arms: There will be two arms, active versus sham rTMS (cTBS) over L-DLPFC. The 
participants, other interventions, and assessments are otherwise identical. In order to preserve 
the blinding, the active rTMS group will be receive active rTMS (cTBS) for both scanner session 
days and the sham rTMS group will receive sham rTMS (cTBS) on both the scanner session 
days(86).  
 
Racial Categories 
 
Not 
Hispanic or Latino Hispanic or Latino  
Female 
Male 
Female 
Male 
Total 
American Indian/ Alaskan Native 
0 
0 
0 
0 
0 
Asian 
10 
2 
0 
0 
12 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
5 
1 
0 
0 
6 
White 
60 
7 
4 
1 
67 
More than one race 
4 
1 
0 
0 
5 
Total 
74 
11 
4 
1 
100 
Table 1: This table describes the breakdown of gender and race across the study. 
 
Study Locations:  
 

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1. Central Laboratory-The Center on Stress and Health: The center provides the office space 
and infrastructure for the personnel and effort necessary for this trial. The Department of 
Psychiatry and Behavioral Sciences has seminar and conference room space that will be utilized 
for the grant-related meetings, training, and consultations. The lab has desktop computers 
equipped with cloud backup and security access control. A laptop computer and a portable LCD 
projector will be made available for presentations and training purposes. The computers are also 
equipped with licensed software packages including SPSS, Antivirus, and Microsoft Office. 
2. The Stanford Center for Cognitive and Neurobiological Imaging: The Stanford Center for 
Cognitive and Neurobiological Imaging (CNI) has been designed to reflect experimental needs in 
the social sciences disciplines. The core instrumentation provided by the CNI is a research-
dedicated 3T MRI scanner, a GE Discovery MR750 that will be used with a Nova Medical 32-
channel head coil. Improvements in fMRI technology are implemented from time to time at major 
academic research environments. Fidelity to sequences used at the beginning of the study will be 
maintained to ensure that changes in signal-to-noise ratio (SNR) do not take place during the 
course of the study.  
 
Duration of Enrollment Period and Follow-up: Given that this is a mechanistic trial, there is no 
follow-up period beyond the two scan sessions. The period of enrollment will be dependent upon 
the availability of the participant and the facility scheduling availability to complete the screening 
visits and the scan sessions. The entire trial is estimated to take approximately 3 years of data 
collection with an additional year of analysis.  
 
TMS System: The Magventure MagPro System is a computerized electromechanical instrument 
that produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce 
electrical currents in localized regions of the cerebral cortex. The Magventure MagPro System 
has been FDA-cleared for use in adult subjects. There is a clinical research option for the 
Magventure MagPro System that provides features necessary to conduct randomized sham-
controlled trials and other TMS research.  
 
The Magventure MagPro System consists of the following equipment and software: 
 
 
System Software 
 
TMS Data Management System software 
 
Stimulation Coils included is a coil with two sides: 
o A blinded sham side (acoustically matched to protect the integrity of the blind) 
o A blinded active side. 
 
TMS Administration: The TMS stimulator (MagPro, Medtronic Functional Diagnostics, 
Skovlunde, Denmark) will be used to generate repetitive biphasic magnetic pulses. Both 

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stimulation groups (active and sham rTMS) will receive simulation from a specially designed coil, 
the Cool-B65 AP Butterfly coil (Magventure Magpro; Farum, Denmark), which is capable of 
delivering stimulation is a double-blind fashion. A manual of rTMS administration procedures is 
included with this protocol and is titled Appendix 2 and 3. 
 
Motor Threshold (MT) Elicitation: Given that accurate elicitation of the motor threshold is crucial 
in establishing a safe and accurate dose of TBS stimulation, the MT will be elicited by two separate 
TMS operators. Each operator will stimulate the hand representation within the left motor cortex 
with single pulses to determine the individual motor threshold by corresponding muscle twitching 
of the subject’s relaxed abductor pollicis brevis (APB). We will utilize the PEST procedure for this 
part of the MT assessment (90). The lower of the two elicited MT numbers will be chosen as the 
MT for that participant. The first MT elicitation will be performed prior to the pre-TMS scan session 
and the second will be performed after the pre-TMS scan session and before the rTMS (cTBS) 
application. There will be a separate TMS operator for each of these elicitations. We will utilize an 
electromyography (EMG) instrument for the first MT elicitation and visual inspection for the 
second elicitation. These methods have been demonstrated to be very closely correlated with 
each other (91). The MT will be elicited using the same coil (C-B60 Butterfly Coil) for both 
measurements. The C-B60 coil is designed with the exact same windings as the TBS stimulation 
coil (Cool B70 A/P Butterfly coil).  
 
Continuous TBS Session: The continuous TBS will be applied using the Cool-B65 A/P coil which 
has a built in sham system. The Cool-B65 A/P coil is capable of delivering either active or sham 
rTMS in a manner that is randomized by the system itself and therefore blinded to the treater. The 
sham setting on this coil looks and sounds similar to the active setting, but has a hidden aluminum 
plate blocking actual stimulation. The Magventure device holds a blinded key code that is kept by 
the unblinded CRC. The operator is instructed to flip the coil to correspond with the key code, but 
does not know the stimulation group (active versus sham). 
 
Stimulation Dose: This study utilizes two applications of 800 pulses of continuous TBS at 80% of 
the resting motor threshold as this has been demonstrated effective in producing a prolonged 
change in cortical excitability (30) as well as being demonstrated as safe(17). We will adjust the 
dose based off of the difference between motor cortex to skull and prefrontal cortex to skull 
measurements as has been previously reported(92). The spaced application of theta-burst 
stimulation (TBS) approach was chosen because this study will require more than an hour of 
modulation of the target in order to complete the scan sessions. The spaced approach has been 
demonstrated to have a much longer duration of effect than a single 800-pulse cTBS stimulation 
session(27, 28, 30, 79). The fifteen minute spacing between the two 800-pulse cTBS applications 
is essential because it has been demonstrated that prolonged stimulation approaches without 
spacing in between can cause a reversal of intended effect(80). 
 
Stimulation Site: The spaced cTBS approach utilized for this study will be applied to the left 
dorsolateral prefrontal cortex (L-DLPFC) in the sub-region that has the highest functional 
connectivity with the dorsal anterior cingulate (dACC). This will be done through the use of 
neuronavigation hardware coupled with the latest in cutting edge targeting(81). This study will 

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utilize a combined structural and functional targeting approach because the area of the L-DLPFC 
that is being targeted to modulate is the area that has the highest connectivity with the dACC. It 
has been demonstrated previously that such an approach can be applied within the L-DLPFC(58). 
Once the pre-TMS scan session is complete, the images will be exported to the Localite 
Neuronavigation System (93) so that while the participant is undergoing their motor threshold 
(MT) elicitation and the neuronavigation targeting is occurring such that the participant’s target 
and dose will be completed in time for the rTMS (cTBS) session. 
 
Stimulation Parameters: 80% of the resting motor threshold (rMT) was chosen as the dose of 
cTBS as this dose has been demonstrated to be optimal in suppressing the MEP. We will adjust 
the skull-prefrontal cortex distance to account for any differences in differential volume loss. We 
will utilize 800 pulses of continuous theta-burst (cTBS) with 30 Hz bursts at 6Hz as this has been 
demonstrated to be optimal in suppressing the MEP(82). We will apply two stimulation trains of 
800 pulses with a 15-minute space in between each train of cTBS as has been previously 
described(27, 30). This stimulation session will be performed in between the pre- and post- TMS 
scanner sessions for both scanner session days (total of two stimulation sessions for each 
participant). The participant will receive cTBS stimulation in the manner described in the manual 
that is attached to the appendix of this protocol. The handle of the coil will be pointed backwards 
(45° angle to the sagittal line) and will be fixated in an arm. In order to preserve the blind, the 
participant will be randomized to the same rTMS (cTBS) condition for both scanner days(86). 
 
Hypnosis Intervention: Hypnosis will be induced while the subject is in the scanner though the 
use of headphones and a pre-recorded induction script. Hypnotic instructions will be standardized, 
and will involve a simple induction instruction that has been used in prior research on the brain 
signature of the hypnotic state (48) as well as in clinical care (94). The instruction includes being 
asked to:  “Look up and close your eyes, take a deep breath, let the breath out, let your eyes 
relax, and let your body float, as though you were in a bath, a lake, a hot tub, or floating in space. 
With your eyes closed and remaining in this state of concentration, enjoy this state of floating 
relaxation and allow yourself to feel it more and more intensely.” The ability to enter and maintain 
the hypnotic state through such an induction mechanism in the fMRI environment has been 
previously demonstrated in by Oakley, who compared induction using these means in the MRI 
environment with hypnotic induction “off-line” (95). An extended description of the hypnosis 
protocol is attached in Appendix 4 (describing hypnotic induction, Hypnotic Induction Profile (HIP), 
and hypnotic analgesia script). 
 
Randomization and Blinding: Both active and sham rTMS groups will receive simulation from 
a specially designed coil called the Cool-B65 AP Butterfly coil (Magventure Magpro; Farum, 
Denmark). This coil is capable of delivering either active or sham rTMS (cTBS) in a manner that 
is randomized by the system itself and therefore blinded to the treater. The sham setting on this 
coil looks and sounds similar to the active setting, but has a hidden aluminum plate blocking actual 
stimulation. The Magventure TMS device holds a blinded key code that is kept by the individual 
that holds the blind. During the rTMS setup, the operator is instructed to flip the coil to correspond 
with the key code, but is unclear as to the active versus sham stimulation group. 
 

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Centralization: Evaluations will be centralized in the Center on Stress and Health, which is 
directed by David Spiegel, MD. The Center on Stress and Health has sufficient office space and 
infrastructure within the Department of Psychiatry and Behavioral Sciences to house the study 
staff for this study. The Department of Psychiatry and Behavioral Sciences has seminar and 
conference room space that would be utilized for the grant-related meetings, training, and 
consultations. The lab has desktop computers equipped with cloud backup and security access 
control. A laptop computer and a portable LCD projector are available for presentations and 
training purposes. The computers are also equipped with licensed software packages including 
SPSS, Antivirus, and Microsoft Office. 
 
 
 

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4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
 
4.1 
Inclusion Criteria 
 
Participants must meet all of the inclusion criteria to participate in this study. 
 
Inclusion Criteria Include: 
1. Fulfill 2010 Fibromyalgia Diagnostic Criteria(1) 
2. Age 18-70 years old 
3. Right-handed(96) 
4. Agree to and able to have at least three fMRI scan sessions as well as rTMS(97) 
sessions 
5. Willingness to suspend use of analgesic drugs or cough suppressants for 24 
hours prior to the scans 
6. Willingness to suspend use of antidepressant drugs for 2 weeks prior to the 
scans (6 weeks for fluoxetine) 
7. Proficiency in English sufficient to complete questionnaires / follow instructions 
during fMRI assessments 
8. US Citizen or resident able to receive payment legally 
9.   Low-Moderate Hypnotizability in the Hypnotic Induction Profile (score of 0-8)(98) 
10. Normal color vision 
11. Not pregnant and if participant is of childbearing potential, must agree to use 
adequate contraception prior to study and for the duration of study participation. 
We will enroll 18-70 year old right-handed(96)*, male and female participants with a confirmed 
diagnosis of Fibromyalgia Syndrome (FMS)(1), low-moderate hypnotizability (a HIP score from 0-
8)(98), no contraindications to rTMS(97) or MRI(89) and no other disease causing pain.  
*Right-hand dominant ambidextrous participants are included. 
Required Diagnostics: Individuals will meet gold-standard criteria for FMS. The confirmation of 
diagnosis involves meeting the gold-standard criteria for the diagnosis of FMS, the American 
College of Rheumatology Preliminary Diagnostic Criteria for Fibromyalgia(1). Participants will 
meet criteria within 2 months prior to the date of first scanning session. Individuals will have a 
normal CBC and inflammatory panel. Participants will have to have labs drawn within 1 year. 
 
Prior Therapy: Participants cannot be taking psychoactive medications (antidepressants, 
opiates) during the rTMS sessions due to increased risk of seizure(99) and/or manipulation of the 
participant’s cortical excitability(100). We will not require participants to have taken any prior 
medications/therapies for FMS to be included in this study. Participants will have to have the 
ability to understand study procedures and to comply with them for the entire length of the study. 

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Participants cannot have been exposed to TMS in any way prior to enrolling in this study because 
it will affect blinding(86). 
4.2 
Exclusion Criteria 
 
All candidates meeting any of the exclusion criteria at baseline will be excluded from 
study participation.  
 
Exclusion Criteria Include: 
1.  A medical condition that would contraindicate the use of rTMS (101) 
2.  Metal implants that would contraindicate MRI (like ferromagnetic metal in their    
body) or contraindicate rTMS (metal in or near the head) (101) 
3.  Pregnancy (99) 
4. Any significant neurologic disease, including dementia, Parkinson's or 
Huntington’s disease, brain tumor, seizure disorder, subdural hematoma, multiple 
sclerosis, history of significant head trauma (101) 
5.  Current use of an antidepressant medication for depression(102) 
6.   Previous exposure to any rTMS approach (86) 
7.   High Hypnotizability in the Hypnotic Induction Profile (score of 9-10)(98) 
8.   High risk for opiate withdrawal due to excessive use as determined on the 
Opiate Risk Tool if the participant is already on opiates (103). 
 
Participant cannot be diagnosed with any condition expected to change their morbidity or mortality 
within 6 months of the start of the study such that appropriate diagnosis, treatment, or follow-up 
for the trial will be affected. Participants with known malignancy will be excluded from this study 
if the malignancy is causing pain that will interfere with the study or if there is any known/potential 
neurological involvement. All drug and alcohol dependence will be excluded from this study 
except nicotine dependence will be allowed. Inability or unwillingness of individual to give written 
informed consent will exclude that individual from participating. 
 
The effects of rTMS on the developing human fetus are unknown(104). We will not be enrolling 
pregnant women to this study. Women of childbearing potential must agree to use adequate 
contraception (hormonal / barrier method of birth control or abstinence) prior to study entry and 
for the duration of study participation.  Females of childbearing-age, will have a pregnancy test 
prior to receiving each rTMS stimulation session.  Should a woman become pregnant or suspects 
she is pregnant while participating in this study, she should inform study staff. 
 
Taking psychoactive medication during the rTMS portion of the study is contraindicated due to 
potential for increase of seizure risk(99) and change in cortical excitability(100). Participants 
taking antidepressants for depression will be excluded. Participants taking antidepressant 
medication for FMS will be offered the option of a wash-out (2 weeks prior to first scan session 
except fluoxetine is 5 weeks due to the half-lives of these medications). Patients taking 

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antidepressants at the time of consent will be excluded from the study. No investigational 
treatments will be allowed during this study. 
4.3 
Study Enrollment Procedures  
 
 
This study will recruit 100 individuals assuming about 20% missing data due to unusable imaging 
data and dropouts as has been previously demonstrated (34). The ability to be hypnotized is a 
stable and measurable trait that can be pre-screened and quantified(94, 105, 106). A member of 
the study team that has been trained by Dr. Spiegel will select subjects prior to randomization 
according to their ability to be hypnotized prior to the MRI visits using the Hypnotic Induction 
Profile (HIP). Hypnotizability is correlated about 0.6 with the ability to experience hypnotic pain 
relief (107). Participants will be selected those with low-moderate hypnotizability (scores of 0-8 
on the HIP from a range 0-10) (94) in order to prevent a ceiling effect (see Appendix IV for the 
manual describing the HIP). IRB approval has been obtained to request that treating doctors at 
Stanford Hospital and Clinics send an invitation to patients they are seeing with Fibromyalgia 
Syndrome to participate in the study. Recruitment efforts will concentrate on physicians at the 
Stanford Center for Integrative Medicine, the Stanford Pain Clinic, the Stanford General 
Neurology Clinic, the Stanford Immunology and Rheumatology Clinic and the Stanford Chronic 
Fatigue Clinic. 
 
The NCCIH Site Screening and Enrollment Log will be utilized to record the consent and screening 
of all subjects and the outcome of each screening. This log will provide a comprehensive list of 
all subjects who were screened for eligibility if the information is not maintained electronically. 
Subjects will be recorded as they are consented, to ensure completeness and accuracy of the 
data. All subjects will be included who were consented and screened, including screen failures. 
This log will not contain identifying information. Subjects will be tracked separately on logs in a 
coded list with a key. Each page will be numbered and maintained in this log in the Essential 
Documents Binder, behind the Screening/Enrollment Log tab. Pages will be stored in reverse 
chronological order, with the newest pages of the log placed at the front of the section. At the 
conclusion of the study, the final page of the log will be identified by checking the box in the footer. 
 
The participant will be consented in the sequence defined by the NCCIH. The consent process 
will start with an introductory paragraph that describes the study. This will be followed by a 
description of the purpose of the research. Next, the procedures will be described and the time 
duration of these procedures and as well as the total study duration. The participant will be notified 
of the discomforts and risks along with the potential benefits of participation in this study. The 
participant will then receive a statement of confidentiality. The participant will be notified that there 
are no costs for participation in this study as well as being notified that there is compensation for 
participation in the study. The participant will be made aware of the research funding source. The 
participant will be given information regarding the fact that their participation is voluntary. The 
participant will then be given the contact information for questions or concerns. Finally, the 
participant will be asked for their signature in order to consent and give permission to be in the 
research study. 

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The consent includes a statement that involves a description of the research. The consent 
includes an explanation of the purposes of the research. The expected duration of the individual’s 
participation is listed in the text of the consent. A description of the procedures to be followed is 
also included in the text of the consent. Identification of the experimental procedures is listed in 
the consent. A description of any reasonably foreseeable risks or discomforts to the participant is 
stated in the consent. A description of the benefits to the participant or to others, which may be 
reasonably expected from the research study is listed in the consent. A disclosure of appropriate 
alternative procedures or courses of treatment if any that might be advantageous to the patient is 
listed in the consent. A statement describing the extent, if any, to which confidentiality of records 
identifying the patient will be maintained is listed in the consent. An explanation of who to contact 
for answers to pertinent questions about the research and participant’s rights and whom to contact 
in the event of a research related injury to the participant is listed in the consent. A statement that 
the research is voluntary, refusal to participate will involve no penalty or loss of benefits to which 
the individual is otherwise entitled and the individual may discontinue participation at any time 
without penalty or loss of benefits, to which he/she is otherwise entitled is listed. A description of 
the clinical trial will be made available on www.ClinicalTrials.gov as required by US Law. The 
participants will be made aware of this and that this listing will not in any way identify them.  

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5. STUDY INTERVENTIONS  
 
5.1 
Interventions, Administration, and Duration  
 
The transcranial magnetic stimulation (TMS) device (MagPro, Medtronic Functional Diagnostics, 
Skovlunde, Denmark) utilized is a computerized electromechanical instrument that produces and 
delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce electrical currents in 
localized regions of the cerebral cortex. Since the TMS device produces a time varying magnetic 
field, its intended effect derives fundamentally from Faraday’s Law, which asserts that a time-
varying magnetic field produces an electrical current in an adjacent conductive substance. During 
TMS application, the conductive substance of interest is the brain, in particular the region of the 
cortex that lies beneath the stimulation coil. 
 
The electric current induced in the targeted region of the cortex travels in a path orthogonal to the 
direction of the alternating magnetic field with the point of maximum field strength and greatest 
current located directly beneath the center of the coil, which is the component that rests against 
the patient’s head and transmits magnetic pulses to the patient’s brain. The induced current is 
tangential to the scalp at the cortical surface, and diminishes in magnitude with increasing depth. 
In the area of the motor cortex targeted for motor threshold acquisition, where field strength 
achieves the stimulation threshold, it is postulated that neuronal depolarization occurs. The peak 
magnetic field strength achieved with each pulse is approximately 0.5 Tesla. 
 
Although the mechanism of action is unknown, it is hypothesized that a TMS device causes direct 
neuronal modulation in brain regions immediately adjacent to the magnetic coil, and also results 
in changes in functional activity and connectivity in areas of the brain that are synaptically 
connected to the brain regions experiencing direct neuronal modulation. It is thought that these 
actions may cause various physiologic changes in the brain. TMS is a technique capable of 
modulating targeted cognitive processes (108, 109). TMS has previously been demonstrated to 
enhance hypnotizability (26). Traditional rTMS has limited duration of after-effects (26, 110). A 
new stimulation approach termed continuous theta-burst stimulation (17) has been demonstrated 
to have an extended duration of after-effects, particularly if administered in a patterned, spaced 
paradigm (27-30, 79).  
 
Administration: The TMS stimulator (MagPro, Medtronic Functional Diagnostics, Skovlunde, 
Denmark) will be used to generate repetitive biphasic magnetic pulses. Magnetic pulses will be 
delivered with a figure-eight-coil (Cool-B65 A/PCoil). The L-DLPFC will be localized according to 
previously described procedures where combined functional and structural imaging is utilized to 
find the area of greatest connectivity with dACC (81). The participant will receive stimulation over 
the left motor cortex with single pulses in order to determine that individual’s motor threshold 
through measurement of the corresponding muscle twitching of the subject’s relaxed abductor 
pollicis brevis as measured by electromyography (EMG) once and visual inspection once (91). 
The PEST procedure will be utilized during the MT acquisition portions of the study (90). Once 
the MT has been determined, the coil will be moved to the neuronavigated L-DLPFC target(81). 
The handle of the coil will be pointed backwards (45° angle to the sagittal line) and will be fixed 
to the stimulation arm (30).  

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Dosing Schedule: A spaced theta-burst technique will be employed that will modulate the neural 
network node in targeted neural network for the entirety of the scanning session (27-30, 79). Theta 
burst TMS will be applied over the left dorsolateral prefrontal cortex (L-DLPFC). Two applications 
of 800 pulses of continuous theta-burst stimulation at 80% of the resting motor threshold will be 
utilized as this has been demonstrated effective in producing several hours of change in cortical 
excitability (30) and safe (17). The decision to choose a 15-minute interval is based on the results 
of the several human experiments using this spaced approach(29, 30) and on long-term 
depression (LTD) protocols used in animals, where it has been demonstrated that cTBS trains 
spaced in the order of 10-15 minute intervals generate more persistent LTD (111). 
 
Potential Adverse Events: Repetitive transcranial magnetic stimulation (rTMS) is generally 
regarded as safe and without any serious or lasting adverse effects (99, 112). A newer form of 
rTMS, termed continuous theta-burst stimulation (cTBS), is an even safer intervention and is 
suggested to be minimal risk in children (21-23). Inadvertent induction of a seizure is the most 
medically significant, potential safety concern. Seizure has only been observed once with cTBS 
and only in exceedingly high stimulation settings (24, 85). Furthermore, with the adoption and 
widespread use of recommendations delineating a safe margin for TMS dosing parameters as 
disseminated in the 1998 TMS consensus safety guideline from the National Institute of 
Neurological Disorders and Stroke (NINDS), the risk for seizures during rTMS in general is 
significantly mitigated. This study will comply with NINDS guideline standards for transcranial 
magnetic stimulation (TMS) (99, 112). It is important to note that there is no evidence in the 
literature to indicate that a single seizure during TMS makes subsequent seizures more likely in 
an otherwise non-seizure-prone individual. There are potential consequences of a seizure, 
regarding employment or insurability in the future. If a subject does experience a seizure related 
to this investigation, a letter from the PI will note that the seizure was produced under experimental 
conditions, and there is no reason to expect another seizure in the future.  
 
There is no known risk of seizure with the currently stated parameters (17, 24). In order to have 
a seizure from inhibitory rTMS (cTBS), one must receive stimulation that is at or greater than 
100% of the participant’s motor threshold (MT) (24). The MT is reflective of stimulation output 
necessary to cause a neuronal depolarization (83). Without neuronal depolarization, seizure from 
rTMS has not been demonstrated to occur. The traditional rTMS parameters have resulted in 
seizure because these require 120% of the MT (84). cTBS has been demonstrated to modulate 
the brain with less than 100% motor threshold (17). Only one case of cTBS has resulted in seizure 
and this case was related to using 100% MT (24, 85). cTBS has been utilized safely in children 
with no incidence of seizure (21, 22) and has been suggested to be similar risk to single and 
paired pulse TMS (21), which has been rated as minimal risk for children (23). Inhibitory rTMS 
(cTBS) will be administered in the Stanford Center for Cognitive and Neurobiological Imaging and 
outside the scanner. Benzodiazepines will be on hand in the event of seizure and the participant 
will be immediately transferred to the Emergency Room. Because of the fixed nature of the 
stimulation dose, there will be no modification to the stimulation parameters. The dose of inhibitory 
rTMS (cTBS) is personalized for each participant through the use of resting motor threshold 
acquisition (90). 

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Hearing Risk: There is the potential risk of alteration in auditory threshold secondary to exposure 
to rTMS. As a result of the rapid changes in the magnetic field during rTMS administration, the 
coil produces an audible, high-energy clicking sound, which may be associated with temporary 
increases in auditory threshold. During previous studies with the rTMS approaches, all subjects 
were required to use hearing protection at a protection rating of ≥30 db. No change in hearing 
was found with air conduction threshold testing in the two randomized clinical studies when this 
method of ear protection was used. All participants will be asked to use earplugs for this study. 
 
Other side effects of TMS: Prophylactic use of acetaminophen or ibuprofen will be allowed for 
subjects reporting sensations at or near the stimulation site, which are uncomfortable or painful. 
Participants reporting headaches during or following study stimulation session will be encouraged 
to take acetaminophen or ibuprofen prior to the stimulation session. All subjects will be monitored, 
and appropriate treatment will be recommended including the possibility of discontinuing the next 
scanner day. Any other potential side effects will be managed symptomatically with treatment(s) 
deemed appropriate by the study site Principal Investigator. All symptomatic interventions will be 
recorded in the subject’s case file and, if applicable, adverse event CRF. 
 
 
5.2 
Handling of Study Interventions  
 
 
Manual of Procedures for Theta-Burst Stimulation: Appendix 2  
 
 
Mechanism for Blinding rTMS: Appendix 3  
 
 
Manual of Procedures for Hypnotic Stroop and Hypnotic Analgesia: Appendix 4  
 
 

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5.3 
Concomitant Interventions  
 
 5.3.1 Allowed Interventions 
 
Zaleplon, zolpidem, or zopiclone (1 dose) as needed for significant insomnia during the night prior 
to the scanner sessions or lorazepam (up to 2 mg) for significant anxiety during the day and night 
prior to the scanner sessions. These medications may be administered up to the night prior to the 
stimulation session (until 8:00 PM), but not during the morning of the sessions or at any time 
during the scanning day (100). The use of alternative hypnotics or anxiolytic compounds requires 
prior approval from the PIs. Hormonal contraceptives are allowed if the subject has been on a 
stable dose for at least 3 months. Short-term treatments for headaches, allergies, colds, and flu 
symptoms will be allowed during the study provided the medications utilized have no established 
psychotropic effects that would be expected to confound interpretation of study outcome 
measures. These medications may include non-sedating, over-the-counter, or prescription 
antihistamines, analgesics and decongestants. 
  
5.3.2 Required Interventions 
 
There are no required interventions. 
 
5.3.3 Prohibited Interventions 
 
Any medication administered for the treatment of any psychiatric or neurologic disorder or any 
other known CNS active drugs, including herbal, over-the-counter, and homeopathic medications, 
MAOIs, other antidepressants, antipsychotics, stimulants, opiates, pain medications, and mood 
stabilizers are prohibited during the day prior to and day of the scanner sessions. Use of zaleplon, 
zolpidem, zopiclone or lorazepam too close to the time of stimulation or beginning a new regimen 
of hormonal contraception may lead to excluding the subject from the study. 
 
5.4 
Adherence Assessment  
 
Because this is a mechanistic trial involving a screening visit and three mandatory scanner visits, 
adherence will be determined by whether or not the participant arrives to his/her scanner 
sessions. We will make every effort that every participant completes this protocol and given the 
limited time commitment, it is likely we will have good study adherence.  
 
 

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6. STUDY PROCEDURES  
 
6.1 
Schedule of Evaluations 
 
Assessment 
Redcap Screening: 
Online  
 
Baseline, Enrollment, 
Randomization: Visit 
1 (Day 0) 
TMS Target  
Scan Day 
Hypnotic Stroop 
Scan Day 
Hypnotic Analgesia 
Scan Day 
Online Consent 
X 
 
 
 
 
Informed Consent 
Form 1 (Screening)  
 
X 
 
 
 
Demographics 
X 
 
 
 
 
Screening Forms 
X 
X 
X 
X 
X 
Medical History  
X 
X 
 
 
 
Current 
Medications  
X 
X 
 
X 
X 
Informed Consent 
2 (Full) 
 
X 
 
  
 
Blood Chemistries 
 
X 
 
 
 
Urine Analysis 
 
 
 
X 
X 
Inclusion/Exclusion 
Criteria  
X 
X 
 
 
 
Enrollment/ 
Randomization 
 
X 
 
 
 
Stimulation Log 
 
 
 
X 
X 
Concomitant 
Medications 
 
X 
 
X 
X 
Adverse Events  
 
X 
X 
X 
X 
HIP/SOARS 
 
X 
 
X 
X 
HIS 
 
 
 
X 
X 
Pain Induction  
 
 
 
 
X 
Stroop Task  
 
 
 
X 
 
 
Table 2: The table includes the schedule for all of the assessments.

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6.2 
Description of Evaluations  
 
6.2.1 Screening Evaluation 
 
Consenting Procedure 
 
Consenting Processes: There will be three consent processes: one online screening process 
for absolute contraindications, one consent process for in-person screening, and the other for 
study procedures. For the first in-person consent process, the clinical research coordinator (CRC) 
will screen the participant’s eligibility for participation in the study. Dr. David Spiegel or Dr. Nolan 
Williams will consent the participants for the second in-person phase of the consenting process, 
which involves discussing the risk of the rTMS procedure and MRI scanning. The participant will 
be consented in the sequence that has been defined by the NCCIH. 
 
Education and Informed Consent Process: The consent process will start with an introductory 
paragraph that describes the study. This statement will be followed by a description of the purpose 
of the research. Next, the procedures will be described and the time duration of the procedures 
and study. The participant will be notified of the discomforts and risks along with the potential 
benefits. The participant will receive a Statement of Confidentiality. The participant will be notified 
as to the costs for participation (none) as well as the compensation for participation. The 
participant will be made aware of the research funding source. The participant will be given 
information regarding the fact that their participation is voluntary. The participant will then be given 
the contact information for questions or concerns. Finally, the participant will be asked for their 
signature in order to consent and give permission to be in the research study.  
 
Plan for Review of Consent Document: The signed consent document will be confirmed by Dr. 
Spiegel or Dr. Williams and will be rechecked by the CRC assigned to this study.  
 
Documentation of Signed Consent: The NCCIH Site Screening and Enrollment Log will be 
utilized to record the consent and screening of all subjects and the outcome of each screening. 
This log will provide a comprehensive list of all subjects who were screened for eligibility and this 
information will be maintained electronically in REDCAP. Subjects will be recorded as they are 
consented in order to ensure completeness and accuracy of the data. All subjects who were 
consented and screened will be included in this long, including screen failures. This log will not 
contain identifying information. Subjects will be tracked separately on logs in a coded list with a 
key. Each page will be numbered and maintained in this log in the Essential Documents Binder, 
behind the Screening/Enrollment Log tab. Pages will be stored in reverse chronological order, 
with the newest pages of the log placed at the front of the section. At the conclusion of the study, 
the final page of the log will be identified by checking the box in the footer. 

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Screening Visit 
 
During screening, participants will be screened using the following: 
 
Hypnotic Induction Profile (HIP): This is a clinician-administered instrument. Will allow for 
assessment of level of hypnotizability(113). Those individuals with a score of 0-8 (low-moderately 
hypnotizable) on the HIP will be selected in order to prevent a potential ceiling effect(26). HIP will 
be assessed twice during the in-person screening visit. 
 
2010 Fibromyalgia Diagnostic Criteria: This is a clinician-administered instrument. Participants 
must fulfill diagnostic criteria for FMS(1). This gold-standard assessment will be utilized to 
ascertain that the participant does in fact meet standardized criteria for FMS. It is important to 
establish the formal FMS diagnosis to have a homogenous group of participants. 
 
Massachusetts General Hospital (MGH) Antidepressant Treatment Response Questionnaire 
(ATRQ): This is a clinician-administered instrument. Participants taking SSRIs will be asked if 
they are willing to discontinue(114). Participants actively taking antidepressants will be offered a 
wash-out or excluded for theoretical seizure risk(102). This form is an established tool that allows 
for the assessment of past and current antidepressant use in depression and pain(114). 
 
The Mini-International Neuropsychiatric Interview (M.I.N.I): The MINI is a short structured 
diagnostic interview, developed jointly by psychiatrists and clinicians for Diagnostic and Statistical 
Manual of Mental Disorders-IV (DSM-IV) and International Classification of Diseases (ICD) 10th 
revision psychiatric disorders. The M.I.N.I. was designed to meet the need for a short but accurate 
structured psychiatric interview for multicenter clinical trials and epidemiology studies and to be 
used as a first step in outcome tracking in non-research clinical settings(115).  
 
Transcranial Magnetic Stimulation Adult Safety Screen (TASS): This is a participant self-report 
instrument. Participants will fill out a TASS questionnaire to determine risk of seizure related to 
rTMS(88). Any identified seizure risk will disqualify the participant. This assessment is utilized in 
order to minimize the risk of seizure induction with rTMS. 
 
MRI Safety Screening Form: This is a participant self-report instrument. Participant will fill out a 
MRI Safety Screening Form to determine if the participant is safe to receive an MRI. We will utilize 
this screening tool to make sure that the participant has no contraindications for MRI that would 
exclude the participant from participating(89). 
 
Edinburgh Handedness Inventory: This is a clinician-administered instrument. Participants must 
be right-handed to participate in this study(96). It is standard to restrict rTMS studies to right-
handed individuals only due to variability in hemispheric dominance of left-handed individuals.  
 
The Opioid Risk Tool (ORT): This is a brief, self-report screening tool designed for use with adult 
patients in primary care settings to assess risk for opioid abuse among individuals prescribed 
opioids for treatment of chronic pain. Patients categorized as high-risk are at increased likelihood 
of future abusive drug-related behavior (103). 
 
The Brief Pain Inventory: The BPI measures both the intensity of pain (sensory dimension) and 
interference of pain in the patient's life (reactive dimension). It also queries the patient about pain 

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relief, pain quality, and patient perception of the cause of pain(116). The BPI has been validated 
in FMS(117). 
 
Short-Form McGill Pain Questionnaire (SF-MPQ): The SF-MPQ is a shortened version of of the 
MPQ providing information pertaining to the sensory, affective, and evaluative dimensions of the 
pain experience. 
 
Ishihara Color Vision Test: The Ishihara color vision test will be administered during the screening 
visit to ensure normal color vision per inclusion criteria. 
 
Sense of Agency Rating Scale (SOARS): This scale is administered in conjuction with the HIP to 
assess the subjective experience of the participant during the HIP. 
 
Tellegens Absorption Scale (TAS): This scale is administered during the screening visit to assess 
the absorption experiences participants have throughout their lives. This scale is shown to be 
correlated with hypnotizability. 
 
Pain Numeric Rating Scale (PNRS): This scale is administered to assess subjective intensity of 
pain.  
 
Dissociative Experiences Scale (DES): This scale is administered to assess dissociative 
experiences participants have throughout their lives. 
 
Screening Complete Form: This checklist includes a list of all of the obtained screening 
questionnaires to verify participant eligibility and ensure the completion of all required 
documentation. 
 
6.2.2 Enrollment, Baseline, and Randomization 
 
 
Enrollment 
 
 
All participants will be provided a careful consent discussion prior to enrollment.  
 
At the time of the enrollment visit, potential subjects will be provided with a written copy of the 
current IRB-approved informed consent form.  
 
Due to the nature of a sham-controlled trial, all subjects will need to understand that during the 
trial, they will be randomized to either the active stimulation condition or the sham stimulation 
condition.  

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Case Report Forms: This study utilizes the NCCIH Case Report Forms (CRFs) for each subject 
enrolled into the study to ensure consistent data collection.  
 
Data will be captured by qualified study staff who will perform primary data collection from source-
document reviews to case report forms (CRF).  
 
Data will be collected for this study utilizing the following methods: 
 
1. Data will be transcribed from the Electronic Medical Record (EMR-an electronic source that will 
be available for review) onto the CRF. A copy of the EMR will be printed and placed in the subject’s 
case file as source documentation. 
 
2. Data will be captured directly onto the CRF and transcribed into the EDC system by study staff 
and paper documentation will be retained and available for review. Data reported in the CRF will 
be consistent with the source documents and any the discrepancies will be explained. 
 
 
 
 
Baseline MRI Session for TMS Targeting 
 
TMS Target Baseline Scan Session: This scan session includes all of the scans 
necessary to identify the r-TMS target for subsequent hypnotic pain and hypnotic 
stroop experimental sessions. 
 
MRI Acquisition  
o Structural Acquisition (T1): This structural scan is necessary for several 
reasons: demonstration that the participant’s brain is structurally 
normal, imaging analysis, and rTMS targeting (81).  
o BOLD fMRI Acquisitions 
 
Resting State : Task independent BOLD fMRI will be acquired 
while the participant eyes are open. Individuals with high 
hypnotizability have been demonstrated to have higher 
functional connectivity between the dorsolateral prefrontal 
cortex (DLPFC) and the dorsal anterior cingulate (dACC) (31). 
Clusters in the L-DLPFC identified to have the greatest 
correlation with the dACC will be used for r-TMS targeting. 

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 
Thumb Tapping: Alternating right and left thumb tapping will be 
used to identify the thumb motor area for each participant and 
may be implemented to make r-TMS intensity adjustments. 
 
Spectroscopy: Non-invasive magnetic resonance spectroscopy 
(MRS) will be used to quantitatively measure brain metabolites, 
including both inhibitory and excitatory neurotransmitters as 
well as markers of inflammation. 
Pre-rTMS Stroop Assessment 
 
Hypnotic Stroop and Non-Hypnotic Stroop Pre-rTMS Scan Session: This session 
includes all of the pre-rTMS questionnaires, behavioral evaluations and scans 
necessary to compare to the post-rTMS. 
 
Medication Washout, Drug Screen, Pregnancy Test Form: This form will be 
administered at the beginning of each pre-rTMS assessment to ensure 
medication washout compliancy (if applicable), document drug screen results, 
and screen for pregnancy (if applicable).  
 
Hypnotic Induction Profile: This administration of the HIP will serve as the 
baseline measure for comparison after the rTMS stimulation session(87). HIP 
will be measured on three separate occasions throughout the stroop 
assessment visit - 1) immediately following the pre-rTMS stroop MRI session, 
2) immediately following rTMS, and, 3) immediately following the post-rTMS 
stroop MRI session. 
 
Stroop Task: This administration of the Stroop task will serve as the baseline 
measure for comparison to the post-rTMS session(32, 118). 
 
Pre-TMS Hypnotizability Scan Session (1 hour duration) 
o Structural Acquisition (T1): This structural scan is necessary for several 
reasons: demonstration that the participant’s brain is structurally 
normal, imaging analysis, and rTMS targeting(81).  
o BOLD fMRI Acquisitions 
 
Resting State: This is the baseline scan required for the primary 
endpoint. Individuals with high hypnotizability have been 
demonstrated to have higher functional connectivity between 
the dorsolateral prefrontal cortex and the dorsal anterior 
cingulate cortex (31). 
 
 
Stroop Task: Brain activity while performing conflict tasks has 
been demonstrated to be different depending on a subject’s 
level of hypnotizability. This baseline would demonstrate the 
subject’s normal functional brain response to the Stroop Task 

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(32). Functional brain response to the stroop task will be 
measured following hypnosis (Hypnotic Stroop) and non-
hypnosis (Non-Hypnotic Stroop) audio instructions. These 
acquisitions will be randomized to prevent order effects. Highly 
hypnotizable individuals can have a loss of the Stroop Effect 
with specific post-hypnoitc instruction (119, 120) which 
correlates with the reduction in neural activity during conflict 
(35). 
 
Pre-rTMS Analgesia Assessment 
 
Pre-rTMS Analgesia Session: This hour-long scan session includes all of the pre-rTMS 
questionnaires, behavioral evaluations, and scans necessary to compare to the post-rTMS. 
 
 
Medication Washout, Drug Screen, Pregnancy Test Form: This form will be administered 
at the beginning of each pre-rTMS assessment to ensure medication washout compliancy 
(if applicable), document drug screen results, and screen for pregnancy (if applicable).  
 
 
Pain Thresholds: Baseline heat-pain thresholds and supra-pain thresholds will be 
determined for each volunteer based on responses to computer-controlled thermal stimuli 
delivered to the left forearm with a 30 x 30 mm advanced thermal stimulator (ATS) 
thermode (Medoc Pathway Model ATS). Thresholds will be measured using a standard 
method of limits protocol. Specifically, thermal pain threshold and tolerance values will be 
assessed outside the MRI scanner to identify a moderate pain intensity value that will be 
applied during the hypnotic and non-hypnotic analgesia MRI scans. The moderate pain 
intensity value will be used for both pre- and post-rTMS analgesia MRI sessions. 
 
 
Hypnotic Induction Profile: This administration of the HIP will serve as the baseline 
measure for comparison after the rTMS stimulation session(87). HIP will be measured on 
three separate occasions throughout the stroop assessment visit - 1) immediately 
following the pre-rTMS analgesia MRI session, 2) immediately following rTMS, and, 3) 
immediately following the post-rTMS analgesia MRI session. 
 
 
 
Pre-TMS Scans 
o Structural Acquisition (T1): This structural scan is necessary for several reasons: 
demonstration that the participant’s brain is structurally normal, imaging analysis, 
and rTMS targeting (81). 
o BOLD fMRI Acquisitions 
 
Resting State: This is the baseline scan required for the primary endpoint. 
Individuals with higher hynotizability have been demonstrated to have 

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higher functional connectivity between the dorsolateral prefrontal cortex 
and the dorsal anterior cingulate cortex (31). 
 
Pain Induction: Functional brain responses to acute, thermally, induced 
pain, will be measured using the moderate pain intensity value following 
hypnosis 
(Hypnotic 
Analgesia) 
and 
non-hypnosis 
(Non-Hypnotic 
Analgesia) audio instructions. These acquisitions will be randomized to 
prevent order effects. Hypnotic analgesia during pain induction has been 
demonstrated to be instruction specific (38, 44) and produce alterations in 
functional connectivity (123). 
 
Randomization 
 
The randomization occurs at the time immediately preceding the stimulation session. The 
stimulation session will be initiated immediately after randomization. We will perform 
randomization using permuted block to ensure balancing between arms. The operator is 
instructed to flip the coil to correspond with the key code, but is unclear as to the treatment group.  
 
 
6.2.3 Blinding 
 
Blinding and Unblinding methods: For stimulation sessions, this study utilizes the Cool-B65 
A/P coil, which has a built-in position sensor used to ensure that the correct (active or sham) side 
of the coil faces towards the patient's head. If the coil position is wrong the operator will get a "Flip 
Coil" prompt on the MagPro screen. To ensure best possible blinding of patients, the current 
stimulation pads (provided with the Cool-B65 A/P coil) should be used to stimulate the patient's 
skin and simulate the sensation of active rTMS. When a stimulation session is completed, the 
session data is stored on both the Patient Key and the Operator Key. Dr. David Spiegel and Dr. 
Nolan Williams are authorized to break the blind.  
 
Circumstances for Breaking the Blind: While the safety of the subject always comes first, it is 
important to seriously consider if unblinding the study randomization assignment is necessary to 
ensure a subject’s safety. In the event of a serious adverse device effect, the PIs will carefully 
assess whether breaking the blind will critically affect how a subject is treated in response to the 
adverse effect and whether this knowledge outweighs the implications to the scientific soundness 
of the study. In the case of most serious adverse effects, the study would be discontinued and 
symptoms treated symptomatically irrespective of the knowledge of whether the stimulation 
received was active or sham in nature. In these instances, having this information would not 
significantly alter the treatment of the adverse effect(s). As an additional safeguard against bias, 
the Independent Monitoring Committee (IMC) has been charged with making the final 

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recommendations for breaking the study blind. If the IMC recommends unmasking the study, 
NCCIH will be contacted and the key to active or sham stimulation will be obtained. Notation 
regarding the nature of the type of stimulation that the subject had been receiving will be 
documented in the subject’s source document. If the decision to break the blind is made 
immediately upon learning of the adverse event, this information will be reported to the NCCIH 
and reviewing IRB at the time of initial adverse event reporting. If the unblinding occurs after the 
initial reporting, the NCCIH will be notified of the action within ten working days from the time of 
breaking the blind. The reviewing IRB will be notified according to their reporting guidelines if the 
decision is made to break the study blind after the initial reporting. 
Procedure for Breaking the Blind at Study Completion: To minimize any source of bias, 
unblinding of the study will not be done until all subjects have completed all study phases. 
However, unblinding will occur if the Independent Monitoring Committee, consistent with their 
assigned charter and associated stopping rules, determines that it necessary to do so. At the end 
of the study Patient Keys are returned to the Principal Investigator for data analysis. The MagPro 
double-blinded research system ensures efficacy, accuracy and consistency. The system comes 
with a MagLink software program specifically developed for data collection in double-blinded 
studies. The program is used to define the stimulation protocol for each patient (real or sham 
stimulation). 
 
 
 
6.2.4 rTMS Administration (Active and Sham) 
 
 
Hypnotic Stroop and Hypnotic Analgesia Scanner Session Days (Same Protocol 
for Both Days) 
o Evaluation of Adverse Events 
o Motor Threshold Acquisition 
 
PEST(90) 
 
Visualization and MEP monitor (Electromyography)(132) 
 
o Neuronavigation 
 
Structural Targeting(81) 
 
Functional Connectivity Targeting(81) 
 
Continuous Theta-Burst Stimulation(17)800 pulses of continuous 
theta-burst stimulation at 80% rMT (30) 
 
15 minute break(30) 
 
800 pulses of continuous theta-burst stimulation at 80% rMT (30) 

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o Evaluation of Adverse Events 
 
 
 
 
 
6.2.5 Post-rTMS (Active and Sham) Evaluations 
 
Post-rTMS Stroop Assessment 
 
Hypnotic Stroop and Non-Hypnotic Stroop Pre-rTMS Scan Session: This session 
includes all of the post-rTMS  behavioral evaluations and scans necessary to compare 
to the pre-rTMS. 
 
Hypnotic Induction Profile: This administration of the HIP will serve as the post-
rTMS measure for comparison to the pre-rTMS stimulation session. 
 
Post-TMS Hypnotizability Scan Session (1 hour duration) 
o Structural Acquisition (T1): This structural scan is necessary for several 
reasons: demonstration that the participant’s brain is structurally 
normal, imaging analysis, and rTMS targeting(81).  
o BOLD fMRI Acquisitions 
 
Resting State: This is the scan required for evaluation of the 
primary endpoint. Individuals with high hypnotizability have 
been demonstrated to have higher functional connectivity 
between the dorsolateral prefrontal cortex and the dorsal 
anterior cingulate cortex (31). 
 
 
Stroop Task: Brain activity while performing conflict tasks has 
been demonstrated to be different depending on a subject’s 
level of hypnotizability. These scans will demonstrate the 
subject’s functional brain response to the Stroop Task post-
rTMS. Functional brain response to the stroop task will be 
measured following hypnosis (Hypnotic Stroop) and non-
hypnosis 
(Non-Hypnotic 
Stroop) 
audio 
instructions. 
Randomization of hypnosis and non-hypnosis scan order for 
each participant will be kept consistent between both pre- and 
post-rTMS scans. Highly hypnotizable individuals can have a 
loss of the Stroop Effect with specific post-hypnoitc instruction 
(119, 120) which correlates with the reduction in neural activity 

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during conflict (35). 
 
Post-rTMS Analgesia Assessment 
 
Post-rTMS Analgesia Session: This hour-long scan session includes all of the post-rTMS 
behavioral evaluations and scans necessary to compare to the pre-rTMS. 
 
Hypnotic Induction Profile: This administration of the HIP will serve as the baseline 
measure for comparison after the rTMS stimulation session(87). 
 
Pre-TMS Scans 
o Structural Acquisition (T1): This structural scan is necessary for several reasons: 
demonstration that the participant’s brain is structurally normal, imaging analysis, 
and rTMS targeting (81). 
o BOLD fMRI Acquisitions 
 
Resting State: This is the baseline scan required for the primary endpoint. 
Individuals with higher hynotizability have been demonstrated to have 
higher functional connectivity between the dorsolateral prefrontal cortex 
and the dorsal anterior cingulate cortex (31). 
 
Pain Induction: Using the same moderate thermal pain values identified 
above, functional brain responses to acute pain, will be measured following 
hypnosis 
(Hypnotic 
Analgesia) 
and 
non-hypnosis 
(Non-Hypnotic 
Analgesia) audio instructions. Randomization of hypnosis and non-
hypnosis scan order for each participant will be kept consistent between 
both pre- and post-rTMS scans.  Hypnotic analgesia during pain induction 
has been demonstrated to be instruction specific (38, 44) and produce 
alterations in functional connectivity (123). 
 
MR Spectroscopy Assessment (Optional)  
 
 
Imaging Procedure 
o Structural Acquisition (T1/T2/DWI): A structural scan will be acquired for imaging 
analysis. 
o 1H-MRS Spectroscropy: MEGA-PRESS (GABA/Glx) and NFL-PRESS (Broad 
spectra) spectroscopy sequences will be acquired bilaterally within the left and 
right DLPFC using a cutting-edge automated voxel placement procedure that 
precisely targets the identified connectivity coordinates. 
o Resting State fMRI: A BOLD fMRI acquisition will be acquired while the participant 
is at rest to assess functional connectivity between the insula and DLPFC 
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7. SAFETY ASSESSMENTS  
 
 
7.1 
Specification of Safety Parameters 
 
 
Subject Screening: The Transcranial Magnetic Stimulation Adult Safety Screen (TASS) will be 
utilized to confirm that the potential participant does not have any conditions or devices that would 
contraindicate rTMS (TBS) administration (101). We will use the MRI screening form to assure 
that there are no contraindications to MRI scanning (89). 
 
MRI Practices: The CRCs will be trained to ensure that the participant does not enter into the MRI 
room with any ferromagnetic objects(89). 
 
Motor Threshold Acquisition: The participant’s motor threshold will be determined to be accurate 
through the use of a combination of PEST software (90), visualization, EMG monitoring (91), and 
neuroimaging of the cortical target of the hand representation. The MT will be attained twice in 
order to assure accuracy. Each MT acquisition will be performed by a separate TMS operator and 
the lower of the two MT acquisition trials will be utilized. 
 
Dose Calculation: The dose (80% of the rMT) will be assured to be calculated correctly. Two 
separate calculations will be done to assure that the dose was correctly calculated.  
 
 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
 
 
Monitoring of Mental Status during rTMS: All personnel will be familiar with the procedures for 
subject screening for risk factors prior to treatment, individual risks and potential benefits for 
specific subjects, appropriate discussion of the risks and potential benefits of study participation 
as outlined in the informed consent document, the stimulation parameters to be used in this study, 
monitoring subjects for the potential development of seizures by continuous visual inspection 
during the course of each treatment session (especially the more subtle signs and symptoms of 
frontal lobe seizures), and first responder management in the event of a seizure (99). All TMS 
treaters will be certified in basic life support training(99). 
 

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7.3 
Adverse Events and Serious Adverse Events  
 
 
An adverse event (AE) is any untoward, undesired, or unplanned event in the form of signs, 
symptoms, disease, or laboratory or physiological observations occurring in a person who has 
received stimulation with a TMS device or an MRI scan. The event need not be causally related 
to the TMS device or the MRI scan.  
 
 
An AE includes, but is not limited to: 
 
 
Any clinically significant worsening of a pre-existing condition; 
 
An AE occurring from overdose (i.e., a dose higher than that described in the protocol) of 
a TMS device, whether accidental or intentional; 
 
An AE occurring from abuse (e.g., use for non-study reasons) of a TMS device; 
 
An AE that has been associated with a preexisting condition is a clinical condition 
(including a condition being treated) that is diagnosed before an informed consent form is 
signed and is documented as part of the subject’s medical history. 
 
 
The questions concerning whether the condition existed before the start of the active phase of 
the study and whether it has increased in severity and/or frequency will be used to determine 
whether an event is an intervention-emergent AE (IEAE).  
 
An AE is considered to be intervention-emergent if [1] it was not present when the active phase 
of the study began and is not a chronic condition that is part of the subject’s medical history, or 
[2] it was present at the start of the active phase of the study or as part of the subject’s medical 
history, but the severity or frequency increased during the active phase. The stimulation phase of 
the study begins at the time of the first administration of the TMS stimulation (active or sham).  
 
For this study, the treatment follow-up period for adverse events is defined as 30 days following 
the last study visit.  
 
Follow up will be documented in the subjects study file. 
 
 

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A serious adverse event (SAE) is defined as an AE that: 
 
 
Results in death: 
 
Is life threatening (see below) 
 
Requires inpatient hospitalization or prolongation of an existing hospitalization (see below) 
 
Results in a substantial disruption of a person's ability to conduct normal life functions, i.e., 
the adverse event resulted in a significant, persistent or permanent change, impairment, 
damage or disruption in the patient's body function/structure, physical activities and/or 
quality of life 
 
Necessitates medical or surgical intervention to preclude such impairment 
 
Results in a congenital anomaly or birth defect 
 
Additionally, important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered SAEs, based upon appropriate medical judgment.  
 
Life threatening refers to immediate risk of death as the event occurred or use or continued use 
of the device or other medical product might have resulted in the death per the reporter. A life-
threatening event does not include an event that, had it occurred in a more severe form, might 
have caused death, but as it actually occurred, did not create an immediate risk of death.  
 
Hospitalization is to be considered only as an admission. Hospitalization or prolongation of a 
hospitalization constitutes an AE to be classified as serious.  
 
Note: Hospitalizations planned before the start of the study, for a preexisting condition that has 
not worsened, do not constitute an SAE (e.g., elective hospitalization for a total knee replacement 
due to a preexisting condition of osteoarthritis of the knee that has not worsened during the study).  
 
An adverse event of special interest is a device-specific adverse event designated by the PI 
for transmission in the same time frame as an SAE, even if it does not meet serious reporting 
criteria. For this protocol, seizure should be reported as an adverse event of special interest.  
 
If there is any doubt whether the information constitutes an SAE, the information should be treated 
as an SAE for the purpose of this study. 
 
 
Timing for Reporting of Serious Adverse Events: Any SAE, regardless of causal relationship, 
must be reported immediately to the Independent Monitoring Committee (within one business 

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day) by faxing a completed serious adverse event form to the chair of the committee, Dr. Alan 
Schatzberg. Compliance with this time requirement is essential so that the Sponsor may comply 
with its regulatory obligations. Follow-up information relating to an SAE will be reported to the 
Independent Monitoring Committee and the NCCIH within one business day after the information 
is sent to the PI by faxing a completed serious adverse event form to the chair of the committee, 
Dr. Alan Schatzberg. The subject should be observed and monitored carefully until the condition 
resolves or stabilizes or its cause is identified. Any emergency will be reported to NCCIH and the 
Independent Monitoring Committee immediately (within one business day) by contacting the Dr. 
Alan Schatzberg. 
 
Data Collected to Assess Safety During rTMS: Treaters will be monitoring subjects for the 
potential development of seizures by continuous visual inspection during the course of each 
stimulation session (especially the more subtle signs and symptoms of frontal lobe seizures), and 
first responder management in the event of a seizure. The study personnel have immediate (i.e., 
within minutes) availability of more sophisticated medical support, including access to an 
emergency room, in the event that a seizure is not a self-limited event, access to antiepileptic 
medications, and to life support equipment including oxygen, suction, blood pressure monitoring 
and cardiopulmonary (CPR) equipment. 
 
Seizure and the following are AE’s that will be reported at solicited events: 
 
Table 2: Adverse events with an incidence in active rTMS at a rate of > 5% and at least 2x sham 
in the safety exposure study population.  These symptoms have occurred only during and not 
after rTMS administration. 
7.4 
Reporting Procedures 
 

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Research staff will be trained to attend to signs of adverse events (AE) and to report any potential 
AE immediately to the PI regardless of whether the possible cause of the AE is related to the 
research study. If adverse events occur, appropriate medical and/or psychiatric care will be 
offered immediately to the research participant, and an official written report will be completed 
using the Stanford University Human Subjects Adverse Event form and submitted to the 
Institutional Review Board at Stanford University and NIH within 7 days. The NCCIH Program 
Officer will be informed of any actions taken by the IRB as a result of any adverse events within 
7 days of notification by the IRB (e.g. study modifications imposed by the IRB). 
 
Adverse events will be monitored continuously by the clinical research coordinators and Principal 
Investigator who will be responsible for ensuring that unanticipated problems, including adverse 
events, are reported to the IRB in compliance with their requirements for reporting serious and 
unexpected adverse events. Reporting will be conducted in compliance with guidelines specified 
by the Stanford University Research Compliance Office. All subjects will have telephone and 
email contact information to reach the Principal Investigator in case of any distress or adverse 
response to the hypnosis or other components of the study. Dr. Spiegel has 40 years of 
experience as a psychiatrist in clinical and research psychiatry involving hypnosis, stress 
management, and psychotherapy, and he will respond to all inquiries immediately. Dr. Yeomans 
has over 25 years of experience in the field of analgesia experimentation, and he will also be on 
hand to address any concerns if they arise. Dr. Nolan Williams is a neurologist and psychiatrist 
who has 10 years of rTMS experience and will also be on hand to address any concerns if they 
arise. 
 
An AE or SAE can occur from the time that the subject signs the informed consent form to 7 days 
from the subject’s last study visit regardless of relationship to the protocol or TMS device. This 
includes events that emerge during the pre-study screening phase. All AEs and SAEs will be 
recorded on source documents and recorded on the subject’s case report forms (CRFs). All AEs 
and SAEs that occur after the pre-study screening period will be recorded on the subject’s CRFs, 
which will be provided to the NCCIH. The Independent Monitoring Committee (IMC) will instruct 
the Principal Investigator to follow all AEs, SAEs, and other reportable events until the event has 
subsided or values have returned to baseline, or in case of permanent impairment, until the 
condition stabilizes. The Investigator will provide all relevant documentation pertaining to an SAE 
(e.g., additional laboratory tests, consultation reports, discharge summaries, postmortem reports, 
etc.) to the IMC and NCCIH in a timely manner. Reports relative to the subject’s subsequent 
course will be submitted to the IMC and NCCIH until the event has subsided or, in case of 
permanent impairment, until the condition stabilizes. Other information reportable to the IMC and 
NCCIH, while not meeting the definition of an AE, is reportable to NCCIH and the IMC with the 
timeliness of an SAE.  
 
This includes: 
 
Seizure 

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 
Pregnancy occurring during the study period in which the subject was exposed to the TMS 
device; 
 
Overdose (e.g., a dose higher than that prescribed by a healthcare professional for clinical 
reasons) with or without AEs; 
 
Abuse (e.g., use for non-clinical reasons) with or without an AE; 
 
Inadvertent or accidental exposure with or without an AE; 
 
Device malfunction that would likely result in death, serious injury or other significant 
adverse event. 
 
At each required study visit, all AEs that have occurred since the previous visit will be recorded in 
the adverse event record of the subject’s CRF. The information recorded should be based on the 
signs or symptoms detected during the physical examination and clinical evaluation of the subject.  
 
In addition to the information obtained from those sources, the subject should be asked the 
following nonspecific question: "How have you been feeling since your last visit?" Signs and 
symptoms will be recorded using standard medical terminology. 
 
The following AE information must be included (when applicable): the specific condition or event 
and direction of change; whether the condition was preexisting (i.e., an acute condition present 
at the start of the study or history of a chronic condition) and, if so, whether it has worsened (e.g., 
in severity and/or frequency); the dates and times of occurrence; severity; causal relationship to 
the TMS device; action taken; and outcome. 
 
Causal relationship options and definitions are as follows: 
 
 
Definitely related: Event can be fully attributable to administration of the TMS stimulation 
or the MRI device. 
 
Probably related: Event is most likely to be explained by administration of the TMS device 
or MRI device, rather than the subject’s clinical state or other agents/therapies. 
 
Possibly related: Event is as likely explained by administration of the TMS stimulation or 
MRI device, as by the subject’s clinical state or other agents/therapies. 
 
Probably not related: Event is most likely to be explained by the subject’s clinical state or 
other agents/therapies, rather than the TMS stimulation or MRI device. 
 
Definitely not related: Event can be fully explained by the subject’s clinical state or other 
agents/therapies, rather than the TMS stimulation or MRI device. 
 
When assessing the relationship between an investigational product/protocol and an AE, the 
following parameters are considered: 
 

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 
Temporal relationship between the TMS device/protocol and the AE 
 
Biologic plausibility of relationship 
 
Subjects’ underlying clinical state or concomitant agents/therapies 
 
Where applicable, whether the AE abates on discontinuation of the TMS device or MRI 
device (de-challenge) 
 
Where applicable, whether the AE reappears on repeat exposure to the TMS device or 
MRI device (re-challenge) 
 
Sensations of pain (needle-like sensation, hurting) during the ~45 second TMS sessions will be 
an expected AE. 
SAEs that are not TMS/MRI device-related may nevertheless be considered by the Principal 
Investigator or the IMC to be related to the conduct of the study, i.e., to a subject's participation 
in the study. 
7.5 
Follow-up for Adverse Events 
 
 
All clinical personnel involved in the motor threshold determinations and the TMS stimulation 
sessions will be familiar with the ISTS Consensus Statement on Managing the Risks of Repetitive 
Transcranial Magnetic Stimulation, with specific attention to the requirements of medical 
supervision and first-responder capability in the event of a seizure as outlined in that document. 
Specifically, all personnel will be familiar with the procedures for subject screening for risk factors 
prior to treatment, individual risks and potential benefits for specific subjects, appropriate 
discussion of the risks and potential benefits of study participation as outlined in the informed 
consent document, the stimulation parameters to be used in this study, monitoring subjects for 
the potential development of seizures by continuous visual inspection during the course of each 
treatment session (especially the more subtle signs and symptoms of frontal lobe seizures), and 
first responder management in the event of a seizure.  
 
The Stanford Center for Cognitive and Neurobiological Imaging will have immediate (i.e., within 
minutes) availability of more sophisticated medical support, including access to an emergency 
room, in the event that a seizure is not a self-limited event, access to antiepileptic medications, 
and to life support equipment including oxygen, suction, blood pressure monitoring and 
cardiopulmonary (CPR) equipment.  
 
For this study, the treatment follow-up period for adverse events is defined as 30 days following 
the last study visit.  
 
 
7.6 
Safety Monitoring  
 

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The Independent Monitoring Committee for this study is comprised of Drs. 
, 
 
 and 
. Drs. 
, 
 and 
 are not associated with this research 
project and work independently of the PI, Dr. David Spiegel. Dr. 
 is a physician 
and has previously served on a monitoring committee. Dr. 
 
 is a neuro-
anesthesiologist and an expert in pain. Dr. 
 is a biostatistician and will serve the role of 
evaluation of the data. They are not part of the key personnel involved in this grant. No member 
of the Committee has collaborated or co-published with the PI within the past three years. They 
are qualified to review the patient safety data generated by this study because of their unique 
expertise. 
 
 
 

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8. INTERVENTION DISCONTINUATION  
 
 
 
Subjects may withdraw voluntarily from the study at any time.  
 
 
 
Subjects may be withdrawn from the study by the Principal Investigator if a subject: 
 
 
 
Experiences a seizure 
 
 
Is non-compliant with study procedures 
 
 
The randomization code is broken for this subject 
 
 
 
The Principal Investigator may also withdraw a subject if he/she believes that for safety reasons 
it is in the best interest of the subject to be withdrawn.  
 
 
Discontinuation information [e.g., date and the reason(s) for discontinuation] must be recorded in 
the subject’s CRF (i.e., Study Completion Form). 
 
 
Subjects withdrawn from the study due to an AE will be followed up for 30 days or until resolution. 
Subjects withdrawn from the study will be replaced if withdrawal occurs prior to scanner session. 
An effort will be made to determine why a subject does not return for the required visits or is 
dropped from the study. This information will subsequently be recorded on the subject’s CRF. 
 
 
Subjects will be encouraged to remain compliant with all expected study visits. Non-adherence to 
expected study visits will be documented and may result in removal from the study. This will be 
clearly discussed during the consent/assent process and reinforced throughout the study through 
regular screening for issues with compliance. 
 
 

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9. STATISTICAL CONSIDERATIONS  
 
 
9.1 
General Design Issues  
 
 
Statistical Hypotheses: In the Primary Mechanistic Hypothesis (previously functional 
connectivity portion of Hypothesis 1a-in grant), we will examine the effect of active rTMS on the 
functional connectivity between L-DLPFC and dACC. In the Relevant Clinical Hypothesis 
(previously Hypothesis 2b), we will examine the effect of active rTMS on hypnotic analgesia.  In 
Secondary Hypothesis B (previously Hypothesis 1b-in grant), we will examine the effect of rTMS 
on hypnotizability and hypnotic intensity using the same analytical strategy. In Secondary 
Hypotheses E (previously Hypotheses 2a in grant), we will repeat our investigation with various 
secondary outcomes including activation and connectivity among anterior cingulate, dorsolateral, 
insular, and somatosensory cortices. Finally, we will explore whether the effect of rTMS on 
hypnotizability is mediated by the change in functional connectivity in DLPFC and dACC.  
 
Rationale for Study Design: The randomized, double-blind, counterbalanced, mechanistic 
clinical trial design allows for the most definitive assessment of the feasibility of modulating the 
neural circuitry underlying hypnotizability with rTMS along with the measuring the effects of this 
neuromodulation strategy on the underlying neural circuitry. The same subjects are utilized for 
both scan session days, that is, for the hypnotic stroop scan session (to address the hypnosis 
stroop interference aims) and for the hypnotic analgesia scan session (to address hypnotic 
analgesia aims). The rationale for using the same sample twice is to achieve sufficient statistical 
power with the moderate sample size. The order will be counterbalanced and the two groups 
(rTMS versus sham) will be cross-sectionally compared treating the contrast (baseline vs post 
rTMS) as one univariate outcome, which is customary in imaging studies.  
 
Washout Period: Due to risk of seizure (97), we will implement a washout period for all 
psychoactive medications (99, 102) that will be implemented prior to the first scan session and 
continued through to the second scan session day. For all antidepressant medications other than 
fluoxetine, there will be a 2-week washout. For fluoxetine, there will be a 5-week washout 
period(102). The reason for 2 weeks for all antidepressants except fluoxetine (5 weeks) has to do 
with the half-life of the antidepressants(102). We will only washout those individuals who are 
taking antidepressants for pain. We will not washout antidepressant prescribed for depression 
due to the risk of exacerbating depression. If participants find this portion of the study intolerable 
from a mood/pain standpoint, we will exclude the participant prior to the scanner portion of the 
study and this participant will be considered a screen failure and replaced. 
 
The safety monitoring protocol for the medication wash-out has been successfully employed in 
two former randomized controlled trials for suicide prevention in which the Chair of the 
Independent Monitoring Committee was a mentor (DOD/MSRC [W81XWH-10-2-0178] and NIH 

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[K23MH093490]). All procedures will be closely supervised by the study PIs and on-site 
Independent Monitoring Committee, Dr. Schatzberg (Mood Disorders Expert). Suicide risk 
assessment will be conducted using empirically-established risk categorizations (minimal, mild, 
moderate, severe, imminent) to routinize clinical decision-making and emergency referral 
procedures for suicidal behaviors. This study will utilize a comprehensive, in-built infrastructure 
and set of standard operating procedures that support safe conduct of the current trial. Based on 
evidence-based best practices in standardized risk assessment and management, subjects at 
imminent risk will be referred for immediate hospitalization. Proposed procedures have been used 
in previous IRB-approved proposals consistent with DSMP protocols employed by Drs. 
Schatzberg.  
 
Best practices in suicide risk assessment and management procedures will be reviewed at the 
outset of the anti-depressant washout with all individuals requiring this intervention, as a central 
component to the informed consent process. Notification of next of kin procedures, and 
permission to contact this individual in the event of a no-show or elevation in risk, will be reviewed 
prior to study enrollment, in addition to all confidential and non-confidential referral resources 
available to the participant in the event of an elevation in symptoms. Participants will be referred 
to a supervising clinician if a participant experiences distress at any point during the medication 
wash-out. This will prompt standardized suicide risk assessment according to established 
frameworks. All safety and risk assessment interactions will be closely supervised by a licensed 
clinician, and thoroughly documented. 24-hr on-call clinical coverage teams will be assembled 
and in place throughout the wash out period. The PIs will oversee on-call (via pager) 24-hour 
clinical coverage to assist in evaluating suicide risk and need for mental health services using an 
in-use protocol for an MSRC-funded and IRB-approved clinical trial (NCT01958541).  
 
The SSI-C will be administered on the phone weekly as well as if the individual calls in with 
distress. A score > 6 on the SSI-C will prompt standardized suicide risk assessment and 
administration of The Suicide Checklist and Suicide Assessment Decision Tree (See Below). 
 
a. If risk is elevated but not imminent, established behavioral methods will be used to effectively 
manage risk on an outpatient basis. The PI will closely monitor decision-making and assessment, 
and action taken will be clearly documented. 
b. If risk is imminent, participants will be referred for immediate hospitalization and emergency 
mental health services. The PI/Co-Is will closely monitor decision-making and assessment, and 
action taken will be documented. 
 
 
 

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Primary Mechanistic Objective and Relevant Clinical Objective 
 
Primary Mechanistic Objective: To determine the effect of active, inhibitory rTMS (continuous 
theta-burst stimulation-cTBS) over left dorsolateral prefrontal cortex (L-DLPFC) on modulating the 
neural network that underlies hypnotizability and hypnosis. In other words, the Primary 
Mechanistic Outcome Measure is the change in functional connectivity between the L-DLPFC 
and the dACC and associated reduction in activity in the L-DLPFC and dACC in active versus 
sham rTMS.  
 
Primary Mechanistic Hypothesis: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate 
the neural network that underlies hypnotizability and hypnosis by producing greater increases in 
functional connectivity between L-DLPFC and dACC as compared to sham rTMS (sham cTBS). 
We hypothesize that active, inhibitory rTMS (continuous theta-burst stimulation) will produce 
increases in functional connectivity between the L-DLPFC and the dACC (47), producing a 
transient phenotype (30) appearing on neuroimaging like a high hypnotizable (31).  This increase 
in functional connectivity, coupled with inhibition of activity in the DLPFC, would be 
hypothesized to reduce activity in the dACC as well, which is what we have shown to be 
associated with entry into the hypnotic state.  Thus rTMS induced increase in functional 
connectivity should increase hypnotizability and, coupled with inhibited activity, enhance hypnotic 
intensity as well. 
 
Validity of the Approach: Resting-state fMRI has survived the (appropriate) initial skepticism 
with which it was met (134) and has been buttressed by multimodal imaging in humans (135-137) 
supporting a neural origin of these BOLD signal fluctuations.  Advances in artifact reduction (138-
140) and analysis (141) have proceeded apace and the reproducibility of this method has been 
established (142).  Resting-state fMRI has emerged as among the most rapidly growing sub-fields 
of functional imaging. Functional connectivity MRI has been proposed to be the optimal method 
for tracking rTMS-induced changes in the human brain (53). 
 
Reliability of the Approach: It has been demonstrated across multiple studies that both 
traditional rTMS as well as theta-burst stimulation (56, 57) is capable of modulating functional 
connectivity (54). This approach has been assessed not only in the motor system, but also across 
numerous cortical nodes, including the left dorsolateral prefrontal cortex (46, 47, 143). 
 
Relevant Clinical Objective: To determine the effect of active, inhibitory rTMS (cTBS) over L-
DLPFC on enhancing HA-related reduction in nociception. 
Relevant Clinical Hypothesis: Active, inhibitory rTMS (cTBS) over L-DLPFC will enhance HA 
as compared to sham rTMS (sham cTBS). 
Validity of the Approach: HA has been demonstrated to be effective in reducing subjective pain 
sensation in both normal controls (144) as well as participants with FMS (7).  Thermal pain has 
been demonstrated to be fiber specific (145).  
Reliability of the Approach: Thermal pain as an experimental pain paradigm is a highly validated 
approach for activating pain fibers and the neural structures that are connected to these pain 
fibers (146-149). Hypnotic analgesia has been demonstrated to be a physiological phenomenon 
that is reliable in highly hypnotizable individuals (150, 151).  

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Secondary Objectives 
 
Secondary Objective A: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on modulating the neural network that underlies hypnotic intensity. 
Secondary Hypothesis A: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies hypnotic intensity by decreasing activity in L-DLPFC and dACC as 
compared to sham rTMS (sham cTBS) as measured by BOLD and interleaved TMS-BOLD. 
Validity of the Approach: Hypnotic intensity is strongly correlated with measured hypnotizability 
(133). rTMS has been demonstrated to affect hypnotizability and it is suspected that rTMS (TBS) 
(26) will therefore affect the neural networks that underlie hypnotic intensity (133).  
Reliability of the Approach: It has been demonstrated that both the BOLD and functional 
connectivity measures are statistically, significantly different in the hypnotic state as in comparison 
to the resting, waking state (133, 152). 
 
Secondary Objective B: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on enhancing hypnotizability (as measured by the Hypnotic Induction Profile-HIP and Stroop 
Task) and hypnotic intensity (as measured by the Hypnotic Intensity Scale-HIS). 
Secondary Hypothesis B: Active, inhibitory rTMS (cTBS) over L-DLPFC will increase the HIP 
and HIS scores as well as Stroop Effect as compared to sham rTMS (sham cTBS). 
Validity of the Approach: It has been previously demonstrated that inhibitory rTMS over the L-
DLPFC can modulate the level of hypnotizability of the subject (26). Because rTMS has been 
demonstrated to affect hypnotizability and it is suspected that rTMS (26) will therefore affect 
hypnotic intensity (133). It has been demonstrated that rTMS can manipulate the Stroop effect bi-
directionally, in a frequency-dependent manner (118, 153, 154). It has also been demonstrated 
that performance on conflict tasks such as the Stroop task and the flanker task are correlated with 
hypnotizability (32).  
Reliability of the Approach: It has been demonstrated across numerous studies that rTMS is 
capable of modulating cognitive tasks in a frequency-dependent manner (155-157). 
 
Secondary Objective C: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network underlying the conflict regulation system as a reflection of effective 
modulation of the neural circuitry underlying hypnotizability.  
Secondary Hypothesis C: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies conflict regulation system by decreasing activity in right inferior frontal 
gyrus (rIFG) and the connectivity of the rIFG to the default mode network (DMN). 
Validity of the Approach: Difference in hypnotizability has been correlated with difference in 
neural strategy for conflict tasks such as the Stroop task and the flanker task (32). 
Reliability of the Approach: It has been demonstrated that both the BOLD and functional 
connectivity measures are reliable across numerous studies (51). 

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Secondary Objective D: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network underlying post-hypnotic Stroop Effect. 
Secondary Hypothesis D: Post-hypnotic instruction of word blindness after active, inhibitory 
rTMS (cTBS) over L-DLPFC will reduce dACC activity during the Stroop task (similar to high 
hypnotizables) as compared to sham rTMS (sham cTBS). 
Validity of the Approach: It has been demonstrated that a post-hypnotic instruction of word 
blindness will produce a loss of the Stroop Effect in highly hypnotizable individuals (119, 120). It 
has also been demonstrated that the loss of the Stroop Effect is correlated with reduction in 
conflict signaling in the dorsal anterior cingulate (35). 
Reliability of the Approach: It has been demonstrated across numerous studies that the post-
hypnotic instruction of word blindness is capable of eliminating the neural response to the Stroop 
task (35, 36). 
 
Secondary Objective E: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on modulating the neural network that underlies hypnotic analgesia (HA). 
Secondary Hypothesis E: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies HA by producing a decrease in activity and an increase functional 
connectivity among the anterior cingulate, dorsolateral, insular, and somatosensory cortices 
(hypnotic analgesia network) as compared to sham rTMS (sham cTBS). 
Validity of the Approach: It has been demonstrated that high hypnotizables have reduced 
activation of the pain system when thermal pain is applied and these subjects are under hypnotic 
analgesia(144). It has been demonstrated that there is a differential brain response between high 
and low hypnotizable individuals with FMS (7). 
Reliability of the Approach: Thermal pain has been demonstrated to be effective in eliciting 
fiber-specific pain and therefore particular brain activation across numerous studies (146-149). It 
has been demonstrated that there are circuit-specific changes that can be observed with hypnotic 
analgesia is high hypnotizables (144). 
 
Secondary Objective F: To determine the association between metabolic concentrations and 
clinical pain measures.  
Secondary Hypothesis F: L-DLPFC GABA levels will be negatively associated with clinical pain 
measures in participants with FMS.  
Validity of the Approach No study has utilized a functional connectivity defined approach to 
investigate L-DLPFC neurochemistry – a hub for pain modulation and a potential target to 
increase hypnotizability. To overcome arbitrary MRS voxel placement, especially challenging for 
DLPFC spectroscopy, we will first identify the L-DLPFC cluster coordinates representing the 
greatest resting state functional connectivity to the dACC and then use a novel automated 
coordinate-based voxel placement strategy.  
 

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Reliability of the Approach: In FMS, changes in MRS signatures and functional connectivity 
have been identified in separate populations [175], however, an association between MRS 
metrics and functional connectivity has not been reported, but could illuminate mechanisms of 
central network dysfunction. 
 
Secondary Objective G: Determine the relationship between the metabolic alterations pre and 
post-TMS and the association with hypnotic analgesia. 
Secondary Hypothesis F: cTBS neuromodulation of L-DLPFC-dACC connectivity is mediated 
by inhibitory inter-neuronal cortical pathways measured by GABA MRS in the L-DLPFC. 
Neuromodulation induced by TMS has been shown to increase L-DLPFC-dACC connectivity, but 
the neurochemistry underlying these changes is unknown.  
Validity of the Approach: MRS has been used to characterize associations between these 
neurotransmitters in regions of altered functional connectivity in response to acupuncture, 
intermittent TMS (excitatory), or cTBS (inhibitory) 175, 176, 177]. 
Reliability of the Approach: Implementation of novel image-guided-approach for MRS ensures 
the reliability of voxel placement that is superior to manual voxel placement. 
 
9.2 
Sample Size and Randomization 
 
For the power estimation, this study will use the significance level of .05 with two-tailed test. This 
study will recruit 100 individuals assuming about 20% missing data due to unusable imaging data 
and dropouts. In the Primary Mechanistic Hypothesis (formerly connectivity portion of Hypothesis 
1a), power was estimated by focusing on the functional connectivity between DLPFC and dACC 
as the Primary Mechanistic Outcome. According to one prior study (47), the change in connectivity 
between DLPFC and dACC from pre to post rTMS is change in the quite large (d=0.69). We have 
augmented this one finding with numerous findings from other rTMS connectivity and functional 
activity studies, which demonstrated quite large effect sizes (see table 3 and table 4 below). 
Therefore, a somewhat conservative effect size of d=0.8 is being utilized for this study. The 
change from baseline to post-stimulation will be negligible in the sham rTMS group. Given this 
scenario, with the usable sample of 80 (40 rTMS, 40 sham), the estimated power is 0.8 
(alpha=.05, two-sided). For the Relevant Clinical Hypothesis (formerly Hypothesis 2b) and 
Secondary Hypotheses E (formerly Hypothesis 2a) as well as Secondary Hypotheses A, C, and 
D, both effect sizes and p-values will be monitored, with more emphasis on gathering information 
on effect sizes. 
 
 
Manuscript 
Site of Stimulation 
Functional Connectivity Pair 
Effect 
Size 
Eldaief et al 
L Posterior Intraparietal Lobule 
rpIPL<->mPFC 
0.72 
Eldaief et al 
L Posterior Intraparietal Lobule 
rpIPL<->PCC 
0.62 
Nettekoven 
Primary motor cortex 
Primary Motor Cortex<->Premotor Cortex 
0.9 
Halko et al 
Lateral cerebellum 
 DMN<->Posterior cingulate 
1.26 
Valchev et al 
Primary somatosensory 
Premotor 
0.79 

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Vercammen  
Temporal-Parietal-Junction 
Temporal-Parietal-Junction<->Right 
Insula 
1.33 
Watanabe et 
al 
Left Motor Cortex 
Left Motor Cortex<-> Right Motor Cortex 
1.79 
Watanabe et 
al 
Left Motor Cortex 
Left Motor Cortex<-> Right Motor Cortex 
2 
 
Table 3: Effect sizes for rTMS induced changes in functional connectivity as a surrogate for 
hypnotizability (Hoeft 2012)(31) modulated by rTMS(54, 56, 57, 158-160). 
 
 
Manuscript Stimulation Site 
MRI/PET 
Effect Size 
Hubl 
Frontal Eye Field 
BOLD 
0.4242 
Bestmann 
Motor/Somatosensory cortex 
BOLD 
2.36686405 
Bestmann 
Motor/Somatosensory cortex 
BOLD 
2.30589176 
Cho 
Right Dorsolateral prefrontal cortex 
PET (CBF) 
1.70333333 
Valchev 
Motor/Somatosensory cortex 
BOLD 
2.86192037 
Valchev 
Motor/Somatosensory cortex 
BOLD 
1.23857467 
 
Table 4: Effect sizes for rTMS induced changes in brain activity as a surrogate for hypnosis 
(Jiang 2016)(34) modulated by rTMS(159, 161-163). 
 
 
As our study is a randomized controlled study, in line with the intention to treat principle, our 
primary analysis will be a straightforward comparison of the active versus sham groups using a 
linear model. Following the convention in imaging studies, we will conduct our primary analyses 
treating the contrast (baseline vs post) as one univariate outcome.  The univariate model 
described below can be estimated either using linear regression or analysis of variance 
procedures. 
 
A continuous outcome Y for individual i (i=1,2,3…., N) can be expressed as  
Yi = α + γ Zi + εi, where α is the mean of the sham group, Zi is the randomized treatment 
assignment status (0=sham, 1=active), γ is the treatment effect, and εi ~ N(0, σ2). According to 
random assignment, the estimate of γ will be interpreted as causal effect of treatment assignment.  
 
We do not expect much variation across our narrowly defined subjects, although some variation 
is still possible. As a way of sensitivity analysis, we will also analyze the data in the linear mixed 
effects modeling framework allowing for random intercepts, although this is not customary in 
imaging studies.  The linear mixed effects model described below will be estimated using the 
maximum likelihood estimation method implemented in SPSS or in Mplus. 
  
 
The outcome Y for individual i at time point t (t = 1,2 for pre and post) is now expressed as  
 
Yit  = η0i + ηliWt + εit,  (2) 
η0i = η0  + γ0Zi   + ζ0i    (3) 
ηli  = ηl   + γlZi    + ζLi    (4) 
 

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where η0i is the initial status and ηli is the linear growth. The set of time scores Wt reflects the 
linear growth (0,1) for the pre and post assessments. The residual εit is allowed to vary across 
time, and is assumed to be normally distributed in out parametric estimation approach. The 
intercepts in (3)-(4) can be interpreted as the main initial status (ηl) and linear growth (η2) for the 
sham group. The random effect residual ζ0i is assumed to be normally distributed, whereas ζLi is 
fixed at zero as we only have two time point data. The effect of treatment on initial status (γ0) will 
be fixed at zero in line with the random assignment. The estimate of γl will be interpreted as causal 
effect of treatment assignment on the pre and post change in the outcome.  
 
 

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9.3 
Stimulation Group Assignment Procedures 
 
Stimulation Group Assignment Procedures: Random assignment is a procedure used in 
experiments to create study groups with similar characteristics so that the groups are equivalent 
at the beginning of the study. We perform randomization using permuted block to ensure 
balancing between arms. 
 
Randomization Rationale and Procedure: The MagLink software program is used by the 
principal investigator to define the stimulation protocol for each patient enrolled in the study. This 
includes defining whether a given patient is to receive real or sham stimulation. When the protocol 
has been defined it is downloaded to a Patient Key (USB memory device). 
 
Maintenance of Randomization Codes: In order to use Active/Placebo (A/P) for different 
groups, an Excel spreadsheet with number series for operators and subjects (active stimulation 
as well as placebo stimulation) is stored by a separate clinical research coordinator who is trained 
to maintain the blind. Subjects codes (Randomization Stimulation Numbers) are followed by 0 or 
1, where “0” is placebo stimulation and “1” is real stimulation.  
 
Maintaining Appropriate Masking: All site personnel will be masked to the stimulation group 
assignment (active versus sham) for each subject. Specific aspects of the trial design are intended 
to optimize the integrity of the masking and all staff will be trained to the procedures for masking 
during the site initiation visit. In addition to those procedures, the treater will be provided with 
individually sealed and numbered envelopes, corresponding to subject randomization numbers.  
 
Procedures for Planned and Unplanned Breaking of Randomization Codes: In the case of 
an emergency, an envelope may be opened to identify the TMS stimulation group assignment for 
a particular subject. In all circumstances, the Principal Investigator (PI) will notify NCCIH prior to 
unmasking the TMS stimulation group assignment for any subject, if possible. In the event that 
the emergency circumstances preclude first notifying NCCIH immediately, the PI will contact 
NCCIH within one business day and provide the reason(s) for unmasking and date of opening of 
the envelope must be documented in the subject’s files. The unmasking must also be documented 
on the Adverse Event page of the CRF, and in the subject’s source documents. Additionally, the 
PI will submit a written explanation describing the unmasking within 5 working days to NCCIH.  
 
Blinding and Unblinding methods: For stimulation sessions, MagLink will require use of the 
Cool-B65 A/P coil that has a built-in position sensor used to ensure that the correct (active or 
sham) side of the coil faces towards the patient's head. If the coil position is wrong the operator 
will get a "Flip Coil" prompt on the MagPro screen. To ensure best possible blinding of patients 
the current stimulation provided with the Cool-B65 A/P coil should be used to stimulate the 
patient's skin. When a stimulation session is completed, the session data are stored on both the 

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Patient Key and the Operator Key. Dr. David Spiegel and Dr. Nolan Williams are authorized to 
break the blind.  
 
Circumstances for Breaking the Blind: In the event of a serious adverse device effect, the 
Principal Investigator will carefully assess whether breaking the blind will critically affect how a 
subject is treated in response to the adverse effect and whether this knowledge outweighs the 
implications to the scientific soundness of the study. In the case of most serious adverse effects, 
the study would be discontinued and symptoms treated symptomatically irrespective of the 
knowledge of whether the stimulation received was active or sham in nature. In these instances, 
having this information would not significantly alter the treatment of the adverse effect(s). As an 
additional safeguard against bias, the IMC has been charged with making the final 
recommendations for breaking the study blind. If the IMC recommends unmasking the study, the 
key to active or sham stimulation will be obtained from the unblended CRC. Notation regarding 
the nature of the type of stimulation that the subject had been receiving will be documented in the 
subject’s source document. If the decision to break the blind is made immediately upon learning 
of the adverse event, this information will be reported to the NCCIH and reviewing IRB at the time 
of initial adverse event reporting. If the unblinding occurs after the initial reporting, the NCCIH will 
be notified of the action within ten working days from the time of breaking the blind. The reviewing 
IRB will be notified according to their reporting guidelines if the decision is made to break the 
study blind after the initial reporting. 
 
Procedure for Breaking the Blind at Study Completion: To minimize any source of bias, 
unblinding of the study will not be done until all subjects have completed all study phases. 
However, unblinding will occur if the Independent Monitoring Committee, consistent with their 
assigned charter and associated stopping rules, determines that it necessary to do so. At the end 
of the study Patient Keys are returned to the principal investigator for data analysis. The MagPro 
double-blinded research system ensures efficacy, accuracy and consistency. The system comes 
with a MagLink software program specifically developed for data collection in double-blinded 
studies. The program is used to define the stimulation protocol for each patient (real or sham 
stimulation). 
 
9.4  
Definition of Populations 
 
We will compare individuals assigned to the active rTMS condition and individuals assigned to 
the sham condition as randomized in line with the ITT principle. Noncompliance with rTMS (or 
sham) is not expected, although in that case, we will compare groups as randomized regardless 
of the compliance status in line with ITT. Missing assessment due to unusable imaging data or 
dropout will be handled as missing at random conditional on observed information. 
 
 

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9.5 
Interim Analyses and Stopping Rules 
 
 
Because of the anticipated low level of adverse events of TMS and MRI, the IMC will be charged 
with reviewing adverse events at least every six months. Serious adverse events will be reviewed 
on a monthly basis, unless a more urgent review is requested. Only under extreme circumstances 
or if it were determined that a high level of side effects was due to TMS and/or MRI, would the 
IMC be charged with breaking the study mask. This study will be stopped prior to its completion 
if: [1] the intervention is associated with adverse effects that call into question the safety of the 
intervention; [2] difficulty in study recruitment or retention will significantly impact the ability to 
evaluate the study endpoints; [3] any new information becomes available during the trial that 
necessitates stopping the study; or [4] other situations occur that might warrant stopping the 
study. 
 
 
9.6 
Outcomes  
 
 
9.6.1 Primary Outcomes  
 
 
Primary Mechanistic Outcome Measure: To determine the effect of active, inhibitory rTMS 
(cTBS) over L-DLPFC on modulating the connectivity of the neural network that underlies 
hypnotizability. 
 
This study will test an augmentation approach where one modality (rTMS) (30) is being used to 
modulate the neural circuitry underlying another technique (hypnotizability) in an effort that this 
combinatory approach may transiently produce the high hypnotizable phenotype on formal 
testing(31). It will be determined if modulation of the neural circuitry that underlies hypnotizability 
with rTMS can potentially produce a brain connectivity pattern that resembles a highly 
hypnotizable individual(31). This study proposes to measure the change in hypnotizability by 
contrasting the functional connectivity between the L-DLPFC and dACC at pre- and post-rTMS 
for both rTMS conditions (active versus sham cTBS) (31).  
 
Hypnotizability Scans for Primary Outcome Measure: All participants will receive the same 
identical pre-rTMS resting state scan(31, 51). After randomization (to either active DLPFC rTMS 
or sham rTMS) where one half (n=45) will receive active DLPFC rTMS (cTBS), and one-half sham 
DLPFC rTMS (cTBS) (n=45)(30), all participants have their hypnotizability post-rTMS scan 
session(31, 51).  
 

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fMRI Preprocessing and Analysis: All fMRI data will be preprocessed and analyzed using FSL 
(FMRIB Software Library, version 5.0) (88). Physiological signals will first be removed using 
RETROICOR and RVHRCOR (97, 98). The first 6 volumes will be discarded to allow for signal 
stabilization. The following standard preprocessing steps will then be applied: motion correction 
using least square minimization (99), removal of non-brain tissues (100), resampling to 2 x 2 x 2 
mm3 voxels, spatial smoothing with a 6 mm full-width at half-maximum (FWHM) Gaussian kernel 
to improve functional alignment between participants, and mean-based intensity normalization of 
all volumes by the same factor and high pass temporal filtering with a Gaussian-weighted least-
squares straight line fitting, and linear registration using the FMRIB’s Linear Registration Tool 
(FLIRT, 6 degrees of freedom (DOF)) to T1-weighted anatomical images and Montreal 
Neurological Institute (MNI) standard space. 
 
For each run, a first-level general linear model (GLM) will be conducted using FMRIB’s improved 
linear model prewhitening convolved using a boxcar regressor model (101). Across runs and for 
each contrast, a within-subject fixed effects analysis will be performed. For group analysis, 
FMRIB’s local analysis of mixed effects will be used within a mask of our a priori ROIs dACC and 
L-DLPFC, thresholded using family-wise error (FWE) corrected Z>2.3; cluster p<0.05. Average 
contrast of parameter estimate values will be extracted from our ROIs and Spearman’s 
correlations will be calculated between these values and differences in active versus sham rTMS. 
 
Primary Mechanistic Hypothesis: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate 
the neural network that underlies hypnotizability by producing greater increases in functional 
connectivity between DLPFC and dACC and reduced activity in both L-DLPFC and dACC. 
 
Connectivity between L-DLPFC and dACC will be assessed with resting state functional 
connectivity MRI(31, 51) at the baseline time-point and as well as at the post-rTMS time-point for 
both rTMS conditions (active and sham). It is hypothesized that inhibitory rTMS (cTBS) to DLPFC 
will result in increased fc between the DLPFC and dACC. Analyses will be restricted to the dACC 
and L-DLPFC for the Primary Outcome Measure. To determine if the active rTMS condition is 
specifically associated with change in dACC and DLPFC functional connectivity, a mask restricted 
to dACC and DLPFC will be utilized to extract the fMRI connectivity data. It is expected that the 
correlation in active rTMS group over L-DLPFC to be stronger than the correlation obtained in the 
sham rTMS group. Regression analysis will be used to investigate whether greater connectivity 
will be present between L-DLPFC and dACC for active versus sham rTMS (cTBS).  Activity in 
both regions will be measured using the fractional amplitude of low-frequency fluctuation (fALFF) 
of the fMRI signal to measure the amplitude of regional spontaneous activity throughout the brain. 
(164) It is a ratio of the power spectrum of low-frequency (0.01-0.08 Hz) to that of the entire 
frequency range, thereby controlling for overall physiological noise.  
 
 
Relevant Clinical Outcome: To determine the effect of active, inhibitory rTMS over DLPFC on 
enhancing hypnotic analgesia. 

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This aim explores if active rTMS + HA will have produce greater anti-nociceptive effects on pain 
thresholds than sham rTMS. Inhibitory rTMS (cTBS) will be applied to L-DLPFC and it is expected 
that the stimulation-induced augmentation of hypnotic analgesia will be greater in the active rTMS 
condition over the sham rTMS condition. It is expected that the strength of this correlation will be 
greater than in the active rTMS + HA condition versus sham rTMS + HA given that the hypothesis 
is that the rTMS will increase fc between L-DLPFC and dACC which is believed to transiently 
modulate these participants to have similar response to hypnotic analgesia as do high 
hypnotizables(31) given the 0.6 correlation between measured hypnotizability and the ability to 
achieve hypnotic analgesia. HA network activation/connectivity to painful thermal stimulation will 
be assessed at baseline, during pre-rTMS hypnotic analgesia, after rTMS, and during post-rTMS 
HA. Changes in mean pain ratings between baseline pain and active rTMS + HA (TBS) and sham 
rTMS + HA conditions will be compared using ANOVA. It is expected that there will be a 
significantly greater mean decrease in pain ratings with the active rTMS + HA than the sham rTMS 
+ HA condition at the p<0.05, level. 
 
Relevant Clinical Hypothesis: Active, inhibitory rTMS over DLPFC will enhance hypnotic 
analgesia as compared to sham rTMS. 
 
It is hypothesized that the rTMS modulation in hypnotizability(26) will result in greater hypnotic 
analgesia than sham rTMS. It is expected that a significantly greater mean increase across 
measures active rTMS than with the sham rTMS condition at the p<0.05, level. This hypothesis 
will be tested with linear mixed modeling. It is hypothesized that the rTMS modulation will result 
in greater analgesia than sham rTMS. This study will measure the response to thermal pain stimuli 
at baseline and after active rTMS versus sham rTMS. In particular, it is hypothesized that the 
temperature necessary to produce threshold level heat pain during the pre-TMS period will not 
produce pain following active rTMS + HA. The temperature for evoking threshold and moderate 
pain will be assessed prior to and at 5-minute intervals for 30 minutes following the application of 
rTMS + HA.  It is expected that the active rTMS stimulation + HA will temporarily eliminate pain 
following thermal stimulation at an intensity, which produced threshold level pain prior to rTMS + 
HA.  It is also hypothesized that temperatures that produced moderate pain prior to rTMS will be 
significantly reduced following active rTMS versus sham. This hypothesis will be tested with linear 
mixed modeling and changes p<.05 are considered statistically significant.   
 
 

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9.6.2 Secondary Outcomes   
 
Secondary Outcome Measure A: To determine the effect of active, inhibitory rTMS (cTBS) over 
L-DLPFC on modulating the activity and connectivity of the neural network that underlies the 
hypnotic state.  
 
This study is designed to measure the change in hypnotic intensity by contrasting the BOLD 
activity(133), TMS-BOLD activity(130), and functional connectivity(133) between the L-DLPFC 
and dACC at pre- and post-rTMS time-points for both rTMS conditions (active L-DLPFC rTMS 
(cTBS) and sham L-DLPFC rTMS (cTBS))(31).  
 
Hypnosis Scans for Secondary Outcome Measure A: All participants will receive the same 
identical pre-rTMS resting state scan(31, 51). After randomization (to either active DLPFC rTMS 
or sham rTMS) where one half (n=45) will receive active DLPFC rTMS (spaced cTBS), and one-
half sham DLPFC rTMS (spaced cTBS) (n=45)(30), all participants have their hypnotizability post-
rTMS scan session(31, 51).  
 
fMRI Preprocessing and Analysis: All fMRI data will be preprocessed and analyzed using FSL 
(FMRIB Software Library, version 5.0) (88) and in the manner described in the Primary Outcome. 
For group analysis, FMRIB’s local analysis of mixed effects will be used within a mask of our a 
priori ROIs ACC and DLPFC, thresholded using family-wise error (FWE) corrected Z>2.3; cluster 
p<0.05. Average contrast of parameter estimate values will be extracted from our ROIs and 
Spearman’s correlations will be calculated between these values and differences in active versus 
sham rTMS. 
Secondary Hypothesis A: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies hypnosis by producing greater increases in activity and functional 
connectivity between L-DLPFC and dACC. 
 
Connectivity between L-DLPFC and dACC will be assessed with resting state functional 
connectivity MRI(31, 51) at the baseline time-point and as well as at the post-rTMS time-point for 
both rTMS conditions (active and sham cTBS). Analyses will be restricted to the dACC and L-
DLPFC for this Secondary Outcome Measure. To determine if rTMS condition during the hypnotic 
state is specifically associated with change in dACC and DLPFC activity and functional 
connectivity, a mask restricted to dACC and DLPFC will be utilized to extract the fMRI activity and 
connectivity data. It is expected that the correlation in active rTMS group over L-DLPFC to be 
stronger than the correlation obtained in the sham rTMS group. Regression analysis will 
determine the strength of the relationship between the reductions of fMRI activity between dACC 
and L-DLPFC during the active versus sham rTMS conditions. Regression analysis will be used 
to investigate whether greater connectivity will be present between L-DLPFC and dACC for active 
rTMS versus sham rTMS. 

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Secondary Outcome Measure B: To determine the effect of active, inhibitory rTMS (cTBS) over 
L-DLPFC on enhancing hypnotizability (as measured by the Hypnotic Induction Profile-HIP and 
Stroop Task) and hypnotic intensity (as measured by the Hypnotic Intensity Scale-HIS).  
 
Augmenting hypnosis with active rTMS may potentially produce an intervention that works better 
(i.e. deeper hypnotic state) and/or extends to a larger part of the population (makes more of the 
population hypnotizable)(26).  
 
Hypnosis Related Measures: All participants will receive a baseline Stroop task, HIP, and HIS. 
After randomization (to either active DLPFC rTMS or sham rTMS) where one half (n=45) will 
receive active rTMS (cTBS), and one-half sham rTMS (cTBS) (n=45)(30), participant will be 
placed back in scanner and their HIS will be reassessed. After the post-rTMS scans, all 
participants will be reassessed with the Stroop task and the HIP. 
 
Analysis of Measures: Changes in HIP, Stroop Effect, and HIS between active DLPFC rTMS and 
sham rTMS conditions will be compared using ANOVA. It is expected that there will be a 
significantly greater mean increase in HIP, HIS, and Stroop Effect with active rTMS condition than 
with the sham rTMS condition at the p<0.05, level. 
 
Secondary Hypothesis B: Active, inhibitory rTMS over DLPFC will increase hypnotizability and 
hypnotic intensity as compared to sham rTMS. 
 
There are four decades of research on the effects of psychopharmacology on hypnotizability 
suggesting that while hypnotizability is a trait, it can be modified for the duration of the 
intervention(70). It is hypothesized that inhibitory left DLPFC rTMS (cTBS) will increase 
hypnotizability. It is expected that there will be a significant change in the pre-rTMS to post-rTMS 
HIP scores. It is hypothesized that the change in hypnotic depth (pre-rTMS to post-rTMS) 
achieved will be greater for the active rTMS group over the sham rTMS group given the early pilot 
work that has already been performed(26). It is expected that there will be a significantly greater 
mean increase in hypnotizability ratings with active rTMS than with the sham rTMS condition at 
the p<0.05, level. 
 
Secondary Objective C: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network underlying the conflict regulation system as a reflection of effective 
modulation of the neural circuitry underlying hypnotizability.  
 
It has been demonstrated that high hypnotizables recruit the right inferior frontal gyrus (rIFG) 
during conflict tasks while lows recruit the attentional network(32). Inhibitory rTMS has been 
demonstrated to not only modulate the hypnosis circuitry, but also change the manner in which 
the brain attends to stimuli(61). 
 

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Hypnosis Scans for Secondary Outcome Measure C: All participants will receive the same 
identical pre-rTMS Stroop task scan(32). After randomization (to either active DLPFC rTMS or 
sham rTMS) where one half (n=45) will receive active DLPFC rTMS (cTBS), and one-half sham 
DLPFC rTMS (cTBS) (n=45)(30), all participants have their post-rTMS Stroop task scan 
session(32).  
 
fMRI Preprocessing and Analysis: All fMRI data will be preprocessed and analyzed using FSL 
(FMRIB Software Library, version 5.0) (88) and in the manner described in the Primary Outcome 
Measure. For group analysis, FMRIB’s local analysis of mixed effects will be used within a mask 
of our a priori ROIs rIFG, DMN nodes, and attentional network nodes, thresholded using family-
wise error (FWE) corrected Z>2.3; cluster p<0.05. Average contrast of parameter estimate values 
will be extracted from our ROIs and Spearman’s correlations will be calculated between these 
values and differences in active versus sham rTMS. 
 
Secondary Hypothesis C: Active, inhibitory rTMS (cTBS) over L-DLPFC will modulate the neural 
network that underlies conflict regulation by producing greater activity in rIFG as well as increases 
in functional connectivity between the right inferior frontal gyrus (rIFG) and the default mode 
network (DMN) as compared to sham rTMS (sham cTBS). 
 
Connectivity between rIFG and DMN will be assessed with BOLD and resting state functional 
connectivity MRI at the baseline time-point and as well as at the post-rTMS time-point for both 
rTMS conditions (active and sham)(32). It is expected that the stimulation-induced functional 
connectivity between these the rIFG and the DMN would be increased compared to change in 
the connectivity in those receiving sham rTMS. It is hypothesized that inhibitory rTMS (cTBS) to 
L-DLPFC will result in increased fc between the rIFG and the DMN as well as increased activity 
in rIFG(32). 
Analyses will be restricted to the rIFG and the nodes of the DMN for this Secondary Outcome 
Measure(32). To determine if rTMS condition during the hypnotic state is specifically associated 
with change in rIFG and DMN activity and functional connectivity, a mask restricted to rIFG and 
DMN will be utilized to extract the fMRI activity and connectivity data(32). It is expected that the 
correlation in active rTMS group over L-DLPFC to be stronger than the correlation obtained in the 
sham rTMS group. Regression analysis will determine the strength of the relationship between 
the reductions of fMRI activity between dACC and L-DLPFC during the active versus sham rTMS 
conditions. Regression analysis will be used to investigate whether greater connectivity will be 
present between rIFG and DMN for active rTMS versus sham rTMS. 
 
Secondary Objective D: To determine the effect of active, inhibitory rTMS (cTBS) over L-DLPFC 
on the neural network underlying the post-hypnotic suggestion Stroop Effect.  
 
Post-hypnotic 
suggestion 
of 
word-blindness 
eliminates 
the 
Stroop 
effect 
in 
high 
hypnotizables(119). High hypnotizables demonstrate reduced conflict signaling during the Stroop 
task after the post-hypnotic suggestion of word-blindness(35). 

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Hypnosis Scans for Secondary Outcome Measure D: All participants will receive the same 
identical pre-rTMS post-hypnotic suggestion Stroop task scan(35). After randomization (to either 
active DLPFC rTMS or sham rTMS) where one half (n=45) will receive active DLPFC rTMS 
(cTBS), and one-half sham DLPFC rTMS (cTBS) (n=45)(30), all participants have their post-rTMS 
post-hypnotic suggestion Stroop task scan session(35).  
 
fMRI Preprocessing and Analysis: All fMRI data will be preprocessed and analyzed using FSL 
(FMRIB Software Library, version 5.0) and in the manner described in the Primary Outcome 
Measure. For group analysis, FMRIB’s local analysis of mixed effects will be used within a mask 
of our a priori ROIs ACC and DLPFC, thresholded using family-wise error (FWE) corrected Z>2.3; 
cluster p<0.05. Average contrast of parameter estimate values will be extracted from the ROIs 
and Spearman’s correlations will be calculated between these values and differences in active 
versus sham rTMS. 
 
Secondary Hypothesis D: Post-hypnotic instruction of word blindness after active, inhibitory 
rTMS (cTBS) over L-DLPFC will reduce dACC activity during the Stroop task (similar to high 
hypnotizables) as compared to sham rTMS (sham cTBS). 
 
Activity in dACC will be assessed with fMRI(35) at the baseline time-point and as well as at the 
post-rTMS time-point for both rTMS conditions (active and sham). Long-lasting (~1 hour) 
inhibitory rTMS (spaced continuous theta-burst stimulation approach(30)) will be applied to L-
DLPFC and expect that the stimulation-induced functional connectivity between these two nodes 
would be increased as a surrogate of increased hypnotizability and therefore increased post-
hypnotic Stroop Effect. 
 
Analyses will be restricted to the dACC and DLPFC for this Secondary Outcome Measure. To 
determine if rTMS condition during the hypnotic state is specifically associated with change in 
dACC and DLPFC activity, a mask restricted to dACC and DLPFC will be utilized to extract the 
fMRI activity. The correlation in active rTMS group over L-DLPFC is expected to be stronger than 
the correlation obtained in the sham rTMS group. Regression analysis will determine the strength 
of the relationship between the reductions of fMRI activity between dACC and L-DLPFC with 
active versus sham rTMS conditions.  
 
Secondary Outcome E: To determine the effect of active, inhibitory rTMS over DLPFC on 
modulating the neural network that underlies hypnotic analgesia. 
 
This aim explores if L-DLPFC rTMS modulated increase in hypnotizability will have downstream 
effects on the hypnotic analgesia modulation of the rest of the hypnotic analgesia network (ACC, 
insula and/or the somatosensory cortex) by strengthening the activations/deactivations induced 
by HA as well as strengthening the functional connectivity induced by HA.   

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Hypnosis Scans for Secondary Outcome Measure D: The participants will have a baseline scan 
with baseline pain induction in the scanner. For this scanning session, task fMRI data will be 
collected while participants are randomized to receive and rate painful thermal stimulations after 
either active rTMS (cTBS) + hypnotic analgesia (HA) or sham rTMS + hypnotic analgesia. The 
differences in pain ratings and regional brain activity of the networks related to hypnotic analgesia 
(restricted to masks of the insula, somatosensory, L-DLPFC, and anterior cingulate cortices) as 
well as analyzing the functional connectivity changes between dACC and the L-DLPFC, insula, 
somatosensory cortices as well as between L-DLPFC and the dACC, insula, and somatosensory 
cortices will be analyzed. Given the relative mechanistic independence of these two putative 
interventions (rTMS and HA)(37, 68), it is possible that active rTMS would also directly affect 
analgesia, although unlikely given stimulation frequency. Certainly the downstream neural 
network effects of both interventions have overlapping and non-overlapping brain regions that are 
specific to the intervention(37, 68). rTMS, however, has been demonstrated to reach what were 
previously thought to be non-connected regions of a given neural network in a given condition or 
state(46). It is possible that rTMS alone may activate certain network nodes in one state, but in a 
different mental state activate other network nodes(125). This study strives to determine if rTMS 
modulation of hypnotizability can produce the downstream effect of increasing functional 
connectivity and decreasing activation of anterior cingulate, insular, and somatosensory cortices, 
which are areas involved in the HA network(37).  
 
fMRI Preprocessing and Analysis: All fMRI data will be preprocessed and analyzed using FSL 
(FMRIB Software Library, version 5.0) and in the manner described in the analysis description for 
the Primary Outcome Measure. For group analysis, FMRIB’s local analysis of mixed effects will 
be used within a mask of our a priori ROIs (L-DLPFC, dACC, insula, and somatosensory cortices), 
thresholded using family-wise error (FWE) corrected Z>2.3; cluster p<0.05. Average contrast of 
parameter estimate values will be extracted from our ROIs and Spearman’s correlations will be 
calculated between these values and differences in active versus sham rTMS. 
 
Secondary Hypothesis E: Active, inhibitory rTMS over DLPFC will modulate the neural network 
that underlies hypnotic analgesia by producing a decrease in activity and an increase functional 
connectivity among the anterior cingulate, dorsolateral, insular, and somatosensory cortices 
(hypnotic analgesia network) as compared to sham rTMS. 
 
The neural network involved with HA (anterior cingulate, dorsolateral prefrontal, insular, and 
somatosensory cortices) will be assessed at baseline (after pre-TMS hypnotic analgesia 
instruction) hypnosis and after rTMS 
(again after hypnotic analgesia instruction). 
Activation/deactivation as well as connectivity between baseline and post-TMS will be contrasted 
to determine if only the active rTMS condition results in greater reductions of activity within the 
network involved in hypnotic analgesia(6, 37) in comparison to sham rTMS. Changes in activity 
and connectivity between baseline scan and HA + active DLPFC rTMS and HA + sham rTMS 
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activity and increase in connectivity with the HA + active rTMS conditions than the HA + sham 
rTMS condition at the p<0.05, level. 
 
Analyses will be restricted to the anterior cingulate, L-DLPFC, insular, and somatosensory 
cortices. The correlation in the active rTMS + HA condition is expected to be stronger than the 
correlation obtained in the sham rTMS + HA. To determine if a given rTMS condition is specifically 
associated with HA induced change in that stimulated L-DLPFC activity, a mask restricted to 
dACC, DLPFC, insula and somatosensory cortex will be utilized to extract the fMRI activity data. 
Regression analysis will determine the strength of the relationship between the reductions of fMRI 
activity within the hypnotic analgesia network(4, 19) during the active versus sham rTMS 
conditions. Regression analysis will be used to investigate whether greater activity and 
connectivity will be present in the HA network (anterior cingulate, L-DLPFC, insular, and 
somatosensory cortices) for active rTMS-augmented hypnotic analgesia versus hypnotic 
analgesia alone (sham rTMS). 
 
Secondary Outcome Measure F:   
 
F.1.To evaluate cortical excitatory and inhibitory neurotransmitters, 1H-MRS will be acquired to 
determine the concentrations of GABA and glutamate/glutamine (Glx).  
 
F.2. We will evaluate the associations between neurotransmitter levels and functional connectivity 
as well as behavioral measures of clinical pain level and duration.  
 
F.3. As an exploratory aim, we will acquire a broad spectra MRS scan to determine 
dysregulation in other neurometabolites, particularly myo-inositol - a marker of 
neuroinflammation linked to glial reactivity. 
Secondary Hypothesis F: L-DLPFC GABA levels will be negatively associated with clinical pain 
measures in participants with FMS. 
MRS Analysis: 
GABA and Glx Spectra Analysis GABA and Glx MRS will be analyzed using Gannet software 
implemented within MATLAB. Analysis will be conducted in two principal stages: 1) processing 
of raw time-domain data from the scanner into GABA-edited frequency-domain difference 
(DIFF) spectra with the following steps – line broadening, zerofill, fast Fourier transform, and 
extraction of water frequency; 2) Spectra fitting to quantify the edited GABA signals. To perform 
GABA J-difference editing two acquisitions will be acquired differing in the manipulation of the 
GABA spin system. Subsequent subtraction of the manipulated acquisitions will reveal GABA 
signals under the more prominent creatine (Cr) signal at 3 ppm. Next difference editing will be 
applied by subtracting the larger Cr signal to identify the smaller GABA signal. Next, Cr signal 
frequency-domain fitting will occur in the editing-OFF spectra. This will be conducted because 
the small GABA signal is susceptible to magnet instabilities including scanner drift and 
experimental quandaries such as subject movement. Quantification of GABA spectra will be 
obtained by applying a Gaussian model with linear baseline to the GABA signals in the DIFF 
spectra constrained within frequencies from 2.8 to 3.6 ppm, a Lorentzian model for the Cr 
signals in the OFF spectra constrained between 2.7 and 3.1 ppm, and a GuassianLorentzian 
model for the unsuppressed water spectrum constrained between 2.8 and 3.6 ppm. The 
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to water in institutional units (i.u.). Glx ratio will be derived from LCModel version 6.3-1 software 
using a simulated basis set, the jMRUI Amares algorim in a similar method descried by 
O’Gorman and colleagues [178]. Integration of the co-edited Glx signal at 3.75 ppm will carried 
out using a linear fit to the baseline and the sum of two Lorentzians to fit the doublet peak. A 
regression and/or correlation analysis will be used to determine the relationship between 
changes in connectivity, MRS and behavioral metrics (clinical pain measures and 
hypnotizability). We will include regressors of non-interest for time between study visits, sex, 
and age. 
 
Secondary Outcome Measure G:   
 
G.1. Using MRS, we will evaluate the L-DLPFC GABA concentrations before and after cTBS in 
a double-blinded sham-controlled design. The cartesian coordinate of the L-DLPFC cTBS target 
will be used for MRS voxel placement. As an internal control, right DLPFC MRS will be acquired 
for each subject to distinguish the laterality of the hypnosis effect.  
 
Aim G.2. We will test whether changes in functional connectivity and behavioral measures of 
hypnotizability and hypnotic analgesia are associated with alterations in GABA MRS 
concentration. 
Secondary Hypothesis G: cTBS neuromodulation of L-DLPFC-dACC connectivity is mediated 
by inhibitory inter-neuronal cortical pathways measured by GABA MRS in the L-DLPFC. 
Neuromodulation induced by TMS has been shown to increase L-DLPFC-dACC connectivity, but 
the neurochemistry underlying these changes is unknown. 
MRS Analysis: 
MRS analysis will be conducted identical to the Secondary Outcome Measure F. A subtraction of 
metabolic concentrations between pre- and post-TMS sessions will be used for subsequent 
correlation between changes in hypnotic analgesia and clinical pain measures. After completion 
of the study, unblinded data will be used to determine active versus sham changes in metabolic 
concentrations. 
 
 
9.7 
Data Analyses  
 
The Primary Mechanistic Outcome Measure for this study is increased functional connectivity 
between the L-DLPFC and dACC. The Relevant Clinical Outcome Measure is change in hypnotic 
analgesia as measured by change in pain thresholds. For secondary aims, the emphasis is on 
identifying the magnitude of effects (clinical significance, effect size) instead of statistical 
significance. We will test whether the change in connectivity from baseline to post-treatment is 
greater in the active rTMS group as compared to the sham group. Following the convention in 
imaging studies, we will conduct our primary analyses treating the contrast (baseline versus post) 
as one univariate outcome.  We do not expect much variation across our narrowly defined 
subjects, although some variation is still possible. Given that, we will also analyze the data in the 
linear mixed effects modeling framework (165, 166) allowing for random intercepts (although this 
is not customary in imaging studies) as a way of sensitivity analysis. The same analytical strategy 
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Hypothesis A (previously activity portion of Hypothesis 1a-in grant), activity during conflict task 
(Secondary Hypothesis C), and during post-hypnotic instruction conflict task (Secondary 
Hypothesis D).  
We are using thermal pain stimuli percept-matched to the individual receiving the intervention. 
Examining the treatment-effect moderating the role of the pain level is not a primary aim of this 
project.  
 
Moderator/mediator investigation: We will explore various baseline variables as potential 
moderators of rTMS effect. For this investigation, we will employ the McArthur approach (167, 
168) for moderator analysis.  We will also examine potential mediators of rTMS effect using the 
McArthur approach (167, 168) as well as contemporary causal mediation approaches (169-174), 
which we believe will provide valuable insights regarding the neuromodulation mechanism for the 
next phase of investigation.  
 
Handling of missing data: We use the same sample twice to achieve enough statistical power with 
our moderate sample size, not to model the change between scanning sessions. With no 
longitudinal components, the two groups (rTMS versus sham) will be cross-sectionally compared 
in our primary aims. The impact of missing data due to attrition is minimal. Further, time between 
assessments is so narrow that the probability of having cases with missing data (dropout, attrition) 
is very low.  As a way of assessing the impact of missing scan sessions, we will repeat our main 
analyses treating outcomes measured in the hypnosis scan and in the hypnotic analgesia scan 
as multivariate outcomes. This will allow us to include all participants in the analysis as long as 
one of the two scans is available. In this analysis framework, missing data will be handled 
assuming that it is missing at random conditional on observed scan session data (maximum 
likelihood estimation). Analyzing the data using both univariate and multivariate analysis 
approaches will also serve as sensitivity analyses. Additionally, we will include the order of scan 
sessions in the model to account for the carryover and order effects. 
 
 

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10. DATA COLLECTION AND QUALITY ASSURANCE 
 
 
10.1 Data Collection Forms  
 
 
Participants entering the study will be assigned a unique and random participant ID. All research 
material will be identified by ID number, which will be unrelated to the participant’s identity. There 
will be a locked file that links the ID number to identity, but only the PIs will have access. Research 
staff analyzing the data will only have ID numbers to use. Written records will be kept confidential, 
locked in file cabinets in private offices in our research laboratory. The Principal Investigator is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported.  All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  The investigators will maintain adequate case histories of study subjects, 
including accurate case report forms (CRFs), and source documentation. Data collection and 
accurate documentation are the responsibility of the study staff under the supervision of the 
Principal Investigator.  All source documents and laboratory reports will be reviewed by the study 
team and data entry staff, which will ensure that they are accurate and complete.  Unanticipated 
problems and adverse events will be reviewed by the Principal Investigators. 
 
 
10.2 Data Management  
 
 
The study staff will enter data from the CRFs into an electronic data capture (EDC) system that 
is compliant with 21 CFR (Code of Federal Regulations) Part 11 FDA (Food and Drug 
Administration) requirements. Edit checks, electronic queries, and audit trails are built into the 
system to ensure accurate and complete data collection and security. Details of the study 
stimulation sessions including stimulation parameters, such as motor threshold measurements 
(MT) for each subject, will be retained within the TMS device and REDCAP system. In addition, 
a printed report of the scan sessions will be stored as part of the subject’s source documents. 
Details from the study sessions will be entered into EDC. Case files will be created for each 
subject where completed CRFs will be stored. 
 
The database will be centralized on a dedicated file server located on a secure rack in the Stanford 
University Forsythe Hall data center. The data center is maintained by Stanford University IT 
Services and includes secured entry, 24/7 monitoring, environmental control systems, fire 
detection and suppression, and an Uninterruptible Power Supply (UPS) for protection against 
power anomalies. A Backup and Recovery Service (BaRS) is available. The file server is only 
accessible through the Stanford University network (SUNET), however off campus access to the 

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file server through SUNET is sometimes necessary and a secure connection is available through 
the Stanford Virtual Private Network (VPN) service. This file server has been utilized in the past 
to store databases for previous studies and have also use the VPN service without incident. All 
raw data forms received will be promptly stamped, entered or scanned, and filed in a locked filing 
cabinet. No information will be released to persons other than the patient without permission. 
Confidentiality is assured. Results of all studies are published in a manner that does not reveal 
the identity of individual subjects. 
 
 
Database and Web servers will be secured through controlled physical access. For security 
reasons, and in compliance with regulatory guidelines, EDC system access is granted to the user 
who owns the sign on identification and password in use. Access codes are non-transferrable. 
Personnel who have not undergone training will not access the study eCRF’s until appropriate 
training is completed and documented. The eCRF data elements do not reside on the users 
workstation; they are transmitted to a secure database as forms are completed or updated. 
Protocol-specified source documents (e.g. hospital discharge summaries, operative/procedural 
reports) will be retrieved as necessary. Copies of all study-related documentation will be retained 
within the central laboratory. Case files will be located in a secured area at each study site. All 
completed CRFs will be de-identified and subjects will be referred to using only their assigned 
study subject identifier and initials. Information stored in the source documents will be 
safeguarded according to institutional guidelines. 
 
 
Access to the database would be restricted and only the database manager can alter the complete 
database. The research assistants will be able to modify parts of the database to enter data or 
make necessary corrections to the data. Access to specific parts of the database can be granted 
to other project members with permission obtained through the Principal Investigator. All 
personnel will be required to successfully complete HIPAA training. Access to the database on 
the file server is monitored and controlled through SUNET and separate SUNET IDs and 
passwords are required. Secure email alternatives will be used to safely communicate information 
or send data between project members. Stanford IT Services provides a Secure Email service, 
which is very easy and seamless to use. To achieve email encryption, only the word “SECURE:” 
needs to be added to the subject line in an email message. Stanford School of Medicine 
Information. Resources and Technology (IRT) group also provides MedSecureSend (MSS) 
service for large files up to 20GB. Secure Email is only available to project member and 
collaborators with SUNET IDs. For collaborators outside of campus, a MedSecureSend email 
message can include an option to invite a recipient to create a MedSecure account before the 
content of the email can be opened or read. 
 

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10.3 Quality Assurance 
  
10.3.1 Training 
 
Staff training: 
 
 
rTMS Training: Every TMS operator on this study will be trained in a basic knowledge of 
brain physiology, of basic mechanisms of TMS, of the potential risks of the rTMS 
procedure, of the physiological changes induced by rTMS (99). Nolan Williams (PI) or a 
certified TMS technician will train all TMS operators and provide a letter for completion of 
training. Training will also include the ability and certification to deal with potential acute 
complications of TMS. This training will be uploaded into REDCAP database. In order to 
operate the rTMS device, the operator must have a verified rTMS training completion form 
loaded into REDCAP. 
 
 
Thermode Training: All thermode operators will be trained on the safe use of the Medoc 
Pathway Model ATS and its computer software by Dr. Yeomans or a certified Medoc 
technician. They will receive a letter certifying completion for safety training. This training 
will be uploaded into REDCAP database. In order to operate the thermode device, the 
operator must have a completed thermode safety completion form loaded into REDCAP. 
 
10.3.2 Quality Control Committee  
 
The Independent Monitoring Committee for this study is comprised of Drs. Alan Schatzberg, Jane 
Kim, and Boris Heifets. These investigators are not associated with this research project and work 
independently of the PI, David Spiegel. Dr. Schatzberg is a physician and has previously served 
on a monitoring committee. Dr. Heifets is a neuro-anesthesiologist and an expert in pain. Dr. Kim 
is a biostatistician and will serve the role of evaluation of the data. They review source documents, 
regulatory documents, data collection instruments, and study data. 
 
10.3.3 Metrics 
 
The EDC database will have consistency checks programmed into the system to inform the 
investigators of potential data issues as the data entry progresses. The exception log for entries 
will be reviewed by the IMC to identify potential training and/or data integrity issues. NCCIH will 
perform site monitoring, including review of the CRFs with verification to the source 
documentation to verify accuracy of CRF data. During monitoring visits, the study staff will make 
their computer and/or high-speed internet access available to the NCCIH study monitor so that 
he or she may verify the data entries with the source documentation as needed. If data integrity 
issues are suspected, they will be reported to the NCCIH immediately. 

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10.3.4 Protocol Deviations 
 
 
Protocol deviations that constitute unanticipated problems involving risks require prompt reporting 
to the Stanford IRB.  
 
 
A protocol deviation that constitutes an unanticipated problem involving risks to subjects or to 
others will be reported promptly to the IRB, as follows: 
 
1. Emergency deviations:  When a deviation occurs in an emergency situation, such as when a 
departure from the protocol is required to protect the life or physical well being of a participant.  
The NCCIH and Stanford IRB will be notified as soon as possible and no later than 5 days after 
the emergency situation occurred. The PI will submit a report to the Stanford IRB in eIRB under 
the Further Study Action activity, and use the Problem/Event Report.  
 
2. Major, non-emergent deviations without prior approval:  A planned deviation that is non-
emergent and represents a major change in the protocol as approved by the Stanford IRB.  The 
Stanford IRB must approve the request before the proposed change is implemented.  The PI must 
submit non-emergent deviations to the IRB for review in eIRB under the Further Study Action 
activity, and use the Change in Research activity.  If a major, non-emergent deviation occurs 
without prior IRB approval the event is considered non-compliance.  Non-compliance will be 
reported to the IRB promptly, in eIRB under the Further Study Action activity, and use the 
Problem/Event Report.  The PI’s failure to report promptly any major, non-emergent deviation for 
which the PI did not obtain prior approval is itself an incident of non-compliance. 
 
Protocol deviations that are only minor or administrative: At Stanford, minor or administrative 
protocol deviations are defined as those, which do not affect the scientific soundness of the 
research plan or the rights, safety, or welfare of human subjects.  If a protocol deviation occurs 
which meets this definition, the deviation will be reported to the Stanford IRB at the time the 
continuing review application is submitted. Examples of minor or administrative deviations could 
include:  follow up visits that occurred outside the protocol required time frame because of the 
participant’s schedule, or blood samples obtained at times close to but not precisely at the time 
points specified in the protocol. 
 
 
 

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10.3.5 Monitoring 
 
An Independent Monitoring Committee (IMC) will be assembled to oversee the safety of the study, 
subjects, and the scientific validity and integrity of data collected as part of the study. This IMC 
will include members from Stanford and will consist of one non-study, board-certified psychiatrist, 
one pain expert, and one biostatistician. The responsibilities and decision points for the IMC will 
be captured in the IMC charter. The IMC has oversight for the overall safety of the study. This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as 
noted above, as well as the construction and implementation of a data and safety-monitoring plan. 
Medical monitoring will include a regular assessment of the number and type of serious adverse 
events.  
 
Following written standard operating procedures, the monitors will verify that the clinical trial is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, Good Clinical Practice (GCP), and the applicable regulatory requirements. The 
investigational site will provide direct access source data/ documents, and reports for the purpose 
of monitoring and auditing by the NCCIH, and inspection by local and regulatory authorities. 
Quality control procedures will be implemented beginning with the data entry system and data 
quality control checks that will be run on the database will be generated.  Any missing data or 
data anomalies will be communicated to the IMC for clarification/resolution. 
 
Ongoing quality control will include regular data verification and protocol compliance checks to be 
performed by the PI (Nolan Williams, MD) and his research team. An ongoing review of study 
procedures will be done to ensure that the privacy of participants and confidentiality of data is not 
violated. There will also be adequate provisions for monitoring the collected data to ensure the 
safety of participants and to maintain the confidentiality of the research data. This second CRC 
will be responsible for addressing quality assurance issues (correcting procedures that are not in 
compliance with protocol) and quality control issues (correcting errors in data entry). 
 
Source data comprise all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data 
are contained in source documents. Examples of these original documents and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. When applicable, information recorded on the CRF shall match the source data 
recorded on the source documents. 
 

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Data will be entered by one clinical research coordinator and will be re-checked by a separate 
clinical research coordinator (monitor) to ensure accuracy. Following written standard operating 
procedures, this monitor will verify that this mechanistic clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements. 
 
 
Documents to be reviewed: 
CRFs: Reviewed by CRC and PI (N. Williams), reviewed every 3 months. 
Clinic Notes: Reviewed by CRC and PI (N. Williams), reviewed every 3 months. 
Questionnaires: Reviewed by CRC and PI (N. Williams), reviewed every 3 months. 
Neuroimaging: Reviewed by post-doc and PI (N. Williams), reviewed every 3 months. 
 
The PI (Nolan Williams) is the individual responsible for addressing quality assurance issues 
(correcting procedures that are not in compliance with protocol) and quality control issues 
(correcting errors in data entry). The frequency of internal QA review will be weekly. Measures to 
be taken for corrective action include closer monitoring of the CRC responsible for the data entry 
on first error and reassignment of this individual if pattern of errors continues.  A statement 
reflecting the results of the ongoing data review will be incorporated into the Annual Report for 
the Independent Monitoring Committee. 
 
 
 

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11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
 
 
11.1 Institutional Review Board (IRB) Review  
 
This protocol and the informed consent document (Appendix 1) and any subsequent modifications 
have been reviewed and approved by the Stanford Institutional Review Board, which is 
responsible for oversight of this study.  
 
 
11.2 Informed Consent Forms 
 
A signed consent form will be obtained from each participant.  
 
For participants who cannot consent for themselves, such as those with a legal guardian (e.g., 
person with power of attorney), this individual must sign the consent form. The consent form will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation.  
 
A copy will be given to each participant or legal guardian and this fact will be documented in the 
participant’s record.  
 
 
11.3 Participant Confidentiality  
 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
 
Those regulations require a signed subject authorization informing the subject of the following: 
 
 
What protected health information (PHI) will be collected from subjects in this study 
 
 
Who will have access to that information and why 
 
 
Who will use or disclose that information 
 
 
The rights of a research subject to revoke their authorization for use of their PHI. 
 

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In the event that a subject revokes authorization to collect or use PHI, the Principal Investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects who have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (long term survival status that the 
subject is alive) at the end of their scheduled study period. Subject confidentiality is strictly held 
in trust by the investigators, study staff, and the NCCIH.  This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to any study information relating to 
subjects.  
 
The study protocol, documentation, data, and all other information generated will be held in strict 
confidence.  No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. The NCCIH may inspect all study 
documents and records required to be maintained by the Principal Investigator, including but not 
limited to, medical records (office, clinic, or hospital) for the study subjects.  The Stanford study 
site will permit access to such records.  
 
Any data, specimens, forms, reports, video recordings, and other records that leave the Stanford 
study site will be identified only by a participant identification number (Participant ID, PID) to 
maintain confidentiality. All records will be kept in a locked file cabinet. All computer entry and 
networking programs will be done using PIDs only. Information will not be released without written 
permission of the participant, except as necessary for monitoring by the IRB,  NCCIH, and OHRP. 
 
 
11.4 Study Discontinuation  
 
The study may be discontinued at any time by the IRB, the NCCIH, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are protected.  
 
 
 

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12. COMMITTEES 
 
List of the Committees: 
 
Steering Committee: David Spiegel M.D., Nolan Williams M.D., David Yeomans Ph.D., Leanne 
Williams Ph.D., and Booil Jo Ph.D. 
Roles: David Spiegel, Chair. Nolan Williams, Co-Chair.  
 
Publication Committee: David Spiegel M.D., Nolan Williams M.D., David Yeomans Ph.D., 
Leanne Williams Ph.D., and Booil Jo Ph.D. 
Roles: David Spiegel, Chair. Nolan Williams, Co-Chair.  
 
 
 

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13. PUBLICATION OF RESEARCH FINDINGS  
 
Publication of the results of this trial will be governed by the policies and procedures developed 
by the Steering Committee. Any presentation, abstract, or manuscript will be made available for 
review by the NCCIH prior to submission.  
 
 

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15. SUPPLEMENTS/APPENDICES