Pilot Study of Neuromodulation for Enhancement of Emotion Regulation in Bipolar Mood Disorders
Phase: NA
Conditions: Bipolar Disorder, Transcranial Magnetic Stimulation
Sponsor: Massachusetts General Hospital

 
 
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CLINICALTRIALS.GOV ID: NCT03622749 
 
PROTOCOL TITLE: 
Pilot Study of Neuromodulation for Enhancement of Emotion Regulation in Bipolar Mood Disorders 
 
PROTOCOL APPROVAL DATE: 
 
Latest Approval: March 07, 2024 
 
Original Approval: September 14, 2018 
 
 
PRINCIPAL INVESTIGATOR: 
Kristen Ellard, PhD 
Dauten Family Center for Bipolar Treatment Innovation 
Massachusetts General Hospital 
50 Staniford Street, Suite 580 
Boston, MA 02114 
 
SITE RESPONSIBLE INVESTIGATOR:  
Joan A. Camprodon, MD, PhD, MPH 
Laboratory for Neuropsychiatry & Neuromodulation,  
MGH East CNY-149, Suite 2653 
13th Street, Charlestown, MA 02129 
 
SITE WHERE THE STUDY WILL BE PERFORMED 
Laboratory for Neuropsychiatry & Neuromodulation,  
MGH East CNY-149, Suite 2653 
13th Street, Charlestown, MA 02129 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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I. BACKGROUND AND SIGNIFICANCE:  
 
Emotion dysregulation contributes to the development and maintenance of a wide range of 
psychopathology, but is especially relevant for individuals with bipolar mood disorders (BD).  These 
individuals experience severe and episodic emotion dysregulation associated with maladaptive functioning, 
interpersonal problems, decreased work productivity, and suicidal ideation and behavior.1-5 To date, both 
pharmacological and psychosocial treatments fail to normalize emotion dysregulation for many bipolar 
patients.6-11 As a consequence, all too many experience poor outcomes. Thus, there is a significant need for 
new innovative approaches to target and improve emotion dysregulation in bipolar patients. Non-invasive 
neuromodulation using transcranial magnetic stimulation (TMS) may provide a viable strategy to help 
improve emotion dysregulation in bipolar mood disorders.  As a first step to test this hypothesis, the current 
proposal seeks to experimentally identify specific neural target sites for improving emotion regulation using 
TMS. If we can demonstrate target engagement of emotion regulation at the behavioral level using TMS, 
this will provide an important first step towards examining the potential utility of TMS as a viable strategy 
to help improve emotion dysregulation in bipolar mood disorders. While this is not a definitive clinical trial, 
the sham-controlled double-crossover design of this study will provide valuable information for target site 
selection for the development of TMS as an intervention strategy to improve emotion dysregulation in BD. 
 
Emotion dysregulation in bipolar mood disorders   
 
Individuals struggling with bipolar mood disorders (BD) experience chronic emotion dysregulation that can 
permeate every aspect of functioning.  The inability to adaptively regulate emotions leads to impulsive, 
risky or self-destructive behaviors; interpersonal problems; disruptions in work productivity; even 
suicidality.1-5 Whereas our current pharmacological treatments oftentimes excel in maintaining overall 
mood stability, they nevertheless fall short of specifically targeting and ameliorating emotion dysregulation 
in many patients with BD.8-10 Similarly, cognitive behavioral (CBT) and other psychosocial treatments fail 
to improve emotion dysregulation in more severely dysregulated patients, whose level of dysregulation 
ironically interferes with the ability to follow the highly didactic nature of these approaches.1,7, 11, 12 Thus, 
there is a significant need for innovative approaches to address the problem of emotion dysregulation in 
BD.  
 
 
What is emotion regulation?   
 
Emotion regulation has been operationally defined as the process by which individuals influence and 
modulate which emotions they have, when they have them, and how they experience and express them.13 
In behavioral terms, this can be interpreted as the ability to enhance or inhibit automatic, emotion-driven 
behavioral responses given current contextual demands, so as to utilize affective information in the most 
optimal, adaptive manner.  In neural terms, this translates to the reliable recruitment of neural structures to 
integrate emotionally salient information with goal-relevant information, and to regulate neural responses 
accordingly. Emotion regulation encompasses both implicit and explicit regulation processes.14 Implicit 
emotion regulation refers to automatic, reflexive regulation of emotions, such as averting one’s gaze when 
confronted with a distressing stimulus so as to dampen feelings of distress.  By contrast, explicit emotion 
regulation refers to effortful, conscious regulation of emotions, such as deliberately ascribing a new, less 
distressing meaning to a distressing situation (e.g. cognitive reappraisal). Both forms of emotion regulation 
are important for healthy, adaptive functioning. 
 
 
Targets for improving emotion regulation 
 
If we think of emotion dysregulation in behavioral terms, there are identifiable behavioral or symptom-
based targets for improvement with both pharmacological and CBT interventions. For example, teaching 

 
 
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emotion regulation skills like cognitive reappraisal through CBT, or dampening the interference of emotion 
intensity through medications.  However, these interventions assume a baseline integrity of neural 
functioning exists that would enable the capacity for successful treatment. A major roadblock to successful 
treatment in BD lies in overcoming the very pathology these interventions are attempting to ameliorate.  In 
concrete terms, patients with BD show deficits in emotion regulation at both behavioral and neural levels 
of examination, which limit the efficacy of existing treatments. Thus, there is a need to: 1) understand the 
neural pathophysiology associated with severe emotion dysregulation in BD; and 2) develop strategies to 
remediate and rehabilitate neural deficits to improve the capacity for adaptive emotion regulation. 
 
 
What are the neural circuits supporting mechanisms of emotion regulation?  
 
Existing studies of healthy individuals implicate a distributed neurocircuitry supporting both implicit and 
explicit emotion regulation. Specifically, converging evidence shows the ventrolateral prefrontal cortex 
(VLPFC), medial PFC (mPFC), anterior cingulate cortex (ACC), anterior insula and amygdala form a 
distributed network supporting adaptive emotion regulation.15-17 Within this circuitry, amygdala and 
anterior insula serve to signal salience and sensory information,16 whereas the VLPFC, ACC, and mPFC 
integrate and regulate this information according to cognitive or situational demands.18, 19 The right VLPFC 
in particular, in conjunction with the anterior insula, has been shown to form a fronto-insular network that 
is crucial for adaptively switching between salience and executive control network processing, and plays a 
key role in regulating the intensity of emotional responses.20 Increased VLPFC activation coupled with 
decreased amygdala activation has been found in studies of emotion regulation,21 motivation and behavioral 
inhibition,22 suggesting the VLPFC plays a particularly key role in maintaining emotional homeostasis for 
healthy, adaptive functioning.  Additionally, unlike the dorsolateral PFC (DLPFC), the VLPFC has direct 
efferent anatomical connections to the amygdala, and afferent connections from the amygdala through 
anterior insula, as well as connections to dorsal and medial PFC, situating this structure in a key position to 
integrate emotional and cognitive information and affect plasticity along this distributed neurocircuitry.15 
Studies of both implicit and explicit emotion regulation have identified the VLPFC as playing a pivotal role 
in successful regulation.21, 23 
 
 
Evidence for a reduced neural capacity for emotion regulation in bipolar disorder   
 
Neuroimaging studies of individuals with BD consistently point to hypoactivation of bilateral VLPFC 
coupled with hyperactivation of limbic structures in the context of emotion processing, as well as aberrant 
amygdala-VLPFC functional connectivity.24-31 For example, relative to healthy controls, decreased VLPFC 
activation and corresponding increased amygdala activation has been demonstrated during emotion 
regulation using cognitive reappraisal in euthymic BD patients.26 Decreased VLPFC activation, and 
corresponding increased amygdala activation, has also been demonstrated during performance on emotional 
Stroop and affect labeling tasks.25, 28, 32, 33 Several studies have shown increased functional connectivity 
between amygdala and VLPFC during emotion regulation and at rest, suggesting inefficient downregulation 
of amygdala by VLPFC.29, 30 This suggests euthymic BD is associated with a functional disruption in a key 
neural pathway by which the VLPFC exerts regulatory control over amygdala responses.  Thus, impaired 
recruitment of VLPFC and disrupted functional connectivity between VLPFC and the broader 
neurocircuitry supporting emotion regulation may play a key role in the severe emotion dysregulation seen 
in bipolar disorder. 
  
 
Evidence for additional potential target sites for neuromodulation 
 

 
 
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Using data from our lab, we have evaluated the baseline integrity of emotion regulation circuitry in BD by 
examining resting state functional connectivity of the insula to key regions of interest in executive control, 
default mode, and salience processing functional networks.34 BD 
patients were distinguished from healthy controls by weaker right 
anterior insula-right VLPFC functional connectivity (p=.04), replicating 
existing studies discussed above.  However, a stronger finding from this 
study showed significantly weaker right anterior insula functional 
connectivity to the left inferior parietal lobule (IPL) distinguished BD 
patients from both HCs and patients with unipolar depression (HC>BD: 
p<.001; MDD>BD: p=.01; Fig 1).  Further, using a receiver-operator 
characteristic analysis, we found anterior insula-IPL functional 
connectivity exhibited moderate to good specificity, sensitivity, and negative predictive value in classifying 
bipolar patients from unipolar or healthy controls. IPL functional connectivity was significantly correlated 
with self-report measures of perceived affective control, such that stronger IPL-insula functional 
connectivity predicted greater perceived control.  As a key node in the fronto-parietal executive control 
network, the IPL has been shown to play a major role in emotion-cognition integration and regulation, and 
is an important regional hub within an integrative multi-network system implicated in orienting attention 
and regulating cognitive resources in response to salient stimuli.35-37 The IPL also shares strong functional 
connections to anterior insula, VLPFC, and dmPFC regions of the salience network, and is strongly 
activated in tasks requiring simultaneous processing of interoceptive or affective cues and cognitive 
demands.38, 39 Thus, both the VLPFC and the IPL may be candidate target sites for improving emotion 
dysregulation in BD. 
 
Why use TMS?  
 
Transcranial magnetic stimulation (TMS) is a noninvasive and well-tolerated method of neuromodulation 
in which magnetic fields applied over the surface of the skull generate electrical currents to stimulate or 
inhibit targeted brain regions40. TMS has a well-established safety profile and it is able modulate brain 
activity without surgery, anesthesia or the generation of a convulsion41. Single and paired-pulse TMS 
protocols have been used since the mid-1980s to study human neurophysiology, with a focus on the motor 
system, cortical excitability and neuroplasticity42. Diagnostic applications have been FDA-approved for 
years, allowing the use of these protocols by clinical neurophysiologist for the assessment of pathologies 
affecting the pyramidal tract (i.e. motor conduction studies)43. Repetitive TMS (rTMS) refers to the 
application of multiple pulses of TMS, repeated over the course of a given session, with frequencies 
commonly varying between 1Hz and 50Hz40. Repetitive TMS has been used extensively in systems and 
cognitive neuroscience research, given its capacity to modulate (both up- and down-regulating) brain 
regions and networks. Importantly, the safe and well-tolerated yet interventional nature of TMS has 
allowed the establishment of causal relationships between brain activity and mental states in humans in 
vivo (e.g.,44), something that other observational noninvasive neuroscience tools (e.g., neuroimaging) are 
unable to do (these are limited to establishing correlations). Repetitive TMS (rTMS) has been suggested 
to induce changes in neural activity at the systems level, which may contribute to its therapeutic effects. 
In the motor cortex, high frequency rTMS (hf-rTMS) has been shown to increase cortical excitability, 
while low frequency rTMS (lf-rTMS) has been shown to decrease excitability45. Clinically, rTMS has 
been FDA approved for therapeutic indications and since 2008 it is used for the treatment of major 
depressive disorders46, 47. Of primary relevance to this study, TMS has been safely administered to the 
cerebellum in wide-ranging studies focusing on saccadic eye movements48-50, spinocerebellar 
degeneration51, visual motion processing52, timing tasks53, 54, ataxia55, 56, motor learning57, Parkinson’s 
disease58, 59, and SZ60.  
 
 
Theta burst stimulation (TBS) is a very efficient rTMS protocol that uses high frequency rTMS burst with 
lower stimulus intensity, smaller number of pulses and much shorter train duration, yet capable of 
facilitating longer-lasting post stimulation effects compared with traditional rTMS61, 62. TBS was 
Fig. 1 Insula  connectivity, HC>BD 
(Ellard et al., in press, Biol Psych: CNNI). 

 
 
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developed in 2004, based on the physiologic pattern of neuronal firing found in the hippocampus of 
animal61. The basic element of TBS contains a three-pulse burst at 50 Hz given every 200 milliseconds 
(i.e. at 5 Hz). By using this basic pattern, two major TBS paradigms were developed: continuous theta 
burst stimulation (cTBS, inhibitory) and intermittent theta burst stimulation (iTBS, excitatory), as shown 
in Figure 2. The stimulus intensity required for TBS (80% of active motor threshold –AMT) is lower than 
that for traditional rTMS protocols, which use 100 to 120% of the resting motor threshold (RMT). Of 
note, not only the percentage is less, but the AMT is also of lower intensity than the RMT. Consecutive 
sessions of TBS have been safely administered in SZ60, 63-65 and in BP66-69. 
 
Figure 2: Continuous and Intermittent TBS protocols (from Chung et al., 2015) 
 
 
 
 
In this study, we will administer iTBS-TMS to the right VLPFC, the left IPL, and sham (inactive) TMS to 
the right dorsomedial PFC (dmPFC), in order to study the relative effects of TMS applied to the VLPFC 
versus the IPL on performance on emotion regulation tasks.  In this way, we can identify a viable 
treatment target to develop and test TMS as an intervention to improve emotion regulation in bipolar 
disorders. 
 
 
Prior evidence for single session TMS-enhanced emotion regulation 
 
Existing evidence suggests using single-session TMS to probe emotion regulation is a viable strategy.  In a 
sample of healthy adults, De Raedt and colleagues70 investigated the effects of a single session of high 
frequency (10 hz) repetitive TMS (HF-
rTMS) over the left dorsolateral prefrontal 
cortex (DLPFC) on the ability to disengage 
from angry faces in order to identify the 
location of a probe.  They found a single 20-
minute session resulted in less engagement 
with angry faces and faster reaction time to 
probe location relative to sham TMS.  
Similarly, Etkin and colleagues (in prep) 
found applying single TMS pulses to the right 
VLPFC during an emotion dot probe task 
resulted in significantly less attentional bias 
towards angry faces and greater attentional 
regulation towards task-related goals (Figure 
3). In a study investigating the effects of HF-
rTMS on attentional control in depression, a 
single session of HF-rTMS over the DLPFC 

 
 
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resulted in significantly faster reaction times during a task switching paradigm relative to sham TMS.71 
Thus, prior evidence suggests single session rTMS is a viable strategy to modulate and improve emotion 
regulation and emotion processing in healthy and neuropsychiatric populations.  
 
 
 
 
 
Why examine two target sites? 
Prior studies indicate TMS can successfully engage VLPFC targets with subsequent regulatory effects.  
However, due to the anatomical location of VLPFC and the likelihood of stimulation-related muscular 
contraction (e.g. periocular, mandibular), concerns over tolerability and feasibility of this target site need 
to be considered (although prior studies have found discomfort to be negligible and stimulation at this site 
to be well tolerated, suggesting this may still be a feasible target for stimulation).72, 73 Nevertheless, if we 
can demonstrate that stimulation to the IPL is at least as effective at improving emotion regulation behavior 
as stimulation to the VLPFC, the anatomical location of IPL may afford a viable TMS target with reduced 
risk for patient discomfort.  Therefore, in order to identify a target site for the development of TMS as an 
intervention to improve emotion dysregulation in BD, the current study will evaluate the relative 
effectiveness of stimulation to these two target sites.   
 
 
II. SPECIFIC AIMS 
 
The specific aim of the present study is to examine the potential for targeted engagement of VLPFC versus 
IPL through iTBS-TMS to enhance emotion regulation performance in BD.  Specifically, we propose to 
recruit 15 patients with BD and 15 healthy controls in a randomized cross-over design to receive excitatory 
iTBS-TMS to the right VLPFC, the left IPL, and sham (control) TMS to the right dmPFC. Before and after 
TMS, subjects will perform three well-validated emotion regulation tasks, one measuring explicit emotion 
regulation (i.e. cognitive reappraisal) and two measuring implicit emotion regulation (see below). Previous 
work in our group has demonstrated the feasibility of conducting similar TMS behavioral studies in patients 
with severe mood disorders and successful achievement of similar recruitment goals.  
 
    Specific Aim: To determine the relative effect of IPL versus VLPFC stimulation on emotion regulation 
circuit dynamics.  
    Hypothesis: We predict TMS to IPL will result in greater improvement in behavioral indices of emotion 
regulation (i.e. decreased reaction times during an implicit emotion regulation task, decreased ratings of 
distress on an explicit emotion regulation task) relative to TMS applied to VLPFC target sites, given the 
role of the IPL in top-down executive regulation of affective processes.    
 
 
The current study will enable us to determine optimal target sites for intervention and inform future 
noninvasive and invasive rehabilitative interventions. The long-term goal of this project is to provide crucial 
target location data to support the development of noninvasive neuromodulatory approaches to improve 
emotion regulation in bipolar mood disorders.  
 
III. SUBJECT SELECTION 
 
We plan to enroll 20 patients diagnosed with bipolar I disorder for the study. 
 
Inclusion Criteria: 
 
• 
Men and women 
• 
Ages 18-50 years 
• 
Patients diagnosed with bipolar I disorder (BD-I), current mood state euthymic. 
otion dot probe task. (Etkin et al., in prep.) 

 
 
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• 
On a stable psychiatric medication regimen for at least a month prior to and during study participation 
 
 
Exclusion Criteria: 
 
• 
Any change in psychiatric medications within a month prior to and during study participation 
• 
Legal or mental incompetency 
• 
Intellectual disability 
• 
Current manic (YMRS > 12) or severe depressive episode (HAM-D-17 > 5) 
• 
Substance use disorder (abuse or dependence) with active use within the last 3 months 
• 
Significant medical or neurological illness 
• 
Prior neurosurgical procedure 
• 
History of seizures 
• 
History of ECT treatment or clinical TMS within the past three months 
• 
Implanted cardiac pacemakers 
• 
Patients who have conductive, ferromagnetic or other magnetic-sensitive metals implanted in their head 
or neck, or are non-removable and within 30 cm of the treatment coil. These include:  
o Aneurysm clips or coils 
o Carotid or cerebral stents 
o Metallic devices implanted in the head (e.g. Implanted pacemaker, medication pump, vagal stimulator, 
deep brain stimulator, TENS unit, or ventriculo-peritoneal shunt) 
o Magnetically active dental implants  
o Cochlear/otologic implants  
o CSF shunts  
o Ferromagnetic ocular implants  
o Pellets, bullets, fragments less than 30 cm from the coil 
o Facial tattoos with metallic ink, permanent makeup less than 30 cm from the coil    
o Pregnancy; breastfeeding or nursing; for women of childbearing a pregnancy test (to be ruled out by urine 
β-HCG) will be conducted prior to study. 
 
. 
 
Source of subjects and recruitment methods 
 
 
Recruitment for the proposed study will take place through the Massachusetts General Hospital (MGH) 
Dauten Family Center for Bipolar Treatment Innovation (Dauten Center).  The Dauten Center is a major 
research group at MGH, and includes 6 psychiatrists, 4 psychologists, 4 research coordinators, a full-time 
receptionist and support staff. Our clinic sees over 600 patients per year, and recruits on average 150 
patients per year into research studies. The Dauten Center patient registry includes over 500 patients who 
have consented to be contacted for participation in research studies.  Research studies are also advertised 
in a quarterly newsletter. In addition, the Dauten Center receives an average of 30 calls with requests for 
treatment per month, and callers are informed of existing opportunities to participate in research. 
Additional advertising for participation in the proposed study will be posted at the MGH Adult Outpatient 
Psychiatry Service.  
 
We will recruit subjects who meet the eligibility criteria using approaches that are standard for 
intervention studies and that the Dauten Center have successfully used in previous clinical trials for 
bipolar disorder. Participants will be recruited via psychiatric referral through the Dauten Center and 
MGH Adult Outpatient Psychiatry Service.  Additional recruitment will take place via advertisement 
through the Dauten Center Patient Registry and Partners Health Care as needed.  

 
 
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IV. SUBJECT ENROLLMENT 
 
Screening for Eligibility  
 
 
Potential participants will be pre-screened for study eligibility using a standardized form (see Healthy 
Control Phone Screen and Patient Phone Screen, attached). The form asks about age, medical and 
neurological illnesses, whether pregnant, psychiatric history, family history of psychiatric illness, 
substance use history, history of ECT or TMS treatments, history of participation in a TMS study, and 
any conditions that would preclude TMS administration (e.g., metal implants near the head or neck). If 
the potential subject cannot rule out the possibility of pregnancy, a pregnancy test will be conducted prior 
to study enrollment. In addition, patients will be screened for the presence of a current depressive or 
manic episode using the Quick Inventory of Depression Symptoms (QIDS) and the Altman Mania Rating 
Scale (AMRS). The screening interview will take approximately 10-15 minutes to complete.  
 
Patient Screening: The research coordinator will be in contact with outpatient treaters within the Dauten 
Center for referrals about potential subjects. Patients who are interested will undergo a screening 
interview for inclusion and exclusion criteria either in person or by telephone.  Patients who contact the 
Dauten Center and express interest in the study will undergo a screening interview by telephone. 
 
 
 
Potential subjects will be informed that all information obtained during eligibility screening will remain 
confidential. Screening forms that are completed for individuals who end up not meeting eligibility 
criteria will be disposed of in the confidential waste bin for shredding, according to hospital guidelines. 
 
 
Procedures of obtaining informed consent 
 
Informed consent will be obtained on all study participants. All subjects who meet eligibility criteria will 
be given a description of the study, and any questions they may have will be answered. Participants must 
be capable of understanding the nature of this study, its potential risks, discomforts, and benefits. Since 
all participants will be 18 or older, they will provide consent without parental or other guidance. We will 
obtain informed consent after the study purpose and procedures have been fully and clearly explained, 
and the potential participant has demonstrated an understanding of the protocol, willingness to participate, 
and capacity to consent.  
 
 
As a means of assessing participants’ understanding of what the study entails, we will conduct a one-on-
one informed consent survey, which asks questions such as, “What illness is being studied in this 
project?” “Are there any risks to participating in this study?” and “Will you lose any of your benefits if 
you refuse to participate in this study?” If the participant is unable to answer the questions or 
demonstrates a lack of understanding, the investigator will review the details of the study again. The 
survey therefore serves to ensure that participants are actively engaged in the informed consent process. 
For each participant, we will re-administer the informed consent survey at the beginning of each visit, in 
order to ensure that the participant is capable of consent throughout the entire study. Participants who are 
unable to answer all questions correctly even after additional information is provided will be excluded 
from the study. 
 
 
We will acquire written informed consent for all participants using the IRB-approved consent form. All 
signed forms will be stored in a file cabinet in a locked office. 
 
 
Treatment assignment, and randomization 

 
 
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All subjects, will receive all three iTBS-TMS interventions over the course of study participation.  During 
each study visit, they will receive either excitatory iTBS-TMS to the right VLPFC, excitatory iTBS-TMS 
to the IPL, or Sham (inactive) TBS-TMS to the right dmPFC. The order in which they receive these iTBS-
TMS interventions and the order of behavioral task presentation will be randomized for each subject by the 
study staff prior to the first TMS administration. Randomizations (TMS protocol, behavioral task order) 
will be conducted using software written by Gerard E. Dallal, Ph.D. of Tufts University 
(https://www.randomizer.org/). The investigators and the research coordinator will not be blinded to the 
randomized order, since all assessments pre- and post-TMS require input solely from the subjects. However, 
subjects will be blinded as to which mode of TMS they receive at each study visit. Sham TMS will use the 
exact same procedure with a sham coil, which is designed to induce the same nonspecific sensory effects 
of TMS (auditory and somatosensory activation) without inducing the neuromodulatory magnetic fields. 
At the end of each study visit, subjects will be asked to speculate on which mode of TMS (active or sham) 
they received as well as the degree of certainty of their judgment so that we can assess the potential 
contributions of subjects' expectations on their task performance. 
 
V. STUDY PROCEDURES 
 
All subjects, including healthy controls, will undergo three visits at the MGH Laboratory for Neuropsychiatry 
and Neuromodulation in the Charlestown Navy Yard Campus, with at least 36 hours separating the visits. 
 
The subject is free to withdraw from the study at any time simply by informing the investigators. Similarly, the 
investigators may decide to stop the study if the purposes of the study cannot be met (technical difficulties, new 
information on subject characteristics, etc.). 
 
Summary of Study Procedures  
The first visit will include the following procedures (for the second and third visits, the clinical 
characterization step will be skipped):  
 
 
• 
Consenting procedures (15-20 minutes) 
• 
Clinical characterization (30 minutes): 
• 
Demographics Questionnaire 
• 
Young Mania Rating Scale (YMRS) 
• 
Hamilton Depression Rating Scale (HAMD-17) 
• 
Affective Control Scale (ACS) 
• 
Difficulties in Emotion Regulation Scale (DERS) 
• 
Pregnancy screen if indicated (5 minutes) 
• 
Baseline/pre-TMS behavioral computer tasks (30 minutes) 
• 
Multisource Interference – International Affective Picture Scale Task (MSIT-IAPS) 
• 
Emotion Conflict Resolution Task (ECR) 
• 
Transcranial Magnetic Stimulation (TMS) (15 minutes) 
• 
Excitatory iTBS-TMS, VLPFC, IPL or sham dmPFC 
• 
Post-TMS behavioral computer tasks (30 minutes) 
• 
Multisource Interference – International Affective Picture Scale Task (MSIT-IAPS) 
• 
Emotion Conflict Resolution Task (ECR) 
 
 
Clinical characterization 
 
For the purposes of clinical characterization, we will record demographic (i.e. age, sex, race/ethnicity, parental 

 
 
10 
education, duration of illness, handedness) and medication information for all subjects during the first visit. For 
healthy control participants, we will administer the MINI, which assesses lifetime history of psychiatric 
symptoms and diagnoses, but not symptom severity, which can fluctuate over time. To capture the clinical 
presentation of patients at the time of the study, we will use the clinician-administered YMRS and HAM-D-17 
to capture the most severe symptoms of mania and depression respectively in the previous month.  The ACS and 
DERS, will be administered for all subjects to assess baseline emotion regulation skills. The clinical 
characterization step will not be repeated at study Visits 2 and 3. 
 
 
 
Scheduling of study visits 
 
This will be a cross-over design, in which participants will undergo excitatory iTBS-TMS to the VLPFC, 
excitatory iTBS-TMS to the IPL, or sham iTBS-TMS to the dmPFC over three study visits (Figure 4), 
separated by at least 36 hours. The order in which participants receive VLPFC vs. IPL vs. sham dmPFC 
TMS will be randomized. 
The effects of a single session of rTMS are acute and reversible, and usually recede in less than an hour. 
Nonetheless, the study visits will be separated by at least 36 hours in order to provide more than ample time for 
the brain to return to homeostatic balance and ensure that there are no potential residual TMS effects from the 
previous study visit. 
 
If scheduling permits, participants may be able to complete all three study visits in as short as one week. 
However, to accommodate scheduling flexibility for research participants, we will allow up to two months for 
participants to complete all three study visits within a single protocol.  
 
 
Figure 4. Protocol for Study Visits 
Visit 1 
≥ 36 
hours 
Visit 2 
≥ 36 
hours 
Visit 3 
Demographics Questionnaire 
  
  
YMRS 
  
  
HAM-D-17 
  
  
MINI 
  
  
ACS 
  
  
DERS 
  
  
 
  
  
 
 
 
MSIT IAPS† 
MSIT IAPS† 
MSIT IAPS† 
ECR 
ECR 
ECR 
 
 
 
TMS – sham dMPFC†† 
TMS - VLPFC†† 
TMS - IPL†† 
MSIT IAPS† 
MSIT IAPS† 
MSIT IAPS† 
ECR 
ECR 
ECR 
 
 
 
Compensation: $30 
Compensation: $30 
Compensation: $30 
+ $10 completion bonus 
†Order of behavioral task presentation randomized.  ††Order of TMS protocol 
randomized 
  
 
 

 
 
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Transcranial Magnetic Stimulation (TMS)  
 
TMS has a well-established safety profile and it is able modulate brain activity without surgery, anesthesia or 
the generation of a convulsion (Rossi et al., 2009). Since its development in the mid-1980s, it has become a 
widely used tool for neuroscience research and for clinical applications, both diagnostic and therapeutic 
(Camprodon, 2014). Repetitive TMS (rTMS) has been suggested to induce changes in neural activity at the 
systems level, which may contribute to its therapeutic effects. In the motor cortex, high frequency rTMS (hf-
rTMS) has been shown to increase cortical excitability, while low frequency rTMS (lf-rTMS) has been shown to 
decrease excitability (Maeda et al., 2000).  
 
We will use a MagVenture MagPro X100 with MagOption stimulator and two dynamic cooled butterfly coils: 
one real and one sham (MagVenture, Denmark) navigated with an infrared TMS Neuronavigation Research 
Premium system (Localite, Germany) to administer the TMS. 
 
We will start by measuring the patient´s motor threshold (MT), which is a measure of cortical excitability used 
to standardize the intensity of stimulation across subjects. To do this, the TMS coil is placed over the primary 
motor cortex (M1). Single pulses are applied with an interpulse interval (IPI) of at least 5 seconds, to prevent 
additive neuromodulatory effects. When pulses are applied at suprathreshold intensities, a volley of activity 
travels through the pyramidal motor pathways and leads to the contraction of the contralateral target  muscle 
(generally the Abductor Pollicis Brevis, Fist Dorsal Interosseus or Tibialis Anterior). The intensity of 
stimulation is sequentially reduced until we reach a point when fewer than 50% of the pulses (usually <3 out of 
6) lead to a muscle contraction (identified by visual inspection or neurophysiological motor evoked potentials). 
The first TMS intensity that is unable to elicit a muscle contraction more than 3 out of 6 pulses is considered the 
motor threshold, and usually expressed as a percentage of the maximum stimulator output. 
 
 
Once the MT is determined, we will apply iTBS to our target site (VLPFC, IPL or dmPFC). Using the 
Localite TMS MR-less neuronavigation system and standardized regional masks, we will place the TMS 
coil over the scalp position that allows direct stimulation of the target region.  
 
In a random order, patients will receive iTBS-TMS (excitatory) to VLPFC or IPL, or sham iTBS-TMS to the 
dmPFC, in each of the 3 sessions. Subjects will be blinded as to which mode of TMS (active versus sham) they 
receive at each study visit. Sham TMS will use the exact same procedure with a sham coil, which is designed to 
induce the same nonspecific sensory effects of TMS (auditory and somatosensory activation) without inducing 
the neuromodulatory magnetic fields. At the end of each study visit, subjects will be asked to speculate on 
which mode of TMS (active or sham) they received as well as the degree of certainty of their judgment so that 
we can assess the potential contributions of subjects' expectations on their task performance. 
 
Assessment measures 
 
1. Affective Control Scale (ACS; Williams, Chambless, & Aherns, 1997).  The ACS is a 42-item self-report 
measure designed to assess fear of loss of control when experiencing strong affective states.  ACS 
subscales expand on the construct of fear of fear, including fear of anxiety, fear of depression, fear of 
anger, and fear of strong positive affective states.  The ACS has demonstrated acceptable internal 
consistency, test-retest reliability, and concurrent and divergent validity (Berg, Shapiro, Chambless, & 
Aherns, 1998; Williams et al., 1997).        
 
2. Difficulties in Emotion Regulation Scale (DERS; Gratz & Roemer, 2004).  The DERS is a 36-item, self-
report measure developed to assess clinically relevant difficulties in emotion regulation.  The DERS is 
divided into six subscales assessing the following dimensions of emotion regulation: 1) nonacceptance 
of emotional responses (Nonacceptance); 2) difficulties engaging in goal-directed behaviors (Goals); 3) 

 
 
12 
impulse control difficulties (Impulse); 4) lack of emotional awareness (Awareness); 5) limited access to 
emotion regulation strategies (Strategies); and finally, 6) lack of emotional clarity (Clarity).  The DERS 
has demonstrated excellent internal consistency and good test-retest reliability.  The DERS subscales 
have demonstrated adequate internal consistency and adequate test-retest reliability (Gratz & Roemer, 
2004).  
 
3. Hamilton Depression Rating Scale (HAM-D-17;  Hamilton, 1960). Clinician-rated depressive symptoms 
were assessed monthly using 17-item HAM-D-17.  The HAM-D-17 is a well-established clinician-rated 
structured interview with high reliability and validity, recently re-evaluated in a large meta-analysis 74. 
 
4. Mini Neuropsychiatric Interview (MINI; Sheehan et al., 1992).  The MINI is a brief diagnostic 
assessment measure developed to screen for the presence of current and lifetime DSM-IV or ICD-
10 mood and anxiety disorders.   
 
5. Young Mania Rating Scale 75.  Clinician-rated (hypo)mania symptoms were assessed monthly 
using the YMRS.  The 11-item YMRS is the most widely studied instrument for mania, and its 
reliability and validity are high (Young et al., 1978). 
 
Behavioral Tasks 
 
1. MSIT-IAPS task: The MSIT incorporates aspects of well-established measures of cognitive interference 
(Stroop; Simon, and Eriksen Flanker tasks), and uses two different types of cognitive interference (spatial and 
flanker) to measure cognitive control.76, 77 Each trial of the MSIT is overlaid on an image from the International 
Affective Picture System (IAPS).78 IAPS pictures are either neutral, positive, or negative valenced, 
counterbalanced between the control and interference conditions. During each trial of the MSIT, a three-digit 
number (comprised using the numbers 0, 1, 2, or 3) was presented for 1.7 seconds on the screen. Each set 
contains two identical distractor numbers and a target number that differed from the distractors. Participants 
report via a button press the identity of the target number that differs from the two distractor numbers (Figure 1).  
During Noninterference (control) trials, distractor numbers are always zeros, and the identity of the target 
number always corresponds to its position on the button response pad (100, 020, 003). By contrast, during 
Interference trials, distractor numbers are always numbers other than 0, and the identity of the target number is 
always incongruent with its position on the button response pad (e.g. 211, 232, 331, etc.).  Trial stimuli are 
presented on the screen for 1.7s, followed by an inter-trial interval (ITI) fixation cross of varying lengths (Figure 
1). The trial and ITI sequence is determined using Optseq2 (http://surfer.nmr.mgh.harvard.edu/optseq).79 Trials 
are analyzed to examine the main effect of interference (All Interference – All Noninterference), the main effect 
of valence (All Negative – All Neutral; All Positive – All Neutral), and the interaction of interference and 
valence (Negative Interference – Negative Non-Interference; Positive Interference – Positive Non-Interference; 
Negative Interference – Neutral Interference; Positive Interference – Neutral Interference; Negative Non-
Interference – Neutral Non-Interference; Positive Non-Interference – Neutral Non-Interference).  Task 
behavioral performance is analyzed by calculating the average response time (reaction time, in milliseconds) 
and percentage of correct responses (accuracy) for each trial of interest.  The MSIT-IAPS task was recently 
validated in BD patients (Ellard et al., in press). 
 

 
 
13 
 
 
Figure 5. MSIT-IAPS task. 
 
2. Emotion Conflict Resolution Task (Etkin et al., 2006): The ECR task is a well-validated task designed to 
assess the effects of emotional conflict that arises from the incompatibility between task-relevant and task-
irrelevant emotional dimensions of a stimulus (Figure 6).80 Faces with fearful and happy expressions are 
presented with the words “happy” or “fear” written across them.  Words are either congruent (e.g. “happy” 
written across an image with a happy expression) or incongruent (e.g. “happy” written across an image with a 
fearful expression).  Subjects are asked to identify the emotional expression of the face while ignoring the word.  
Thus, successful completion of the task requires regulation of responses to task irrelevant emotional stimuli in 
order to focus on task relevant goals. Trials are analyzed with regard to immediately preceding trials: 
incongruent trials preceded by congruent trials (CI trials) measure emotion conflict, and incongruent trials 
preceded by incongruent trials (II trials) measure resolution of emotion conflict.  The ECR task has been 
validated in both healthy and psychiatric populations.  
 
 
 
 
Figure 6. ECR task. 
 
 
Compensation 
 
Subjects will be compensated by check for up to $100 for completion of a protocol. The breakdown of 

 
 
14 
compensation is as follows: 
 
• 
1st Visit (Clinical evaluation, TMS, and pre- and post-TMS assessments)  
 
$  30 
• 
2nd Visit (TMS and pre- and post-TMS assessments) 
 
 
 
 
$  30 
• 
3rd Visit (TMS and pre- and post-TMS assessments) 
 
 
 
 
$  30 
• 
Protocol completion bonus 
 
 
 
 
 
 
 
$  10 
            
 
 
 
 
 
 
 
TOTAL 
$ 100  
 
Because data from all three visits (dmPFC sham, VLPFC TMS, IPL TMS) are necessary to interpret the 
results with causal explanatory power, participants will be paid a completion bonus for completing all 
three visits. 
 
If the subject does not complete the entire study he/she will be compensated for the procedures listed 
above that were completed. Subjects are informed that it may take up to 4-6 weeks for them to receive 
their payment. 
 
 
 
VI. BIOSTATISTICAL ANALYSIS 
 
A. Data variables being collected for the study (Data collection sheet) 
 
 
We will collect the following data variables for this study: 
  
Demographic information: 
 
• 
Age 
• 
Gender 
• 
Race 
• 
Ethnicity 
• 
Handedness 
• 
Education level 
• 
Parental education level 
• 
Clinical diagnosis 
• 
Age at onset of illness 
• 
Medications  
• 
Past medical history 
• 
Smoking habits 
• 
Substance use/abuse history 
• 
Results from urine screening for pregnancy and drug use 
 
Scores from clinical scales: 
 
• 
HAM-D-17 (patients only) 
• 
YMRS (patients only) 
• 
ACS (both patients and healthy controls) 
• 
DERS (both patients and healthy controls) 
 
Scores from subject-completed surveys and tasks: 
 

 
 
15 
• 
MSIT-IAPS 
o Reaction time (ms) 
o Accuracy (%) 
o  
• 
ECR Task 
o Reaction time (ms) 
o Accuracy (%) 
 
 
B. Study endpoints 
 
As this study is not a clinical trial, there is no particular outcome measure that will be indicative of a 
study endpoint.  We will end the study when we meet our recruitment goals. In the event that we 
encounter any major adverse events, we will consult with the IRB to discuss whether the study needs to 
be terminated. 
 
 
C. Statistical analysis  
 
We will test for group differences in demographic and clinical variables using SPSS, using χ2 and t-tests 
for ANCOVA as appropriate. For both MSIT-IAPS and ECR behavioral tasks, we will analyze 
differences in trial-by-trial reaction time slopes from pre to post stimulation between IPL, VLPFC or 
Sham stimulation using generalized linear mixed model regressions.  
 
D. Power analysis (e.g. sample size, evaluable subjects) 
 
This is a pilot study. This being the first study of its kind, it is difficult to do a formal power and sample 
size analysis because we do not have a measure of effect size, but given previous similar studies and our 
usual rate of loss to follow up, we estimate we will need 20 participants  for at least 70% power to detect 
a medium effect size (f) of 0.25.   
 
 
VII. RISKS AND DISCOMFORTS 
 
Common risks of TMS procedure 
 
Subject may feel twitching of the scalp muscles during stimulation and/or local discomfort (tapping 
sensation) under the coil. It is possible that the subject may feel a headache after the TMS measurement 
that is generally caused by keeping the head in the same position for a lengthy period of time and/or by 
stimulation of the scalp muscles and nerves by the TMS pulses. TMS may also induce nausea in some 
patients81. The headache or nausea, if present, is typically mild, disappears soon and can be treated by 
mild over-the-counter analgesics. 
 
Although there are no reports suggesting increased risk for TMS during pregnancy, pregnant women are 
excluded from this study due to insufficient knowledge of the effects of the strong magnetic fields on the 
fetus. 
 
Subjects are thoroughly screened by a research assistant prior to their enrollment in the study to ensure 
subject safety. Subjects are carefully assessed before, during, and after TMS administration by study staff 
to ensure that they suffer no adverse reactions. 

 
 
16 
 
Uncommon risks of TMS procedure 
 
Repetitive TMS at high frequencies has the rare potential to induce a seizure even in healthy individuals 
(~ 8 reported cases worldwide since the invention of TMS in 1985, 1 with cTBS), but the risk for seizure 
can be effectively managed by using appropriate subject selection criteria and by keeping the TMS 
parameters within the safety parameters of the international safety consensus (Rossi et al., 2009). 
Compared with traditional low or high frequency TMS protocols, theta burst stimulation (TBS) uses less 
pulses (600 vs. 1200-1800), lower intensity (80% of AMT vs. 120% RMT) and shorter duration (40-190 
seconds vs. 20-30 minutes). With such low intensity, subjects receiving TBS seldom complain of any 
unpleasant sensation that is seen in the other rTMS stimulation protocols, and TBS has been considered 
safer than other TMS protocols. Nevertheless, one should consider that theta burst stimulation uses higher 
frequencies, even if in a patterned manner. One single case has been reported of a seizure using TBS, but 
with a stimulation intensity of 100% of the RMT (higher than the currently used 80% of the AMT). 
Oberman and colleagues published a recent review and meta analysis of the safety of TBS, and concluded 
that the “general risk of adverse events during TBS is comparable to or less than other high frequency 
rTMS protocol (Oberman et al., 2011).  
 
The TMS parameters used in this study will not result in long-term changes. Continuous TBS at an 
intensity of 80% AMT over the primary motor area produces significant inhibition of Motor Evoked 
Potential size lasting for 20 or 60 minutes depending on whether the stimulation is given for 20 seconds 
(300 pulses) or 40 seconds (600 pulses) (Huang et al., 2009). 
To protect the subjects from the risk of a seizure, this study strictly adheres to the international safety 
consensus by using only TMS parameters that have never induced seizures in healthy subjects and by 
excluding subjects at increased risk for seizures  (Rossi et al., 2009). In the unlikely event that a seizure 
occurred, the seizure would stop as soon as the TMS was stopped, and the MGH TMS clinical service 
safety plan would be activated, including transfer of the subject with an ambulance to MGH ER for a 
medical check-up.  No one has ever developed epilepsy as a consequence of TMS. There are no known or 
foreseeable long-term risks associated with TMS. 
 
Subjects are thoroughly screened by a research assistant prior to their enrollment in the study to ensure 
subject safety. Subjects are carefully assessed before, during, and after TMS administration by study staff 
to ensure that they suffer no adverse reactions. 
Psychosocial risks 
 
Answering questions about psychiatric history and symptoms during the psychiatric evaluation may cause 
anxiety or discomfort. However, participants will not be forced to answer any questions, will be given 
multiple opportunities to take breaks, and may completely withdraw from the study without any negative 
consequences. The risk of breach of confidentiality is present by extremely slight, given the precautions 
we take in de-identifying and protecting our data. The subject may feel mildly bored or frustrated while 
participating in the behavioral tasks, but he or she is free to stop at any time.  Viewing images from the 
IAPS may also cause participants minor emotional distress, anxiety or discomfort.  However, these 
images do not exceed graphic content found in mainstream media.  Participants will be informed prior to 
the start of the study of this potential risk.  Further, participants may terminate study procedures at any 
time should they experience distress. 
 
 
Although we anticipate no increase in risk of suicide or self-harm as a result of study procedures or 
participation, we are (a) studying psychiatric patients and (b) our study procedures involve asking 
participants about mood symptoms. Therefore, it is possible that in the course of study participation, 
participants may have and/or express suicidal ideation or intent. If a research staff has any concerns about 
participant suicidality during a study visit, the research team will follow the plan outlined below:  

 
 
17 
 
1. Study staff will page study PI (Dr. Kristen Ellard), site-PI (Dr. Joan Camprodon), or covering clinician (to 
be designated if both Dr. Ellard or Dr. Camprodon cannot be available for a particular study visit). Study 
staff will discuss with the responsible PI/clinician the clinical details relating to the participant's 
safety/suicidality. The responsible PI/clinician will recommend a plan as is appropriate to the clinical 
situation. 
 
2. If the responsible PI/clinician determines that the patient or clinical situation warrants further (i.e., a 
higher level of) evaluation, he/she will physically go to the location where study procedures are being 
conducted, evaluate the research participant in person, and act as the clinical situation warrants. If the 
responsible PI/clinician determines that the participant is at imminent risk of harm, the safety plan may 
include urgent transfer of the participant to the MGH Emergency Room via ambulance, contacting the 
participant’s clinician, and/or other similar procedures."  
 
We will follow a similar plan in the event that a research participant experiences any other psychiatric 
symptoms that are acutely or imminently concerning (not just suicidal thoughts or thoughts of self-harm), 
including but not limited to confusion, agitation, severe anxiety/panic, and paranoia or other psychotic 
symptoms. 
 
Informed Consent 
 
Participants must be capable of understanding the nature of this study, its potential risks, discomforts, and 
benefits. Since all participants will be 18 or older, they will provide consent without parental or other 
guidance. The candidate will obtain informed consent after the study purpose and procedures have been 
fully and clearly explained, and the potential participant has demonstrated an understanding of the 
protocol, willingness to participate, and capacity to consent.  
 
As a means of assessing participants’ understanding of what the study entails, the candidate will conduct 
a one-on-one informed consent survey, which asks questions such as “What illness is being studied in this 
project?” “Are there any risks to participating in this study?” and “Will you lose any of your benefits if 
you refuse to participate in this study?” If the participant is unable to answer the questions or 
demonstrates a lack of understanding, the investigator will review the details of the study again. The 
survey therefore serves to ensure that participants are actively engaged in the informed consent process. 
For each participant, we will re-administer the informed consent survey at the beginning of each visit, in 
order to ensure that the participant is capable of consent throughout the entire study. Participants who are 
unable to answer questions correctly even after additional information is provided will be excluded from 
the study. This process is designed to enroll only participants who have the capacity to make informed 
decisions about participation in this research and to prevent undue influence on the subject to enroll in the 
study by their physician. Participants will be given a copy of the consent form, signed by them and the 
investigator. 
 
Confidentiality 
 
We will collect sensitive clinical and personal information from subjects, as well as measures related to 
brain function and structure. These data have personal meaning, and loss of privacy around them would 
result in substantial harm to all subjects, especially patients with psychotic disorders. 
 
Thus, we will ensure that the data collected in this study remains protected and confidential. All 
information obtained in this study will be kept in a research office under lock and key at the MGH 
Martinos Center for Biomedical Imaging. Research participants will be identified by code numbers only, 
and no description of individual patients will be included in any publication. All databases related to the 

 
 
18 
study will be stored on a desktop computer belonging to the PI in the research office. Only the PI and her 
designated assistant will have access to this information. If data are shared for purposes of analysis, they 
will be transmitted only in pooled form and subjects will be identified by code. If data are shared, they 
will first be “scrubbed,” or removed, of any personally identifying header information and transferred via 
the Partners Research Computing Secure File Transfer and Collaboration system 
(http://rc.partners.org/sFTP), which is secured via 256-bit SSL encryption, scans all files with anti-virus 
software, and is HIPAA compliant. 
 
Subjects will be informed that all the information obtained in this study will be used for research 
investigational purposes only. The names of subjects will never be publicly disclosed at any time. 
Subjects will not be identifiable in any publication that may arise from this research. Subjects will receive 
a copy of the consent document to keep. Subjects will be informed that this research will be conducted 
and administered in compliance with all state and federal laws.  
 
Subjects will be informed of their confidentiality rights in the informed consent form. To ensure that 
subjects’ rights and safety are protected during the conduct of this research study, subjects consent to the 
inspection of medical records by specifically authorized monitors. Such monitoring may be performed by 
the Partners IRB, or by the FDA or other involved federal agency. 
 
Any email communication with subjects will be done using encryption, i.e. using the “Send Secure” 
function in the Partners Healthcare email system. We will also discourage subjects from communicating 
about medical issues via non-secure email. 
 
VIII. POTENTIAL BENEFITS 
 
Potential benefits to participating individuals and society 
 
 
Subjects are informed that there is no direct benefit to them from participating in this study. As mentioned 
in the section on Background and Significance, the potential benefits to society are increased 
understanding emotion regulation in bipolar mood disorders and the role prefrontal cortex regions 
(VLPFC, IPL) play in adaptive regulation. The current research, which uses TMS as a tool to investigate 
with causal explanatory power the role of the VLPFC and IPL in emotion regulation in bipolar disorders 
may provide the basis for the development of TMS as a potential treatment tool in such disorders in the 
future. 
 
IX. MONITORING AND QUALITY ASSURANCE 
 
Human Subjects Protections: 
 
See Section VI (Risks and Discomforts) for measures to protect research subjects from the risks 
associated with the informed consent process, confidentiality, psychiatric evaluations, and TMS 
procedures. 
 
Independent monitoring of source data 
 
 
Kristen Ellard, PhD.,  the Principal Investigator (PI), will be responsible for monitoring the validity and 
integrity of the data, as well as adherence to the protocol. She will be present for the informed consent 
procedures, assessments, and TMS administration for the first several subjects and closely supervise the 
training of all study staff involved in carrying out this research. In addition, co-investigator Joan 
Camprodon, MD, will be on-site at the MGH Laboratory for Neuropsychiatry and Neuromodulation in 

 
 
19 
the Charlestown Navy Yard Campus, to monitor the correct and safe administration of TMS for each 
subject. 
 
 
Standard operating procedures (SOP) will be written, routinely followed, and updated as necessary to 
ensure adherence to the IRB-approved protocol. Any time there is a change in study staff, the PI will 
again provide direct hands-on training in order to ensure that all procedures are conducted in adherence 
with the IRB-approved protocol and that the data collected are of high quality, validity, and integrity. 
Moreover, the PI will meet at least once a week with the study staff to review any issues and data quality. 
Finally, the PI will be responsible for subsequently signing all consent forms, thereby allowing her to 
monitor the informed consent process on a consistent basis. The research coordinator and PI will report 
any minor deviations from the protocol at each yearly continuing review. Major deviations will be 
reported within 5 working days of the incident's occurrence or detection. 
 
Safety monitoring (e.g. Data Safety Monitoring Board, etc.) 
 
The current research uses standard nonsignificant risk applications of TMS in the context of a 
physiological/cognitive study, not a therapeutic clinical trial; thus reporting of adverse events to the FDA 
is not applicable. Given the relatively low risk posed by the study we do not feel that monitoring by a 
DSMB is necessary. 
 
Outcomes monitoring 
 
All subjects’ clinical data will be coded with research numbers that do not contain any identifying 
information. The code linking the research number to personal identifying information will be stored in a 
password-protected encrypted computer file on a locked computer in a locked office at the Martinos 
Center. Subject interview information is stored in locked file cabinets in locked rooms at the Martinos 
Center. 
 
 
 
 
 
 
Medical Follow-up and Referrals 
 
Participants who test positive on the urine pregnancy test conducted as a part of this research study will be 
informed of the positive test result and recommended to follow-up with their primary care doctor or other 
physician. Participants who wish to speak with a medical doctor about the test results will be offered the 
opportunity to consult with the study PI.  
 
Reporting of Adverse Events 
 
As soon as the PI or a member of research staff learns of an adverse event, he/she will first consider the 
immediate safety of the patient. If the patient is not safe, either to him/herself or others, the member of the 
research staff/PI will take appropriate steps to acutely stabilize the patient. Members of the research staff 
will defer to the PI’s judgment. If there is an adverse event without an imminent safety concern, then the 
person who learned of the adverse event will call the PI and/or other members of the research staff and 
decide the best course of action to deal with the event, guided by the principles of Human Subjects 
research. They will then submit an adverse event report to the IRB and regulatory officials using the 
Research Subject Report of Adverse Event form, according to the PHRC reporting guidelines, within 5 
working days or 7 calendar days of the date they become aware of the problem. 

 
 
20 
 
 
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