Decoding Emotional Dynamics Driving Mood Instability in Bipolar Disorder
Phase: NA
Conditions: Bipolar Disorder I or II, Healthy (Controls)
Sponsor: Laureate Institute for Brain Research, Inc.

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i. Cover Sheet: 
Decoding Emotional Dynamics Driving Mood Instability in Bipolar Disorder 
Funding Source: National Institute of General Medical Science (NIGMS) 
 
Principal Investigator:  
Masaya Misaki, Ph.D., Associate Investigator, Laureate Institute for Brain Research 
6655 S Yale Ave, Tulsa, OK 74136-3326 
Phone: 918 502 5137 
FAX: 918 502 5135 
email: mmisaki@laureateinstitute.org 
web: https://www.laureateinstitute.org/masaya-misaki.html 
 
Sub-Investigator:  
Salvador Guinjoan, MD, Ph.D., Principal Investigator, Laureate Institute for Brain Research 
 
Study Site: 
Laureate Institute for Brain Research (LIBR) 
6655 S. Yale Ave, Tulsa, OK 74136 
 
Version Number: v.2.0 
October 9, 2025 
 
Summary of Changes from Previous Version: 
Version 
Information 
Summary of Revisions Made 
Rationale 
V2 
10/13/2025 
1. Section D, Inclusion Criteria:** Added PHQ-
9 to inclusion criterion #8. 
2. Section D, Exclusion Criteria (#4):** 
Revised to read: “Drug or alcohol intoxication 
(based on a positive UTOX or breathalyzer 
test at screening or study session), or 
reported alcohol/drug withdrawal. Last 
cannabis use must be >48 hours prior to the 
study session.” 
1. To accommodate the practical screening 
procedures and maintain consistency with 
a previous project. PHQ-9 is included in the 
NeuroMAP Core data collection, which all 
participants will be recruited through 
(Section E). A PHQ-9 score ≥10 is 
considered equivalent to a MADRS score 
≥15 in depressive severity. 
2. To make the exclusion condition more 
practical and operationally. 

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3. Section D, Exclusion Criteria (#9):** 
Removed the criterion: “Prescription of a 
medication outside of the accepted range, as 
determined by the best clinical practices and 
current research.” 
4. Section F, Table 1:** Moved the clinician-
administered depression and mania 
assessments (MADRS and YMRS) to the day 
of scanning. 
5. Section F, Figure 1:** Removed the second 
resting-state scan from the MRI session. 
6. Section F, Think and Regulate Affective 
States Task (TReAT):** Increased the number 
of attention trials from four 3-second trials to 
six 2-second trials. 
7. Section J, Psychiatric or Behavioral Risk:** 
Added “Current DSM-5 diagnosis of” before 
“moderate-to-severe substance use disorder.” 
3. This exclusion is beyond the scope of 
the study’s monitoring and cannot be 
reliably assessed within the study’s 
procedures. 
4. To ensure that symptom ratings reflect 
participants’ clinical status at the time of 
imaging, as symptoms may change 
between the preparation visit and the scan 
day. 
5. To ensure the total MRI session is 
completed in under two hours and to 
prioritize scans most relevant to the study 
aims. The second resting-state scan was 
deemed least essential. 
6. To increase task demand and more 
effectively clear participants’ thought states 
between affective task periods. 
7. To clarify and specify the diagnostic 
basis for determining exclusion due to 
substance use disorder. 
 
 

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Table of Contents 
A. 
Purpose of the Study .................................................................................................................................. 4 
B. 
Specific Aims .............................................................................................................................................. 4 
C. 
Background and Significance ................................................................................................................... 4 
D. 
Criteria for Participant Selection ............................................................................................................... 5 
E. 
Recruitment and Retention Plans ............................................................................................................. 6 
F. 
Study Procedures and Protocol ................................................................................................................ 6 
G. 
Potential Risks and Anticipated Adverse Events .................................................................................. 12 
H. 
Potential Benefits ...................................................................................................................................... 14 
I. 
Data Confidentiality and Management .................................................................................................... 14 
J. 
Vulnerable Populations and Exclusion Criteria ..................................................................................... 15 
K. 
Compensation for Participation .............................................................................................................. 16 
L. 
Adverse Event Reporting and Emergency Protocols ............................................................................ 17 
M. Data Sharing, Retention, and Publication ............................................................................................... 20 
N. 
Scientific Importance and Potential Impact ........................................................................................... 20 
O. 
References................................................................................................................................................. 21 
 

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A. Purpose of the Study 
The purpose of this study is to investigate the neural mechanisms underlying mood instability in individuals 
with bipolar disorder (BD) by decoding moment-to-moment emotional states using functional magnetic 
resonance imaging (fMRI) and advanced computational methods. Mood instability is a defining and impairing 
feature of BD, yet its dynamic neurobiological underpinnings remain poorly understood. 
This research seeks to understand how emotional states fluctuate over time, how these fluctuations differ 
between individuals with BD and healthy controls (HC), and how the brain supports or disrupts emotional self-
regulation. Findings from this study are expected to inform the development of personalized, neurobiologically 
informed treatments that adapt to an individual’s emotional state. 
 
B. Specific Aims 
(1) Decode momentary emotional states from whole-brain fMRI data using machine learning. 
(2) Quantify dynamic fluctuations in brain state using complexity science (e.g., metastability, fractal scaling) 
and network control theory. 
(3) Evaluate the impact of positive emotion amplification strategies on emotional state stability and 
associated brain dynamics in BD. 
Hypothesis 1: A machine learning classifier can decode different thinking states with statistically significant 
accuracy from fMRI brain activation signals. The decoded state trajectory in BD will be more unstable and 
fluctuating (i.e., exhibit greater temporal irregularity) compared to healthy controls (HC). 
Hypothesis 2: Individuals with BD will exhibit more unstable emotional state trajectories (lower metastability 
and fractal scaling) compared to HC. 
Hypothesis 3: Positive affect amplification will stabilize emotional dynamics and engage cognitive control 
regions in BD participants. 
The outcome of these aims will help the investigators develop a personalized intervention approach to stabilize 
mood fluctuations. 
 
C. Background and Significance 
Bipolar disorder (BD) is a serious mental health condition marked by significant mood instability, which impairs 
emotion regulation and leads to functional difficulties [1]. Unlike unipolar depression, BD involves rapid and 
intense mood fluctuations, including difficulty sustaining negative emotions [2]. These patterns suggest that BD 
is defined more by dynamic instability than by persistent mood states. 
Neuroimaging studies have revealed abnormalities in emotion-related brain circuits, including decreased 
activity in regulatory regions like the anterior cingulate cortex (ACC) and prefrontal cortex (PFC), and increased 
activity in emotion response regions (e.g., amygdala) [3, 4]. BD is also associated with altered connectivity in 
the default mode and frontoparietal networks [5]. Dynamic functional connectivity studies show increased 
variability in brain states, but these methods are limited by low temporal resolution and interpretability [6, 7]. 
To address these gaps, this study will decode emotional states from whole-brain fMRI patterns using machine 
learning [8, 9] and quantify emotional dynamics using complexity science and network control theory [10, 11]. 
We will also evaluate how positive emotion amplification strategies influence emotional stability, informed by 
evidence from Amplification of Positivity (AMP) psychotherapy and neurofeedback [12, 13]. This approach 
offers a novel framework for understanding mood instability in BD and identifying targets for personalized, 
adaptive interventions. 

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D. Criteria for Participant Selection 
Target Recruitment: 
• 
32 individuals with BD (BD-I or BD-II, currently in a depressive or mixed state) 
• 
32 healthy control participants 
Inclusion and Exclusion 
Inclusion Criteria 
1. Age 18 to 65 years 
2. Male or female 
3. BMI between 18.5 and 38.0 kg/m2 at Screening 
4. Capable of understanding and complying with study requirements 
5. Fluent in English 
6. Able to provide informed consent 
BD Group: 
7. Meet the DSM-5 diagnostic criteria for BD-I or BD-II who are currently depressed or mixed state defined 
by the Mini-International Neuropsychiatric Interview (MINI) [14] 
8. Moderate or greater depressive symptom severity (MADRS ≥ 15 or PHQ-9 ≥ 10) 
HC Group: 
9. No current or past psychiatric disorder (verified by MINI) 
Exclusion Criteria 
1. No telephone or easy access to telephone 
2. Significant medical problems as identified by the medical screening questionnaire: e.g. a history of 
unstable liver or renal insufficiency; glaucoma; significant and unstable cardiac, vascular, pulmonary, 
gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, or metabolic disturbance; or any 
other condition that, in the opinion of the investigator, would make participation not be in the best 
interest (e.g., compromise the well-being) of the participant or that could prevent, limit, or confound the 
protocol-specified assessments 
3. A positive test for drugs of abuse, including alcohol (breath test), cocaine, opiates, amphetamines, 
methamphetamines, phencyclidine, benzodiazepines, barbiturates, methadone, and oxycodone 
4. Drug or alcohol intoxication (based on positive UTOX or breathalyzer test at screening or study session) or 
reported alcohol/drug withdrawal, last cannabis use must be >48 hours prior to study session.  
5. Current DSM-5 diagnosis of a psychosis spectrum disorder or moderate to severe substance use 
disorder 
6. Moderate to severe traumatic brain injury or other neurocognitive disorder with evidence of neurological 
deficits, neurological disorders, or severe or unstable medical conditions that might be compromised by 
participation in the study (to be determined by primary care provider) 
7. Current significant suicidal ideation or suicide attempt within the past 3 months. 

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8. Change in the dose or prescription of a medication within the 6 weeks before enrolling in the study that 
could affect brain functioning, e.g., anxiolytics, antipsychotics, antidepressants, or mood stabilizers 
9. Taking drugs that affect the fMRI hemodynamic response (e.g., methylphenidate, acetazolamide, 
excessive caffeine intake > 1000 mg/day) 
10. MRI contraindications as documented on the MR Environment Screening 
11. Unwillingness or inability to complete any of the major aspects of the study protocol, including magnetic 
resonance imaging (i.e., due to claustrophobia), or behavioral assessment. However, failing to 
complete some individual aspects of these assessment sessions will be acceptable (i.e., being unwilling 
to answer individual items on some questionnaires or being unwilling to complete a behavioral task) 
12. Non-correctable vision or hearing problems 
Rationale for Sampling Plan 
A final sample size of 32 per group (after accounting for ~10% attrition) provides sufficient power (80%) to 
detect a medium effect size (d = 0.71) based on pilot findings, particularly in measures like fractal scaling. 
 
E. Recruitment and Retention Plans 
Recruitment Strategy 
Participants will be recruited through: 
• 
The NeuroMAP Recruitment and Assessment Core at LIBR (WCG IRB# 20231660) 
During NeuroMAP Core study procedures, initial eligibility screening will occur via phone. Individuals who meet 
preliminary criteria will be invited for an in-person screening session, where they will undergo a structured 
psychiatric assessment using the MINI interview and standardized self-report measures. No identifying 
information will be collected prior to voluntary contact with LIBR research staff. Once NeuroMAP Core data 
collection is complete, study staff will screen subjects against the eligibility criteria listed above. Trained study 
staff will contact individuals who are determined to be initially eligible to confirm eligibility and interest in 
discussing the informed consent. 
Retention and Compensation 
Participants will complete two sessions: (1) Preparation visit and (2) MRI scan visit. Participants will be 
compensated $20 per hour for time spent completing written and oral tests, and $50 per hour for time spent in 
the scanner (scanning time will not exceed 2 hours). The detailed payment structure is described in Section L. 
Compensation for Participation. Retention is further supported by flexible scheduling, reminder calls/emails, 
and a structured and respectful participant experience. 
 
F. Study Procedures and Protocol 
Study Site 
Participants will complete the study procedures at the Laureate Institute for Brain Research (LIBR) in Tulsa, 
OK. All data will be collected by LIBR staff trained on the study protocol and in research and good clinical 
practices. Data will be stored electronically using REDCap on LIBR networks and IT security. 
Overview of Study Design 
This is a cross-sectional, neuroimaging-based study designed to assess emotional state dynamics in 
individuals with bipolar disorder (BD) and healthy controls (HC) using: 

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• 
fMRI-based Think and Regulate Affectivate states Task (TReAT) 
• 
Resting-state fMRI 
• 
Structural MRI and white matter tractography 
• 
Self-report questionnaires 
• 
Computational metrics (e.g., metastability, fractal scaling, network controllability) 
Session Timeline 
The study sessions consist of two visits: one preparation session and one MRI scanning session. Table 1 
describes the overall outline of this study and measures obtained at different points in time. 
Table 1. Experimental procedure and Assessments 
Content 
Procedures/Assessments 
Visit1 
Visit 2 
1-7 days after Visit 1 
  
  
 
Before MRI During MRI After MRI 
Informed Consent 
X 
 
 
 
Mania 
Young Mania Rating Scale (YMRS)  
 
X 
 
 
Depression 
Montgomery–Åsberg Depression 
Rating Scale (MADRS) 
 
X 
 
 
Trait Rumination 
Ruminative Response Scale (RRS) [15] 
X 
 
 
State Rumination 
Brief State Rumination Inventory 
(BSRI) 
X 
X 
 
 
Hedonic 
Temporal Experience of Pleasure 
Scale (TEPS) 
X 
 
 
 
Emotion Regulation 
Emotion Regulation Questionnaire 
(ERQ)  
X 
 
 
Emotion Regulation 
Difficulties in Emotion Regulation Scale 
(DERS) 
X 
 
 
 
Positive/ 
Negative Valence 
Positive and Negative Affect Schedule-
X (PANAS-X) 
X 
X 
X 
Depression 
16-item Quick Inventory of Depressive 
Symptomatology (QIDS) 
X 
X 
 
 
Social Functioning 
Sheehan Disability Scale (SDS) 
X 
 
 
 
Trait-anxiety 
State Trait Anxiety Inventory (STAI-T) 
X 
 
 
 
State-anxiety 
State Trait Anxiety Inventory (STAI-S)  
 
X 
 
X 
Depression 
PROMIS Depression 
X 
 
 
 
Anxiety 
PROMIS Anxiety 
X 
 
 
 
Hedonia 
PROMIS General Self-Efficacy Scale 
X 
 
 
 
Anger 
PROMIS Anger 
X 
 
 
 

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Hedonia 
PROMIS Positive Affect and Well-
being 
X 
 
 
 
Subjective cognitive 
abilities 
PROMIS Applied Cognition-Abilities 
X 
 
 
 
Subjective cognitive 
concerns 
PROMIS Applied Cognition-General 
Concerns 
X 
 
 
 
Physical function 
PROMIS Fatigue 
X 
 
 
 
Sleep 
PROMIS Sleep Impairment and 
Disturbance 
X 
 
 
 
Thought collection work sheet (study original) 
X 
 
 
 
Emotion Intencity of 
events 
Likert scale for positive or negative 
emotions 
X 
X 
 
 
MRI screening 
MRI safety-screening questionnaire 
 
X 
 
 
Alcohol and drug 
Breathalyzer and urine drug 
screening test 
 
X 
 
 
Pregnancy 
(only for female) 
Urine-screening pregnancy test 
 
X 
 
 
Emotional State 
Affective slider (emotional valence 
and arousal) 
 
 
X 
 
Fatigue 
Likert scale (study original) 
 
 
X 
 
Comfort during the 
session 
Feedback Questionnaire† (study 
original) 
 
X 
Physiological measurement (Cardiogram, Respiration) 
 
 
X 
 
†The Feedback Questionnaire assesses the participant’s overall comfort during the session. It includes the 
following items: 1) How pleasant was the current MRI session for you? 2) How unpleasant was the current MRI 
session for you? 3) How challenging was the current MRI session for you? 4) How successful do you feel you 
were in following the instructions and tasks? 5) How did you feel about the amount of time you spent in the 
scanner? 
 
Preparation Session 
Informed Consent Process 
Informed consent will be obtained by a member of the research team who has received training specific to this 
study. All participant interactions will take place in private interview or exam rooms, or via private virtual 
meetings. The consent review process may be conducted either in person or virtually. 
Documented informed consent will be obtained once the consent form has been reviewed and the individual 
agrees to participate using the IRB-approved informed consent document. Participants will be provided with a 
copy of the signed consent prior to conducting study related activity. All volunteers will be at least 18 years old 
and will be asked to give fully informed, documented consent, following procedures already approved by the 
IRB. Care will be taken to explain the study thoroughly, and the process will be documented with signatures 
from both the participant and the individual obtaining consent. 

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Protection Against Coercion 
The researcher will remind participants that participation is strictly voluntary and that they have the right to 
withdraw at any time without penalty. Family members may be present during the consenting process and may 
assist in discussing the study with the participant, if requested. 
Participant Capacity 
All individuals enrolled in this study will have the capacity to consent. As noted previously, individuals with 
moderate to severe neurocognitive disorders will be excluded from the study. 
Participant/Representative Comprehension 
During the written informed consent process, the participant’s understanding of the study protocol will be 
assessed and documented by trained study staff. If a participant is unable to demonstrate adequate 
understanding of the protocol, they will not be enrolled in the study. 
Self-Report Measures 
After the informed consent document is signed during Visit 1, the study participants will be asked to complete a 
series of questionnaires either in-person using a LIBR iPad or computer, or remotely using a link sent to the 
participant’s email. Data collected from these questionnaires will be used to characterize the study population 
and examine how individual differences relate to brain activation metrics.  
Participants will be asked to complete several questionnaires related to mood, clinical symptoms, traits and 
personality characteristics, daily life functioning, and medical and mental health history. These self-report 
questionnaires are listed in Table 1. Self-report measures may be completed at home using a link from 
REDCap, as needed. 
Participants will recall eight autobiographical events, each clearly associated with one of two thinking patterns: 
rumination (past negative events) or reminiscence (past positive events), which will be used in the MRI task. 
They will generate four events per category and write brief, keyword-based descriptions to assist with memory 
recall inside the MRI scanner. Details of each event will not be requested, allowing participants to provide 
personal events honestly. 
MRI Scanning Visit 
Participants will be scheduled for Visit 2 one to seven days after Visit 1 is complete. The following instruments 
and scans will be conducted during the MR scanning visit. 
Pre-scan Assessments and MRI Preparation 
Prior to scanning, participants will receive task instructions and complete a brief training session (15–30 
minutes) to ensure understanding. They will rate distress levels related to autobiographical memories used in 
the task via a Lickert Scale. Participants will also be instructed on enhancing positive emotion during the 
regulation block using brief strategies adapted from Amplification of Positivity (AMP) psychotherapy [12, 16]. 
MRI eligibility will be confirmed before study entry. On the day of the scan, participants will complete the 
standard MRI Environment Screening Form. Alcohol and drug use will be screened using a breathalyzer and 
urine drug screening kit. Female participants will also undergo a urine pregnancy test. Vision correction will be 
provided if needed. 
All standard MRI safety and comfort measures will be implemented: removal of ferromagnetic items, 
communication setup, ear protection, and physical stabilization (e.g., neck pillow, knee support). Participants 
will be positioned in the scanner, fitted with physiological monitoring devices (pulse oximeter and respiration 
belt), and given an emergency squeeze ball. The scan operator will ensure comfort, verify task screen visibility, 
and initiate communication before starting the scan. 

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MR Safety Screening 
An MR Environment Screening questionnaire will be completed by each participant. The MRI safety-screening 
questionnaire is developed and distributed by the Institute for Magnetic Resonance Safety, Education, and 
Research (IMRSER) in Los Angeles, CA*. The safety-screening questionnaire probes for possible occupational 
exposure to metal slivers or shavings (remnants of which may remain lodged in a participant’s head or neck), 
surgical clips or shrapnel, cochlear implants, or any other form of ferrous metal implanted in or on the 
participant’s body. Participants answering in the affirmative to any of these conditions will be excluded. All 
subjects with any form of implanted wires, metal, or electronic devices will be excluded. All persons involved in 
this protocol will receive MR safety training conducted at the LIBR. 
*INSTITUTE FOR MAGNETIC RESONANCE SAFETY, EDUCATION, AND RESEARCH 7511 McConnell 
Avenue, Suite 100, Los Angeles, CA 90045, http://www.imrser.org 
Although there are no known risks of MR to pregnant women, there may be unknown risks. Therefore, females 
who are pregnant will not participate in this study. To ensure that female subjects are not pregnant at the time 
of the MRI procedure, all female participants will undergo a standard urine-screening pregnancy test prior to 
participation in any MRI scanning. 
Physiological Monitoring 
Physiological signals will be acquired through physiological monitoring of pulse rate using a finger-tip pulse 
oximeter throughout the MRI session [17]. A respiration belt that fits comfortably between the participant's 
chest and waist to measure respiratory changes. The concurrent information on pulse rate will be used to 
remove physiological fluctuations from the fMRI data. 
MRI scanning 
The MRI scan session includes a structural brain scan (T1-weighted image), field map scans (phase-encoding 
direction-flipped images with echo-planar imaging [EPI]), functional scans (T2*-weighted images using EPI to 
acquire blood-oxygenation-level-dependent [BOLD] functional MRI time-series data), and diffusion-weighted 
imaging (for diffusion tensor imaging [DTI] and white matter tractography). Figure 1 (upper panel) illustrates the 
sequence of scans. The total scan time is expected to be under 2 hours. 
Functional MRI scans include both resting-state scans and scans acquired during the Think and Regulate 
Affective states Task (TReAT). The resting-state scan is 12 minutes and participants are instructed to stay still 
while fixating a cross sign displayed on the screen. Participants’ motion will be monitored in real time during 
the MRI scan. If frequent significant motion is observed, the scan will be paused, the participant will be 
reminded of the importance of remaining still, and the scan will be restarted from that session. 
 

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Figure 1 
 
Think and Regulate Affective states Task (TReAT) 
Figure 1 (lower panel) illustrates the sequence of the Think and Regulate Affective states Task (TReAT). 
TReAT consists of seven types of blocks. In the Think block, a short description (keywords) of an 
autobiographical event is presented, and participants engage in self-relevant emotional thoughts for 20 
seconds. These keywords are provided by the participants using a thought collection worksheet (study-
specific) during Visit 1. The Think block is followed by a Rating block, during which participants use the 
Affective Slider [18] to rate valence and arousal based on the preceding Think block while viewing the same 
keywords. Eight seconds (four per measure) are provided for responses. In the Regulation block, participants 
are instructed to amplify positive mood for 20 seconds while continuing to view the same keywords. At the end 
of this block, another Rating block is presented for eight seconds to assess the affective state during the 
Regulation block. In the Attention block, an array of five arrows is presented, and participants must respond to 
the direction of the center arrow within two seconds per trial; each block contains six trials. In the Rest block 
(Rest), a fixation cross is displayed for 16 seconds, during which participants are instructed to clear their minds 
and avoid directed thoughts. A Rating block follows the Rest block to assess the affective state during resting. 
These blocks will be repeated eight times in one fMRI scan run, and four runs will be performed. 
Post-Scan Assessments 
At the end of each scanning run, participants are asked to evaluate their task performance, level of sleepiness, 
and fatigue using a Lickert scale in response to the following questions: 1) How difficult was it to engage with 
your thoughts during the thinking blocks? 2) How successful were you in engaging with your thoughts during 

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the thinking blocks? 3) How sleepy were you during the scan? 4) How emotionally drained do you feel right 
now? 5) How tired are you right now? 
After the scanning session, participants complete the PANAS-X and STAI-S to assess their current emotional 
states. In addition, the Feedback Questionnaire is administered to evaluate the participant’s overall comfort 
during the session (see Table 1). 
Participant Discontinuation and Withdrawal 
Participants will be informed that participation is completely voluntary and that they may withdraw from the 
study at any time. If a participant withdraws or is discontinued, the reason and the method used to determine 
the need for discontinuation will be documented. Participants will be withdrawn if they revoke consent or if the 
investigator determines that continued participation is not in their best interest. This may include newly 
emerging or worsening suicidal ideation. Participants may also be withdrawn if they do not comply with staff 
instructions or are unable to remain still in the MRI scanner and continue to exhibit frequent motion despite 
guidance, as excessive motion renders the MRI data unusable. In the event of a system failure that prevents 
completion of the scanning session, we will attempt to reschedule the session within one week of the canceled 
appointment. If the participant is unavailable during this time, they will be withdrawn from the study. 
Lost to Follow-up 
A participant will be considered lost to follow-up if they fail to return for a scheduled 2nd visit and study staff are 
unable to contact the participant after 3 attempts. 
The following actions must be taken if a participant fails to return for a 2nd session: 
• 
The study staff will attempt to contact the participant, ascertain if the participant wishes to and/or should 
continue in the study, and as needed, reschedule the missed visit. 
• 
Before a participant is deemed lost to follow-up, the study staff will make every effort to regain contact 
with the participant (where possible, 3 telephone calls, 3 text messages, or, if necessary, an email or 
certified letter to the participant’s last known mailing address or local equivalent methods). These 
contact attempts will be documented in the participant’s research record or study file. 
• 
If there is any concern about the safety of a participant lost to follow-up (e.g., due to previously 
recorded suicidal ideation) and study staff are unable to reach the individual, then confidentiality may 
be broken and the COPES hotline (918-744-4800) may be called to help ensure safety of the 
participant. 
• 
Should the participant continue to be unreachable, he or she will be considered to have withdrawn from 
the study with a primary reason of lost to follow-up. 
Estimated Time Commitment 
• 
Visit 1: ~2.5 hours 
• 
Visit 2: ~4 hours (2 hours MRI + 2 hours pre/post assessments) 
• 
Total: ~6.5 hours per participant 
 
G. Potential Risks and Anticipated Adverse Events 
Risks Associated with Study Participation 
The proposed study involves minimal to moderate risk. Potential risks include: 
Psychological Risks 

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• 
Emotional distress may arise during the Think and Regulate Affective states Task (TReAT) when 
participants recall negative experiences. 
• 
Participants with BD may experience temporary mood worsening due to emotional engagement. 
Mitigation Strategies for Psychological Risks 
• 
The task will be paused immediately upon participant request. 
• 
Fatigue and emotional distress are assessed at the end of each TReAT run. If elevated distress is 
indicated in the participant's responses, we will ask the participant about their well-being and their 
willingness to continue the session. 
• 
A clinical psychologist or trained clinical staff will be consulted if the participant reports significant 
emotional discomfort. If recommended by the LIBR staff psychiatrist or clinical staff, the participant may 
be referred to speak to their primary care provider or mental health practitioner, given a list of mental 
health resources, escorted to the Clinical Assessment Department at Laureate Psychiatric Clinic, or 
contact emergency services. 
MRI-Related Risks 
• 
Claustrophobia: Anxiety due to confined space 
• 
Magnetic field hazards 
• 
Peripheral nerve stimulation: Rare muscle twitches or discomfort during scanning 
• 
Noise-related discomfort: MRI scanner produces loud sounds 
• 
Dizziness 
Mitigation Strategies for MRI-related Risks 
• 
To reduce the risk of claustrophobia, participants will be thoroughly informed about the procedure and 
the scanner environment. If there is concern about a participant’s ability to tolerate the scanner, a mock 
scan may be conducted. If a participant is unable to tolerate the confined environment of the MRI 
scanner, their participation will be discontinued. 
• 
Screening conducted to exclude participants with metal implants or devices. 
• 
Participants will be monitored throughout the session; they can communicate with the MRI technician at 
all times. Any reported changes in skin sensations or symptoms like muscle twitching will prompt 
immediate assessment by the scan operator and possible removal from the scanner. 
• 
Participants will wear earplugs and headsets that reduce scanner noise by approximately 20–40 dB. 
They will be instructed to inform staff if the noise causes any physical or psychological discomfort. 
• 
To reduce the risk of dizziness, participants will be instructed to move slowly when rising from the 
scanner table. 
Confidentiality Risks 
• 
Potential loss of privacy due to sensitive data collection (psychiatric history, emotion ratings, 
neuroimaging) 
Mitigation Strategies for Confidentiality Risks 
• 
See mitigation plan in section I Data Confidentiality and Management below 
Medical / Physical Risks 

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• 
Minor fatigue or discomfort due to long session duration 
• 
Standard urine drug screening and pregnancy testing may cause mild embarrassment or 
inconvenience 
Mitigation Strategies for Medical / Physical Risks 
• 
The task will be paused immediately upon participant request. 
• 
Fatigue and emotional distress are assessed at the end of each TReAT run. If elevated distress is 
indicated in the participant's responses, we will ask the participant about their well-being and their 
willingness to continue the session. 
• 
If a pregnancy test is positive, the result will be discussed with the participant, and counseling will be 
offered if the result causes distress. 
Contingency Plans for Suicidality 
See Section M for contingency protocols regarding suicidality. 
 
H. Potential Benefits 
Benefits to Participants 
There are no direct medical or therapeutic benefits to participants. However, participants may gain personal 
satisfaction from contributing to research on bipolar disorder, receive incidental health information (e.g., clinical 
MRI findings), and receive referrals for clinical services if needed (including mental health support). 
Benefits to Society and Scientific Knowledge 
This study has the potential to significantly advance our understanding of neural mechanisms underlying 
emotional instability in bipolar disorder, dynamic brain state transitions associated with mood regulation, and 
the impact of emotion regulation strategies, such as positive affect amplification. These findings may inform 
development of real-time, adaptive interventions and improved diagnostic tools and treatment personalization 
for mood disorders. 
Risk–Benefit Assessment 
The risks associated with the study (e.g., emotional discomfort, MRI-related risks) are minimal to moderate, 
and are well managed through protocol safeguards. The potential scientific and clinical value outweighs these 
risks. 
 
I. Data Confidentiality and Management 
Collection of Personally Identifiable Information (PII) 
The following limited PII will be collected: 
• 
Full name 
• 
Contact information (address, phone, email) 
This information is required solely for screening and scheduling purposes. 
Data Collected: 
• 
Clinical & cognitive: Table 1 

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• 
Behavioral: Emotional ratings (valence/arousal) during the TReAT 
• 
Neuroimaging: T1-weighted anatomical, resting-state fMRI, TReAT task fMRI, DTI 
• 
Physiological: Heart rate (measured via photoplethysmography [PPG]) and respiration (measured via a 
belt sensor) 
The collection and processing of personal data will be limited to what is necessary to achieve the study 
objectives. Study records and urine samples will be assigned code numbers (combinations of letters and 
numbers) that do not directly identify individuals. 
All data will be stored in a centralized repository using the Brain Imaging Data Structure (BIDS), a widely 
accepted standard that facilitates data sharing, export, and integrity validation. 
Electronic data will be collected using REDCap (Research Electronic Data Capture), a secure, HIPAA-
compliant software platform developed by Vanderbilt University and supported by a global consortium. 
REDCap projects use a detailed, study-specific data dictionary developed through an iterative process by the 
research team with IT support, resulting in a well-structured data collection strategy. REDCap servers are 
housed in a local data center at LIBR, with encrypted web-based transmissions, protected by firewalls and 
passwords. 
Paper records containing PII, including consent forms and screening documents, will be stored in a secure 
medical records room accessible only to authorized personnel. 
Privacy and Confidentiality Protections 
• 
Participants will be assigned a unique ID code; names and identifiers will be stored separately in a 
secure, access-restricted database. 
• 
All hard copy materials will be stored in locked cabinets, and electronic data will be stored on 
password-protected, firewall-secured servers. 
• 
Only research team members and IRB-approved staff will have access to identifying information. 
Participant confidentiality will be strictly maintained. Records will only be disclosed as required by law or as 
described in the informed consent document under “Confidentiality.” Authorized parties — such as the study 
doctor, sponsor representatives, the United States Food and Drug Administration (FDA), and the WCG 
Institutional Review Board — may inspect identifiable study records under specific regulatory conditions. 
However, participants will not be identified in any reports or publications. 
 
J. Vulnerable Populations and Exclusion Criteria 
This study does not include any federally recognized vulnerable populations, such as children (participants 
must be 18+), prisoners, or pregnant women/fetuses. All female participants will undergo a urine pregnancy 
test prior to MRI scanning. Pregnant individuals will be excluded from participation and referred for appropriate 
counseling if needed. 
Cognitive or Decisional Impairment 
Participants must demonstrate a clear capacity to understand the study procedures and must be able to 
provide informed consent independently. Individuals judged to be incapable of informed decision-making will 
not be enrolled. 
Psychiatric or Behavioral Risk 

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Participants with any of the following will be excluded: 
• 
Current psychosis 
• 
Current DSM-5 diagnosis of moderate-to-severe substance use disorder  
• 
Active suicidal intent or recent suicide attempt (past 3 months) 
Ongoing monitoring of the participant’s psychiatric status will occur throughout participation. Any new risk will 
trigger immediate mitigation listed in section G. Potential Risks and Discomforts and possible withdrawal from 
the study. 
Additional Exclusions 
• 
MRI contraindications (e.g., metal implants, pacemakers) 
• 
Severe or unstable medical conditions 
• 
Medications that alter fMRI signal (e.g., methylphenidate, excessive caffeine) 
• 
Inability to complete core study procedures (e.g., cognitive tasks, emotional recall) 
 
K. Compensation for Participation 
Payment Structure 
Participants will be compensated $20 per hour for time spent completing written and oral tests, and $50 for 
time spent in the scanner (the scanning time will not exceed 2 hours). Table 2 shows the details of 
compensation. Total compensation is up to $190 for full participation. 
Table 2. Compensation 
Approximate 
Time in Hours 
Estimated 
Compensation 
Incentive 
Earned 
Visit 1  
 
 
 
Consent 
0.5 
$10 
Symptom evaluations 
1.5 
$30 
 
Daily use of emotion regulation strategies (study original), 
Thought collection (study original) 
0.5 
$10 
 
Total for Visit 1 
2.5 
$50 
 
Visit 2 
 
 
 
Pre MRI symptom evaluations 
1.0 
$20 
Task instructions and practice (outside of MRI) 
0.5 
$10 
 
MRI scan 
2 
$100 

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Post MRI symptom evaluations 
0.5 
$10 
 
Total for Visit 2 
4 
$140 
Total for completing the study 
$190 
 
Conditions for Partial Payment 
Participants who do not complete all study sessions will be compensated proportionally for the time they 
participated, including any portion of the preparation session and/or MRI session that was completed. 
Incentive Justification 
This compensation reflects: 
• 
The time commitment (~6.5 hours total) 
• 
The cognitive and emotional effort required 
• 
Time spent in the MRI scanner (more intensive) 
The compensation amounts are reasonable and not coercive, consistent with IRB-approved standards for 
similar research conducted at LIBR. 
 
L. Adverse Event Reporting and Emergency Protocols 
Monitoring for Adverse Events (AEs) 
Participants will be monitored for physical, psychological, and behavioral distress throughout the study by 
trained research staff. This includes monitoring during screening, MRI procedures, and task performance. 
Potential adverse events include emotional distress, claustrophobia, dizziness, and any symptoms suggesting 
suicidal ideation or intent to harm self or others. 
Response to Adverse Events 
Minor events (e.g., mild distress or discomfort) will be addressed by pausing study procedures and offering 
participants appropriate support. 
Serious Adverse Events (SAEs) will be promptly reported and evaluated by the Principal Investigator (PI) or a 
designated LIBR physician. 
If an emergency arises, participants will be immediately referred to emergency medical care or psychiatric 
evaluation, in accordance with the LIBR Psychiatric Emergency Protocol. 
Emergency Medical Protocol 
The study will be performed at the Laureate Institute of Brain Research, 6655 S. Yale Ave, Tulsa OK, 74136. In 
the instance of an adverse event, the following standard procedures will be followed: 
1. The participant will be directly evaluated by a LIBR study team member, and the severity of the adverse 
event will be determined in conjunction with the study principal investigator and a member of the LIBR 
physician team. A psychiatric and/or medical evaluation will be performed if the study personnel has concerns 
about the health of the individual. Depending on the severity of the adverse event, the study may be stopped. 

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2. In the event that a life-threatening medical emergency is detected, in which a participant becomes 
unresponsive, is not breathing, or is only gasping, the LIBR study team member will activate the LIBR medical 
emergency procedure. According to this procedure, if the LIBR study person is alone with the participant, they 
will call for a second rescuer. Once there are two rescuers present, Rescuer 1 (a Basic Life Support (BLS) 
certified member of the study staff) will immediately begin performing cardiopulmonary resuscitation (CPR). 
Rescuer 2 will coordinate help, which includes calling paramedics, getting a LIBR physician, getting the 
nearest automatic defibrillator, and assisting Rescuer 1 with CPR. They may rotate CPR with other Basic Life 
Support (BLS) certified members of the study staff including the study physician until the paramedics arrive. 
3. Simultaneously, a member of the study staff will call for emergency response services by dialing 911. Based 
on prior experience, the response time is approximately 5 minutes for the Emergency Medical Services 
Authority (EMSA). 
4. Immediately after calling for EMSA, the same study staff will bring the Automated External Defibrillator 
(AED) to the scene. LIBR possesses three AEDs. Each AED is positioned in the participant testing areas, 
immediately outside of testing rooms. There is an AED positioned 30 feet outside of the infusion room. 
5. The study staff member will subsequently activate the LIBR emergency response alert, triggering a 
notification via overhead speakers throughout the building. This will call all other BLS certified staff members 
(physicians, and nurses) to the scene. 
6. While awaiting EMSA responders (estimated response time: 5 minutes), all LIBR study staff present (BLS 
certified) will follow BLS protocol including performance of CPR if applicable, and AED deployment if 
applicable. 
7. EMSA responders will determine the need for implementing the appropriate Advanced Cardiac Life Support 
(ACLS) protocol. 
8. Emergency medical services responders will determine the need for transfer to the Saint Francis Healthcare 
System Emergency Department (located across the street) for further evaluation and management. 
Contingency Plans for Suicidality 
Individuals who report having a suicide plan or intent to attempt suicide at any point during the study will be 
excluded from participation. Any participant excluded for these reasons will be immediately referred for 
emergency care in accordance with the LIBR Psychiatric Emergency Protocol. 
If a participant reports suicidal ideation while enrolled in the study, they will be immediately evaluated by a 
LIBR physician and referred for appropriate treatment per the LIBR Psychiatric Emergency Protocol. At any 
time during the study, if a participant reports increased psychological distress, suicidal ideation, or intent to 
harm themselves or others, LIBR physician or a licensed designee will be contacted immediately to ensure 
proper clinical care and to comply with mandated reporting requirements. Emergency services (911) or the 
Community Outreach Psychiatric Emergency Services (COPES, 918-744-4800) will be contacted if necessary 
and in all cases after hours (weekdays after 18:00) or on weekends. If such concerns arise while the 
participant is physically present at LIBR, a LIBR physician or psychiatrist will be available on site during regular 
business hours to address any concerns that arise. This team consists of three psychiatrists. Dr. Salvador 
Guinjoan MD, PhD, a LIBR principal investigator, is a board-certified psychiatrist with 20 years of experience in 
assessing and managing patients with mood and anxiety disorders including suicide assessment and 
management. Dr. Martin Paulus MD (NeuroMAP PI) is a board-certified psychiatrist with 25 years of 
experience in assessing and managing patients with mood and anxiety disorders including suicide assessment 
and management. Dr. Adrienne Taren, MD, PhD is a state licensed emergency medicine physician with 9 
years of emergency medicine experience.. LIBR has set up a rotating coverage system so a board-certified 
physician is always reachable. 

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For participants who are physically present at the LIBR facility and are deemed to be at serious risk for suicide, 
LIBR policy requires referral to the Clinical Assessment Department (CAD) at Laureate Psychiatric Clinic and 
Hospital (LPCH) for further evaluation and crisis support. If the participant agrees, a LIBR staff member may 
accompany them to CAD, which is located approximately 100 yards from the LIBR building. If a participant 
refuses escort and/or chooses to leave the premises, the study clinician will contact the Community Outreach 
Psychiatric Emergency Services (COPES, 918-744-4800), Oklahoma's only free mobile psychiatric crisis 
response service, available 24 hours a day to dispatch a mobile unit to the participant’s location. 
For participants with clinical concerns that do not represent an immediate psychiatric emergency, contact 
information will be provided during the informed consent process. This includes a phone number for reaching a 
LIBR clinician during regular business hours (Monday–Friday, 08:00–18:00), and a number for the 24-hour on-
call psychiatric service provided by the Laureate Psychiatric Clinic and Hospital Call Center during evenings, 
nights, weekends, and holidays. Participants will also be reminded of the availability of the Mental Health 
Lifeline, which can be reached by dialing 988. 
Upon completion of the study or early withdrawal, participants who are currently engaged in mental health 
treatment will continue with their existing treatment provider. Participants who do not have a treatment provider 
will be offered a referral to a community mental health provider from our community. Individually tailored 
referrals will be made for participants residing outside of the Tulsa region, so that they can receive psychiatric 
services that are located near their home or workplace. 
Plan of Action for Incidental Scan Findings 
To account for incidental findings, each participant’s first scan session will include a clinical anatomical imaging 
series (T1-weighted, T2-weighted, and T2-FLAIR scans). These images will be reviewed by a clinical 
neuroradiologist. If an incidental finding is detected, a physician-researcher will verbally inform the participant. 
A written report will also be provided, advising the participant to follow up with their physician. LIBR will provide 
a digital copy of the relevant MRI images to the participant’s physician upon request. The participant will 
complete a Release of Information if they choose for their provider to receive this information. Participants will 
be informed that only incidental findings will be reported, and LIBR does not provide comprehensive clinical 
evaluations. 
Lost-to-Follow-Up Safety Concerns 
If a participant who previously expressed suicidal ideation becomes unreachable, the study team may break 
confidentiality to contact COPES (Community Outreach Psychiatric Emergency Services, 918-744-4800) in 
order to ensure the participant’s safety. 
Emergency Contact and Support 
Participants will receive contact information for: 
• 
The Laureate Psychiatric Clinic and Hospital Call Center (available after hours and on 
weekends/holidays) 
• 
The national Mental Health Lifeline (988) for 24/7 support 
Reporting Requirements 
Any applicable Serious Adverse Events (SAEs) or unanticipated problems involving risks to participants will be 
reported: 
• 
Within 1 business day to the LIBR Human Protection Administrator 
• 
Within 5 business days to the WCG Institutional Review Board 
Reports will follow NIH and institutional guidelines, as applicable. 

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M. Data Sharing, Retention, and Publication 
Data Retention 
All study data, including neuroimaging, behavioral, physiological, and questionnaire responses, will be retained 
for a minimum of three years following the completion of the study, in accordance with institutional and federal 
guidelines. Data will be archived securely in both electronic and physical formats, where applicable. 
Data Sharing 
De-identified data may be shared with public research repositories such as the NIMH Data Archive (NDA). 
Shared datasets may include: 
• 
Participant demographics (de-identified) 
• 
Assessment scores and behavioral responses 
• 
Functional and structural neuroimaging data 
• 
Study participation details 
To enable data sharing with NDA, information needed to generate a Global Unique Identifier (GUID) will be 
collected and processed according to NDA specifications. 
All shared data will be compliant with HIPAA and institutional standards for de-identification. Identifiable 
information will never be shared outside of the research team or the approved IRB and regulatory bodies. 
Publication and Dissemination 
Study findings will be disseminated through: 
• 
Peer-reviewed journal articles 
• 
Scientific conferences and symposia 
• 
Public data repositories, where applicable 
Participants will not be identified in any report or publication. All results will be presented in aggregate or 
anonymized form. Clinical MRI findings deemed medically significant will be reported to participants per 
institutional protocol. 
 
N. Scientific Importance and Potential Impact 
Scientific Rationale 
Bipolar disorder (BD) is a chronic psychiatric condition marked by mood instability, which significantly 
contributes to impaired functioning and reduced quality of life. While much is known about the neurobiology of 
static mood states (e.g., depression or mania), very little is understood about the neural mechanisms 
underlying dynamic mood transitions — the hallmark of BD. 
This study applies innovative, time-resolved fMRI analysis, machine learning-based emotion decoding, and 
computational metrics (e.g., metastability, network controllability) to provide an unprecedented window into 
how emotional states evolve and shift in real time in the bipolar brain. 

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Innovative Contributions 
This study is among the first to integrate: 
• 
Fine-grained emotional state decoding from fMRI 
• 
Complexity science metrics to quantify emotional lability 
• 
Network control theory to identify brain regions that drive emotional state transitions 
• 
Examination of positivity amplification as a potential stabilizer of mood dynamics in BD 
Broader Impact 
Findings from this research will: 
• 
Improve our neurobiological understanding of mood instability 
• 
Inform the development of real-time, adaptive interventions (e.g., neurofeedback, digital therapeutics) 
• 
Support personalized treatment strategies based on brain state and emotional fluctuation patterns 
This study will also provide preliminary data to support future R01-level funding and biomarker discovery 
efforts in mood disorders. 
 
O. References 
1. 
Ortiz, A. and M. Alda, The perils of being too stable: mood regulation in bipolar disorder. J Psychiatry 
Neurosci, 2018. 43(6): p. 363-365. 
2. 
Gruber, J., et al., Letting go of the bad: deficit in maintaining negative, but not positive, emotion in 
bipolar disorder. Emotion, 2013. 13(1): p. 168-75. 
3. 
Janiri, D. and S. Frangou, Precision neuroimaging biomarkers for bipolar disorder. Int Rev Psychiatry, 
2022. 34(7-8): p. 727-735. 
4. 
Houenou, J., et al., Neuroimaging-based markers of bipolar disorder: evidence from two meta-
analyses. J Affect Disord, 2011. 132(3): p. 344-55. 
5. 
Han, K.M., et al., Differentiating between bipolar and unipolar depression in functional and structural 
MRI studies. Prog Neuropsychopharmacol Biol Psychiatry, 2019. 91: p. 20-27. 
6. 
Du, M., et al., Abnormal transitions of dynamic functional connectivity states in bipolar disorder: A 
whole-brain resting-state fMRI study. J Affect Disord, 2021. 289: p. 7-15. 
7. 
Bastos, A.M. and J.M. Schoffelen, A Tutorial Review of Functional Connectivity Analysis Methods and 
Their Interpretational Pitfalls. Front Syst Neurosci, 2015. 9: p. 175. 
8. 
Misaki, M., et al., Aging increases the distinctiveness of emotional brain states across rumination, 
worry, and positive thinking. bioRxiv, 2024: p. 2024.10.29.620853. 
9. 
Misaki, M., et al. Decoding Temporal Dynamics of Emotion Regulation: Reinterpretation, Distraction, 
and Mindfulness. in OHBM 2025 - Annual Meeting Organization for Human Brain Mapping. 2025. 
Brisbane, Australia. 

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10. 
Gu, S., et al., Controllability of structural brain networks. Nat Commun, 2015. 6: p. 8414. 
11. 
Hancock, F., et al., Metastability, fractal scaling, and synergistic information processing: What phase 
relationships reveal about intrinsic brain activity. Neuroimage, 2022. 259: p. 119433. 
12. 
Taylor, C.T., S. Lyubomirsky, and M.B. Stein, Upregulating the positive affect system in anxiety and 
depression: Outcomes of a positive activity intervention. Depress Anxiety, 2017. 34(3): p. 267-280. 
13. 
Misaki, M., et al., Brain activity mediators of PTSD symptom reduction during real-time fMRI amygdala 
neurofeedback emotional training. Neuroimage Clin, 2019. 24: p. 102047. 
14. 
Sheehan, D.V., et al., The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and 
validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry, 
1998. 59 Suppl 20: p. 22-33;quiz 34-57. 
15. 
Nolen-Hoeksema, S. and J. Morrow, A prospective study of depression and posttraumatic stress 
symptoms after a natural disaster: the 1989 Loma Prieta Earthquake. J Pers Soc Psychol, 1991. 61(1): 
p. 115-21. 
16. 
Kryza-Lacombe, M., et al., Changes in neural reward processing following Amplification of Positivity 
treatment for depression and anxiety: Preliminary findings from a randomized waitlist controlled trial. 
Behav Res Ther, 2021. 142: p. 103860. 
17. 
Jubran, A., Pulse oximetry. Critical Care, 2015. 19(1): p. 272. 
18. 
Betella, A. and P.F. Verschure, The Affective Slider: A Digital Self-Assessment Scale for the 
Measurement of Human Emotions. PLoS One, 2016. 11(2): p. e0148037.