Neurofeedback Enhanced Cognitive Reappraisal Training
Phase: NA
Conditions: Anxiety, Social Anxiety Disorder, Panic Disorder, Generalized Anxiety Disorder
Sponsor: University of Michigan

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
PRINCIPAL INVESTIGATOR: Stefanie Russman Block, Ph.D.  
 
v3.21.2025 
 
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Neurofeedback Enhanced Cognitive Reappraisal Training 
 
 
Principal Investigator (PI): Stefanie Russman Block, PhD 
 
 
 
 
 
University of Michigan 
 
 
 
 
Dept of Psychiatry 
4250 Plymouth Road, Ann Arbor, MI 48109 
Email:  srblo@med.umich.edu 
 
Co-Investigator(s): 
Stephan F. Taylor, MD, David Fresco, PhD, Scott Peltier, PhD, Meghan Martz, 
PhD, Kate D. Fitzgerald, MD, Katherine McCurry, PhD, Meghan Martz, PhD 
 
 
 
 
 
 
Sponsor: 
 
 
Brain & Behavior Research Foundation 
 
 
HUM Number: 
 
HUM00209563 
 
 
NCT Number:  
 
NCT06132659 
 
Version: 
 
 
3.21.2025 
 
  
 
 
 

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
PRINCIPAL INVESTIGATOR: Stefanie Russman Block, Ph.D.  
 
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DETAILED IRB PROTOCOL 
 
1. Objective 
 
Anxiety disorders are the most common mental health condition worldwide and a leading cause of 
disability. The development of novel interventions to treat anxiety has lagged the advancements made 
regarding the neurobiology of emotion and cognitive processes directly related to treatment. This proposal 
will utilize real-time functional magnetic resonance imaging neurofeedback (NF) to modulate key brain 
regions involved in emotion regulation to enhance effectiveness of cognitive reappraisal, a central skill 
taught in evidenced-based psychotherapies. This innovative project will identify 1) the ability of adults with 
anxiety to self-modulate brain function in regions specific to healthy emotion regulation using NF and 2) the 
potential impact of neuromodulation on improved emotion regulation ability and anxiety reduction. 
 
2. Specific Aims/Hypotheses 
 
Aim 1A. Evaluate the ability of adults with anxiety to increase prefrontal cortex activity during CR 
based on NF.  
 
Primary outcome 1A: BOLD activation. Change in PFC activity (baseline to transfer run) from 
the reappraise > look contrast.  
 
Hypothesis 1A: Participants receiving veritable-NF will show a greater activation increase in the 
PFC compared to sham-NF. 
 
Aim 1B. Determine the relationship between prefrontal cortex activity recruitment and CR ability in 
adults with anxiety.  
 
 
Primary outcome 1B: Negative affect ratings. Decrease in negative affect ratings (baseline to 
transfer run) from reappraise > look contrast.  
 
Secondary outcome 1B: Prefrontal-amygdala connectivity. Change in amygdala-PFC functional 
connectivity (baseline to transfer) from reappraise > look contrast.  
 
Hypothesis 1B1: Participants receiving veritable-NF will show greater CR ability compared to 
those receiving sham-NF. 
  
Hypothesis 1B2: prefrontal cortex activation will positively correlate with CR ability. 
 
Aim 1C. Assess the impact of NF on anxiety symptoms and CR use over time (exploratory).  
 
Primary outcome 1C1: Clinician-rated anxiety severity: Change in score on the Hamilton 
Anxiety Rating Scale (HAM-A) from initial assessment to one-month follow-up.  
 
Primary outcome 1C2: Self-reported cognitive reappraisal use. Change in score on the 
reappraisal subscale of the Emotion Regulation Questionnaire (ERQ) from initial assessment to 
one-month follow-up.  

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
PRINCIPAL INVESTIGATOR: Stefanie Russman Block, Ph.D.  
 
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Hypothesis 1C1: The veritable-NF group will report decreased symptom severity and increased 
CR use compared to the sham-NF group.  
 
Hypothesis 1C2: Increase in NF-induced brain activation will correlate with decreased symptom 
severity and increased CR use at follow-up.  
 
3. Background Information 
 
Burden of anxiety disorders. Anxiety disorders are the most common mental health condition worldwide 
and a leading cause of disability,2 associated with increased risk for suicide3 and chronic health problems4. 
Over the lifespan, prevalence rates of anxiety increase most dramatically during young adulthood (age 18-
24)5, pointing to a critical developmental period for prevention and treatment. Moreover, heterotypic 
continuity of anxiety disorders is observed from adolescence to young adulthood suggesting common 
underlying mechanisms6. Although cognitive behavioral therapy (CBT) is regarded as a gold-standard 
treatment for anxiety, associated with moderate effect sizes in meta-analyses7,8, remission rates are low9 and 
relapse is common,10,11 resulting in an unmet need to improve beyond existing evidence-based treatments. 
 
Emotion regulation and anxiety disorders. Emotion regulation is the process of modulating emotions 
towards a particular goal12. Cognitive reappraisal (CR) is a type of emotion regulation strategy in which one 
changes the meaning of a situation to alter its emotion content. For example, interpreting a poor grade on a 
test as an opportunity to learn instead of a personal failure. CR matures linearly over the course of 
development13 and is associated with better mental health and higher life satisfaction14. In longitudinal 
studies, greater CR use is associated with greater social connection and buffers against anxiety during the 
transition to college15,16. However, anxious individuals habitually use CR less often than avoidance or 
emotional suppression17. One reason for this decreased use may be that CR is effortful and more difficult to 
deploy than other emotion regulation strategies18,19. In contrast, other work has found no differences in CR 
frequency between those with and without anxiety, but that CR attempts are less effective in individuals 
with anxiety14. With practice, however, CR becomes less effortful and results in desired emotional 
changes19, suggesting that CR training can improve ability to deploy CR to reduce anxiety symptoms. In 
support of this hypothesis, gains in CR mediate CBT response in anxiety14.  
 
Neurobiology of cognitive reappraisal. Decreased CR ability in anxious 
individuals may stem from hypoactivation of prefrontal brain regions 
necessary for CR implementation20. Meta-analyses show that effective CR is 
associated with frontoparietal activations, particularly the left ventrolateral 
prefrontal cortex (vlPFC) and dorsomedial prefrontal cortex (dmPFC)21–23 
(Figure 1). The left vlPFC is involved in appraisal selection and inhibition 
and the dmPFC supports monitoring and self-reflection on the meaning of 
emotional states21,24. Deficits in vlPFC recruitment during CR are common 
amongst clinical populations (e.g., anxiety, mood, substance use, and 
personality disorders), while deficits in dmPFC recruitment during CR, extending to the dorsal anterior 
cingulate cortex (dACC) and supplementary motor area (SMA), appear to be a signature of patients with 
anxiety20,25,26. In theory, enhancing left vlPFC and dmPFC recruitment during CR could improve CR 
efficacy for individuals with anxiety disorders.  
 
dmPFC 
Figure 1. Brain regions 
involved in CR23 
vlPFC 

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
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Real-time fMRI neurofeedback. Despite advances made in our understanding of the brain,  translation of 
knowledge from functional magnetic resonance imaging (fMRI) research into clinical practice has been27, 
possibly stemming from the correlational nature of fMRI design, and the 
reliance of fMRI inferences on group averages. To make fMRI clinically 
applicable, reliable, and valid methods are needed at the level of the 
individual patient. Real-time fMRI neurofeedback (NF) is a tool that has 
the potential to translate neuroimaging research to clinical practice. In this 
technique, participants see feedback based on their own neural signal as 
they engage in different psychological processes, which provides them an 
opportunity to become aware of and self-regulate their own brain 
signals28. As such, NF can test causal relationships about brain and 
behavior29 and can teach individuals a self-regulatory skill that could then 
be applied in real life. The field has cohered around practice standards30 
and two recent meta-analyses31,32 evaluating NF efficacy across 
psychiatric conditions reported medium-large effects sizes for neural 
activity and anxiety symptoms.. Thus, NF could be used to directly target vlPFC and dmPFC activity, 
potentially enhancing CR efficacy and use in adults with anxiety. 
 
Critical lessons learned from prior work. To demonstrate the ability of NF to enhance CR efficacy for 
patients with anxiety, studies need to consider the following factors. 1) Use of an appropriate control group. 
To date, eight studies have examined CR with NF33–39, however, much of this work consists of feasibility 
studies with small sample sizes, lacking adequate control groups. As NF is rewarding and promotes self-
efficacy40,it is important to select a control group that gains the same proportion of success in auto-control 
of brain function as verifiable NF. 2) NF should target brain regions implicated in CR. only one research 
group35,41 has targeted the left vlPFC, an area specific to CR23, reporting positive changes for emotion 
regulation in depression and PTSD. No prior studies, however, have evaluated vlPFC-NF in primary 
anxiety.  To our knowledge, no studies have evaluated the effects of dmPFC modulation with NF, despite 
evidence that is specifically under-recruited during CR in patients with anxiety20,25,42. 3) Measurement of 
affect or mood change. Few studies have examined the relationship between NF-induced change in brain 
activation and change in CR ability. Of note, Zilvestand et al.34 found that insula downregulation was 
associated with decreased anxiety during the CR, while Keller et al.35 reported that increased left vlPFC 
activity was associated with increased CR use at one-month follow-up. Such results are promising, but 
further well-controlled studies are needed to elucidate the causal role between change in brain function and 
CR ability. 4) Careful instruction to ensure participants are practicing CR during NF training. If instruction 
on how to use CR is brief, participants may inadvertently adopt maladaptive strategies, whose use is 
reinforced with NF. For example, when interviewed post-training, participants can report using a variety of 
strategies in addition to CR, including suppression38.  
 
In sum, the existing literature has demonstrated feasibility in using CR in the context of NF, however, lack 
of control groups, differences in brain regions targeted, failure to link change in brain function to change in 
behavior and to provide explicit CR training, as well as limited work in patients with anxiety, indicate the 
critical directions for this line of research to proceed, as we propose here. 
 
 
 
 
Figure 2. Illustration of NF30 

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
PRINCIPAL INVESTIGATOR: Stefanie Russman Block, Ph.D.  
 
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4. Methodology 
 
4.1 Overview 
 
This project will examine the effects of NF training on CR efficacy and use in adults with clinical anxiety. 
The project will occur in 4 phases. In Phase 1 (Task Development), we will scan subjects using pilot funds 
from the fMRI lab to modify and optimize the Emotion Regulation Task (ERT) to measure reappraisal-
related brain activity. Healthy participants will complete the ERT without neurofeedback to evaluate offline 
that the task activates areas of interest using traditional fMRI analytical methods. In Phase 2 
(Neurofeedback Development), healthy participants will perform the ERT with veritable- NF to optimize 
NF delivery. In phases 1 and 2, participants will be recruited in groups of 4-8 to test continued iterations of 
task parameter modifications (e.g., timing, directions, number of trials, images) until significant activation is 
reached in the contrast of interest (reappraise > look). Performance from the participants with veritable-NF 
will be used to develop the sham condition for Phase 3 Randomization. Based on the results of Phase 2, we 
will pick the region of interest in the PFC for Phase 3. In the unblinded arm 1, participants will receive 
veritable-NF targeted at the PFC to optimize NF delivery. In the blinded arms 2 and 3, adults with anxiety 
will be randomized to receive either veritable-NF (arm 2) targeted at the PFC or sham-NF (arm 3).  
 
4.2 Participants 
 
4.2.1 Inclusion/Exclusion Criteria 
 
1. Age 18-55 
2. Primary diagnosis (primary source of distress and/or interference) of generalized anxiety disorder, 
social anxiety disorder, panic disorder or illness anxiety disorder based on structured interview. 
Comorbid phobic disorders allowed, but these cannot be the primary source of interference or 
distress due to the lowered chances of encountering anxiety-provoking stimuli during the study 
period, 
3. Score of 2 or more on at least 1 question from the GAD/CROSS-AD composite 
4. Medically and physically able to consent 
5. Vision greater or equal to 20/30 (± correction) 
6. Not taking any medication, prescription or non-prescription, with psychotropic effects other than:  
a. Buspirone, or antidepressant (e.g., selective serotonin reuptake inhibitor (SSRI) or 
serotonin-norepinephrine reuptake inhibitor (SNRI)) with stable dosage for past 4 weeks 
b. Hormonal contraceptives of any type for any duration 
c. If taking PRN medications not within this scope, must be willing to refrain from use for 
approximately 5 half-lives of the drug leading up to the training and MRI 
7. No current diagnosis of Obsessive Compulsive Disorder, Bipolar Disorder, or Posttraumatic Stress 
Disorder 
8. Current substance abuse or dependence (past 6 months) 
9. No active suicidality with plan or intent 
10. No current psychosis 
11. No history of serious neurological illness or current medical condition that could compromise brain 
function, such as liver failure 
12. No history of closed head injury, e.g., loss of consciousness > ~5 min, hospitalization, neurological 
sequela 

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
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13. For females, not currently pregnant or actively trying to become pregnant 
14. Ability to tolerate small, enclosed spaces without anxiety 
15. No metals, implants or metallic substances within or on the body that might cause adverse effects to 
the subject in a strong magnetic field, or interfere with image acquisition, e.g., aneurysm clips, 
retained particles (metal workers excluded), neurostimulators, foil-backed transdermal patches, 
carotid or cerebral stents, CSF shunts, magnetic dental implants, ferromagnetic ocular implants, 
pacemakers, automatic implantable defibrillators 
16. Size compatible with scanner gantry, e.g., men over 6 feet tall that weigh more than 250 lbs, men 
under 6 feet tall that weigh over 220 lbs, women over 5’11” tall that weigh more than 220 lbs, or 
women under 5’10” tall that weigh more than 200 lbs. Subjects of these weights or greater typically 
have difficult fitting into the fMRI scanner properly 
 
4.3 Recruitment 
 
Adults of all genders will be recruited from several sources. First, participants will be recruited through the 
Psychology Department Subject Pools. Each semester, the Psychology Department maintains a list of 
individuals who are interested in participating in research. Subjects are asked for demographic and contact 
information, as well as handedness and vision. From this list, we will contact potentially eligible participants 
and ask them if they would be interested in hearing about a research study involving an MRI scan. Second, 
participants will be recruited from the University of Michigan Health Research Registry, a website 
(UMHealthResearch.org). Potential study participants go to the website and search for protocols in which they 
can participate. The website also features an email notification system that will let potential participants know 
when a new study is recruiting subjects. Third, participants will be recruited through community and internet 
advertisements. Flyers may be posted throughout southeastern Michigan, including in mental health treatment 
clinic waiting rooms, with relevant permissions. Flyer and social media advertising may direct participants to a 
series of prescreening questions on Qualtrics or UMHR before they are contacted by study staff for an official 
phone screening. 
Participants in Phase 3 will be recruited from the Psychiatry Department Anxiety Disorders Treatment Clinic. 
As the proposed study requires that participants are not currently in psychotherapy treatment, information about 
the study will be distributed to clinical staff, who can inform waitlisted patients and those who are only on 
antidepressant medication about the study. We will also use the University’s self-served data tools (DataDirect 
PHI, EMERSE, Best Practice Alerts, etc.) to query electronic medical records and identify potential patients. 
We will target patients aged 18 to 55 who meet the above inclusion criteria.  
 
4.3 Procedure 
 
4.3.1 Screening 
 
Interested participants from the above sources will be asked to complete a telephone screening. The 
screening will include questions from the Generalized Anxiety Disorder – 2 (GAD-2) and Cross-Cutting 
Symptom Assessment (CROSS-AD), demographic and medication information, as well as questions to 
assess MRI safety. Participants who meet inclusion/exclusion criteria will be invited to schedule Study 
Visit 1. Study Visit 1 will take place either remotely via Zoom or in-person at the Rachel Upjohn 
Building. In person procedures will be conducted following the University of Michigan’s COVID safety 
protocols. 
 

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
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4.3.2 Study Visit 1: Informed Consent, Diagnostic Interview 
Informed Consent. The informed consent form will be mailed in advance of the visit. During this first 
study visit, participants will be given detailed information about the study. During this meeting, the 
potential subject will be encouraged to ask questions about the study, after which the informed consent 
form will be reviewed and signed. Study staff will go through and explain the informed consent 
document to the participant, which will be available and visible on SignNow. After the participant 
digitally signs the document, the research assistant will sign the document.  
 
Diagnostic Interview and Questionnaires. Consented participants will then undergo a diagnostic 
interview, including the clinician-administered SCID-5 and CGI (see Section 4.5.1)This diagnostic 
assessment will be used to make the final determination about study eligibility. Participants will also be 
given the HAM-A to assess baseline anxiety severity in the past week. This visit may take 1-3 hours in 
total, depending on how many symptoms a subject endorses. 
 
Randomization. Participants who meet eligibility criteria following the diagnostic interview will be 
invited to schedule Study Visits 2 and 3. Study Visit 2 will occur 1-5 days before Study Visit 3. In arms 
2 and 3, a designated member of the study staff who will remain unblinded during the duration of the 
study will randomly assign participants to one of the two groups (veritable-NF or sham-NF). 
Approximately one-half of the sample will be assigned to each group. All staff interacting with the 
participant, including the participant themself, will be blinded to group assignment. To this end, the 
unblinded staff member will code the MRI scanning sequences with sets of random numbers that will be 
used to communicate to the MRI Technician which neurofeedback protocol should be employed during 
each study visit without revealing visually or by name if true feedback is being generated. 
 
4.3.3 Study Visit 2: Reappraisal Practice 
Cognitive Reappraisal Practice Training. During Study Visit 2, participants will first complete a 
series of self-report questionnaires assessing mental health symptoms and use of emotion regulation 
strategies (see Section 4.5.1). Next, participants will complete a 30–45-minute practice session with a 
member of the study staff. Negative images, like those that will be shown during the MRI session, will 
be displayed via Zoom if the visit is remote or displayed using the mock scanner if the visit is in-person. 
Participants will be guided to reinterpret situations to reduce negative affect (‘reappraise’ trials). During 
‘look’ trials, participants will be instructed to passively view a picture as they normally would without 
trying to alter the emotional response. Research staff will be recording participants responses and 
performance on the pre-fMRI Scan Image Questions survey in REDCap. This visit may take up to an 
hour. 
 
4.3.4 Study Visit 3: fMRI Scan  
Study Visit 3 will follow the same procedures as Study Visit 2 of Phases 1 and 2, including pregnancy 
testing of female participants. However, half of the participants will be randomized to complete the ERT 
with veritable neurofeedback from the dm/vlPFC, while the other half will be randomized to complete 
the ERT with sham neurofeedback. Participants in the sham group will complete the same ERT as the 
veritable NF-group, however, the thermometer will display a pseudo-random feedback signal. This 
signal is generated to match the spectral characteristics of true feedback (from phases 1 and 2), including 
the same average success rate to control for the rewarding aspects of receiving feedback. 

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In the event of unexpected technical difficulties involving the scanner or neurofeedback software, 
subjects may be invited to complete additional fMRI sessions. 
4.3.5 Study Visit 4: Follow-up Assessments 
Two-week post questionnaires. Two-weeks after the fMRI visit, participants will complete online self-
report measures from home via REDcap (see Section 4.5.3). These measures will take 15-20 minutes to 
complete in total. 
 
One-month post interview. One month after the fMRI visit, participants will complete Study Visit 4, 
either in person or by phone, with a member of the study staff who is blinded to group assignment. 
During this study visit, participants will undergo a follow-up interview to assess anxiety symptom 
severity and complete a series of self-report measures. They will also be asked about how many 
psychotherapy sessions they attended over the course of the study, as well as the psychotropic 
medications they are on, to determine if there was a change in dose or a new medication. The visit may 
take up to an hour. 
 
4.5 Measures and Assessments 
 
 
 
 
 
 
Procedures 
Pre-Screening 
(Pre-Consent) 
Visit 1 
Eligibility 
 
Visit 2 
Baseline + 
Training 
Visit 3 
fMRI 
Visit 4 
2-Week 
Follow-Up 
Visit 5 
1-Month 
Follow-Up 
 
Eligibility 
Pre-NF 
NF 
Post-NF 
 
Phone Screen 
X 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
Demographics 
 
 
X 
 
 
 
 
 
Handedness43 
 
 
X 
 
 
 
 
 
Structured Clinical Interview 
for the DSM-5 (SCID)47 * 
 
X 
 
 
 
 
 
 
Columbia Suicide Severity 
Rating Scale (C-SSRS)48 * ** 
 
X 
 
 
 
 
 
X 
Treatment Follow-Up 
 
 
 
 
 
 
 
X 
Clinical Assessment 
 
Hamilton Anxiety Rating Scale 
(HAM-A49) * 
 
X 
 
 
 
 
 
X 
Clinical Global Impressions 
Scale (CGI)50 * 
 
X 
 
 
 
 
 
X 
Depression, Anxiety and Stress 
Scales-21 (DASS-21)44 
 
 
X 
 
 
 
X 
X 
Penn State Worry 
Questionnaire (PSWQ)45 
 
 
X 
 
 
 
X 
X 
Emotion Regulation 
 
Emotion Regulation 
Questionnaire (ERQ46) 
 
 
X 
 
 
 
X 
X 
Regulatory Emotional Self-
Efficacy Scale (RESE)51  
 
 
X 
 
 
 
X 
X 
Experiences Questionnaire 
(EQ)52 
 
 
X 
 
 
 
X 
X 
Heidelberg Form for Emotion 
Regulation Strategies 
(HFERST)53 
 
 
X 
 
 
 
X 
X 
Perth Emotion Regulation 
Competency Inventory 
(PERCI)54 
 
 
X 
 
 
 
X 
X 
Beliefs & Personality 
 

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
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Items from Stanovich Dualism 
Scale (DS)55 
 
 
X 
 
 
X 
 
 
Theories of Anxiety Scale 
(TOA)56 
 
 
X 
 
 
 
X 
X 
Theories of Intelligence Scale 
(TOI)57 
 
 
X 
 
 
 
X 
X 
Temporal Experience of 
Pleasure Scale (TEPS)58 
 
 
X 
 
 
 
 
 
Task Training 
 
 
 
 
 
 
ERT Training 
 
 
X 
 
 
 
 
 
Pre-NF IAPS Appraisals 
 
 
X 
 
 
 
 
 
Randomization (Arms 2 & 3) 
 
 
X 
 
 
 
 
 
fMRI 
 
fMRI Safety Screen 
 
 
 
X 
 
 
 
 
Pre-NF Interview 
 
 
 
X 
 
 
 
 
Short form composite of the 
Marlowe-Crowne Social 
Desirability Scale (SDS)59 
 
 
X 
 
 
 
 
 
fMRI Neurofeedback Scan 
 
 
 
 
X 
 
 
 
Post-NF Image Appraisals 
 
 
 
 
 
X 
 
 
Post-NF Interview 
 
 
 
 
 
X 
 
 
 
* = Clinician administered 
 
** = As needed 
 
4.5.2 Scan-Related Measures 
 
Pre-NF interview. 
• Belief about brain self-control35 
• Motivation64 
• Expected success to regulate brain during NF and in using CR35  
 
fMRI Scan. 
 
fMRI scanning will occur on a 3.0T GE Discovery MR750 scanner with a 32-channel receiver array 
head coil and a multi-band slice accelerated echo-planar imaging (EPI) sequence: 2.4mm isotropic 
resolution, 60 slices; TR/TE 800/30ms, flip angle=52 ̊; multiband factor=6. Whole-brainT1-weighted 
scans will be acquired with a 3D MPRAGE sequence: 1mm isotropic resolution; 
TR/TI/TE/FA=2850ms/1060ms/2.3ms/8°; parallel acceleration factor=2. This imaging protocol 
matches that of the ABCD Protocol, providing high spatial- and temporal-resolution imaging of the 
functional and structural brain networks and is excellent in signal recovery in areas of high 
susceptibility artifact. 
 
Emotion Regulation Task - Phase 1. Participants will complete 4-6 runs of the Emotion Regulation 
Task (ERT), adapted from Keller et al.35. Each run consists of 18 alternating ‘look’ and ‘reappraise’ 
trials. Each trial will begin with a 1s instruction cue to either ‘look’ or ‘reappraise, followed by a 
presentation of a 6-30s negatively-valanced image from the International Affective Picture System65 
and the Open Affective Standardized Image Set66, and a 4-6s fixation screen. At the end of the run 
participants will rate their negative affect.  
 
Participants in Phase 1 will complete the ERT without neurofeedback to evaluate offline that the task 
activates areas of interest using traditional fMRI analytical methods. Participants will be recruited in 
groups of 4-8 to test continued iterations of task parameter modifications (e.g., timing, directions, 

STUDY: Neurofeedback-Enhanced Cognitive Reappraisal Training 
PRINCIPAL INVESTIGATOR: Stefanie Russman Block, Ph.D.  
 
v3.21.2025 
 
Page 10 
 
number of trials, images) until significant activation is reached in the contrast of interest (reappraise 
> look) averaged across subjects (p < 0.05 small volume corrected for multiple comparisons). 
 
Note: Design parameters are anticipated, as task piloting in Phase 1 may reveal a need to make 
minor changes. Any such changes will not affect subject risk. Changes that do will be submitted for 
approval to the IRB. 
 
Emotion Regulation Task. Half the participants will be randomized to complete the ERT with 
veritable feedback from the PFC as described in Phase 2. The specific region of interest (dmPFC or 
vlPFC) will be determined by the results of Phase 2 and arm 1 of Phases 3 and 4. Participants in the 
sham group will complete the same ERT as the veritable nf-group, however, the thermometer will 
display a pseudo-random feedback signal. This signal is generated to match the spectral 
characteristics of true feedback (established from Phase 2), including the same average success rate 
to control for the rewarding aspects of receiving feedback. As participants are blind to group 
assignment, inclusion of a sham-group controls for practice effects, fatigue, and learning that may 
occur without NF. On each trial of the task, a 4s presentation of vlPFC/dmPFC activity (reappraisal 
trials) or a crosshair (look trials) will appear following the image presentation screen. In the first 
functional run (‘baseline’), participants complete the ERT without NF to establish baseline activity 
in the two regions of interest (ROIs: vlPFC and dmPFC), based on masks from previous CR meta-
analyses (e.g., 20,21). In the middle runs, participants complete the ERT with NF. In the final 
functional run (‘transfer’), participants again complete the ERT without NF to establish ability to 
implement learning from NF training. 
 
The NF set-up will utilize custom software, developed by co-investigator Scott Peltier. This 
includes motion correction, linear trend removal and spatial smoothing for each image presentation. 
The BOLD percentage signal change within the ROI is calculated using most recent “reappraise > 
look” contrast and fed back as a visual display reflecting BOLD signal change. The feedback 
display shows a thermometer whose minimum is initially set at 0% signal change. Bars fill the 
thermometer image to correspond to the increase in participant’s brain activity using custom 
MATLAB scripts. On no feedback runs (baseline and transfer), the display shows a crosshair or a 
static thermometer.  
 
Post-NF interview. 
• Difficulty to complete the task 
• Comments and suggestions about the task, including appraisals, affect, and arousal ratings of 
the images 
• Perceived control of brain activity and perceived success of CR during NF35 
• Tolerability and acceptability of NF 
• Manipulation check of group assignment 
 
 
4.6 Compensation 
 
It is important that participants feel adequately compensated for the time spent participating in the various 
components of the study, including completing the diagnostic interview, being scanned, performing the NF 
task, completing self-report measures, and traveling to the research site. 

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Amount 
Baseline Assessment: 
$20 
Training: 
$20 
MRI Scan: 
$50 
Follow-Up Assessments: 
$20 
 
 
Participants who complete the study will be eligible to receive up to $110. 
 
These values are similar to those used by other fMRI studies at the University of Michigan. If participants 
withdraw from the study early, they will be paid for the parts of the study they completed. Participants will 
be paid by check or gift card. 
 
If a participant is asked to return for a second MRI scan brought on by scanner or neurofeedback 
malfunction, they will be compensated accordingly. 
 
5. Participant Withdrawal 
 
Participants may withdraw from the study at any time for any reason. The reasons a participant may 
withdraw include, but are not limited to: 
• feeling claustrophobic in the MR scanner 
• not desiring to continue 
 
Researchers may withdraw a participant from the study if they have a reason to doubt the quality or validity 
of the data the participant would provide. Reasons may include, but are not limited to: 
• participant being unable to hold still in the scanner 
• participant no longer meeting criteria 
• participant being unable to perform required tasks 
• participant not complying with researcher or MRI tech instructions 
 
6. Statistical Design 
 
Aim 1. Evaluate the ability of adults with anxiety to increase prefrontal cortex activity during CR based 
on NF.  
 
The task will be processed and analyzed using the same methods as Aims 1 and 2. To assess group 
differences in neuromodulation ability (hypothesis 1), a repeated-measures linear mixed effects model 
(LME) with participant as a random intercept, will examine the 3-way interaction of group (veritable-
NF, sham-NF) x condition (reappraise, look) x time (baseline, NF1, NF2, NF3, transfer) on extracted 
BOLD activation from the dm/vlPFC mask. 
 
Aim 1B. Determine the relationship between prefrontal cortex activity recruitment and CR ability in 
adults with anxiety.  
 

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To assess group differences in CR ability (hypothesis 1B1), a repeated-measures LME with participant 
as a random intercept, will examine the interaction of group (veritable-NF, sham-NF) x condition time 
(baseline, NF1, NF2, NF3, transfer) on negative affect ratings and prefrontal-amygdala connectivity 
during the ERT. We will use a psychophysiological interaction analysis to measure prefrontal-amygdala 
connectivity. Deconvolved time series from anatomical bilateral amygdala seeds for each participant 
will be multiplied by a vector for the reappraise > look contrast at each run. Regressors for the seed time 
series, the original condition and the interaction term will be convolved with the canonical 
hemodynamic response function. Contrast maps will be entered into second-level random effects 
analyses to test if veritable-NF shows greater prefrontal-amygdala connectivity than sham-NF. 
 
For hypothesis 1B2, linear regressions will examine run-by-run associations between dm/vlPFC 
activity and 1) negative affect ratings and 2) prefrontal-amygdala connectivity, across all participants 
irrespective of training condition. 
 
 
Aim 1C. Assess the impact of NF on anxiety symptoms and CR use over time (exploratory).  
 
To examine the effect of NF on anxiety (hypothesis 1C1), a repeated-measures LME with participant as 
a random intercept, will examine the effect of time (baseline, 1 month) x group (veritable-NF, sham-NF) 
on the HAM-A. To examine the effect of NF on CR use (hypothesis 1C1), a repeated-measures LME 
with participant as a random intercept will examine the interaction of time (baseline, 2-week, 1-month) x 
group (veritable-NF, sham-NF) on the ERQ.  
 
Linear regressions will examine the association between dm/vlPFC change (transfer-baseline) and 
change in HAM-A and ERQ scores (1 month – baseline) across all participants (hypothesis 1C2). 
Exploratory: Mediation will test if change in dm/vlPFC activity mediates the relationship between NF 
group and change in HAM-A or ERQ scores.  
 
7. Data and Safety Monitoring Plan 
 
7.1 Overall framework 
 
Study monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in 
compliance with the currently approved protocol/amendment(s), with International Conference on 
Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s) 
 
7.2 Roles & responsibilities for regular operations 
 
PI: The PI will meet with study staff on a weekly basis to monitor the progress of the study. During phases 
when subject recruitment is occurring, the PI will review screenings and scheduling of assessments, as well 
as strategies to improve recruitment yield at weekly meetings with the study team. Issues such as 
maintaining confidentiality and privacy of participants during screening, assessment and data collection, 
protocol deviations and adverse events will be reviewed. For serious adverse events, the PI will be notified 
as soon as the SAE comes to the attention of study staff. 
 

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Study coordinator/research assistant: This bachelors level individual will carry out the screening and 
informed consent, and they will provide additional study information, all under the supervision of the PI. 
The individual will be trained in screening, administering consent and information to the participants. 
Questions about eligibility will be discussed with the PI. 
 
7.3 Frequency and type of other study monitoring 
 
Institutional Review Board monitoring: Approval of all procedures, advertisements and materials given to 
subjects will be secured from the University of Michigan IRBMED. Annual reviews will be conducted by 
IRBMED, including the number of subjects screened, enrolled and withdrawn. The IRB will also review 
protocol deviations, adverse events (according to the reporting timetable of IRBMED) and complaints that 
arise in connection with the study. 
 
Data monitoring: Data entry will be audited by study staff, who were not involved in primary data entry. 
Patient questionnaire data will be entered largely through electronic data capture, e.g., REDCap. Research 
data will be maintained on password protected computers, behind UM firewalls. All enrolled participants 
will receive participant identifiers, which will be used to code all research records for this project. Paper 
records with no identifying data beyond the research code are stored in locked cabinets. Copies of executed 
consent forms will be stored in separate locked cabinets. Demographic data will be entered into 
spreadsheets, and behavioral data will be merged into files. Password-protected electronic files separated 
from the research data will track consents, including the link between the research identifier and individual 
participants. This tracking file will be the sole link between participant identifiers and research data. By 
deleting the field linking identifiers with participant names, research records can be effectively anonymized. 
 
7.4 Management of withdrawals and drop-outs 
 
When participants drop out during the assessment, but before enrollment, all data will be destroyed. The 
consent form will be retained until study closure for regulatory purposes. Limited, de-identified data 
regarding ethnicity, age, gender, and diagnosis will be retained through the screening process in order to 
establish the sampling frame. If a participant drops out due to substance use but would otherwise meet the 
inclusion criteria, all data will be retained until the closing of the project, in case the participant becomes 
eligible and wishes to be reconsidered for the study before conclusion of recruitment. When participants 
drop out after enrollment, data may be destroyed, depending upon the wishes of the participant. However, 
consent forms and the research number will be retained. 
 
8. Benefits/Risks 
 
8.1 Benefits 
 
Participants will be taught cognitive reappraisal, an evidenced-based emotion regulation skill. Previous 
work has found a brief single-session CR training to be of benefit to healthy individuals and those with 
anxiety (e.g., Dryman & Heimberg, 201814). Thus, in our study, some may find participation to be a 
positive experience, and some may experience reduced negative affect, however, participants will be 
informed that the primary purpose of the study is not to directly benefit participants, but to inform our 
scientific understanding of the neural basis of cognitive reappraisal and the effects of real-time fMRI 

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neurofeedback. This information will be used to design new or improve existing treatments, which may 
benefit those with psychiatric disorders in the future. 
 
8.2 Risks 
 
8.2.1 Subject Confidentiality  
 
Measures to protect patient privacy. Study staff will make every effort to limit identifiable information on 
potential subjects during recruitment. Conversations in which a patient's name must be mentioned, e.g. to 
determine potential eligibility, will occur in private settings of the clinic. The minimum amount of 
information will be recorded, and staff are alerted to the dangers of printing, faxing and emailing sensitive 
information. Phone conversations with potential research subjects will occur behind closed doors, and staff 
will ask callers if they are in a location where sensitive information can be discussed without danger of 
revealing confidential information. Any information gathered on subjects who prove ineligible will be 
destroyed as soon as possible (a list of patients who have declined or screened out will be maintained 
through the recruitment phase to avoid contacting these subjects again). 
 
8.2.2 Known Potential Risks and Minimization of Risks 
 
(1) Confidentiality risks and Protected Health Information (rare) - Loss of confidentiality around sensitive 
information such as psychiatric status, history of substance abuse, etc.  
 
Minimization of Risk: 
 
• Investigators and research staff who are responsible for conduct, management, and oversight of 
the study will be required to fulfill all training requirements for Good Clinical Practice (GCP). 
All investigators and research staff will be required to handle protected health information as 
outlined by the Health Insurance Portability and Accountability Act (HIPAA).  
• Confidentiality of participant records is assured by assigning a research code and identifying all 
computer and paper files only by this code, except for a single tracking file. Paper records are 
kept in locked drawers in a locked room and electronic records are kept on secure server, to 
which only authorized research personnel have access.  
• Screening forms for subjects who do not qualify for the study will be destroyed, except for 
anonymous information (such as age, gender and education).  
• After the completion of data analysis, the record linking subjects to the research codes will be 
destroyed, thereby anonymizing the data. 
 
(2) Risk of psychological discomfort, stress, or symptom exacerbation (infrequent) - Risks of psychological 
discomfort associated with the questions asked in the clinical interview or on some of the questionnaires. 
 
Minimization of Risk: 
 
• During the assessment process, subjects are reminded that they do not have to answer questions 
that make them feel uncomfortable. 
• Participants are also reminded during the study that they may choose to terminate participation at 
any time throughout the study. 

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• Staff will check in with the participant frequently to if they are alright. Breaks will be offered to 
reduce any fatigue or stress. 
• Interested participants will also be provided with a list of counseling resources. 
 
• Suicide protocol: The suicide protocol begins with assessment of suicidal thoughts, plans, intentions, 
and behaviors with the C-SSRS (at initial screening). If assessment uncovers suicidal plans or intentions 
or recent behaviors, emergency evaluation will occur, and an appropriate plan of action will be followed, 
e. g. referral to psychiatric emergency room. The PI (a licensed clinical psychologist) will be contacted 
and will join the decision-making process about how to manage the suicidal thoughts or behaviors. 
Subjects who experience severe symptom worsening, including suicidal thoughts or behaviors, will be 
withdrawn from the protocol. 
 
(3) The risks associated with potentially disturbing material (e.g., IAPS and OASIS pictures): There is a risk 
that subjects may become uncomfortable viewing the negative content of the IAPS and OASIS pictures. 
 
To minimize risk:  
 
• The research team has had extensive experience with the IAPS picture set, in over 200 subjects, 
including persons with psychiatric diagnoses such as schizophrenia and post-traumatic stress 
disorder. This image set has been used at laboratories all over the world, and subjects tolerate the 
images without significant difficulty. The most aversive pictures consist of images that one 
would encounter in a "very gory R-rated movie," as we explain this to our subjects. The OASIS 
picture is a well-validated dataset, designed at Harvard, to include updated images with similar 
content to the IAPS. When we inform our subjects about the study, we remind them they 
maintain control over their experience, and we encourage them to close their eyes for any image 
they find too intense. We also remind them that they can terminate the study, at any time. We 
have presented the images and discussed the protocol with members of the University of 
Michigan IRB, as well as community members at the local mental health agency. Mindful of 
potential psychological harm that some images could present for vulnerable psychiatric patients, 
we have excluded images suggestive of suicidal behavior from those we would present to our 
subjects. If any participant should become upset while viewing the pictures, the PI would be 
available to counsel the subjects and reinforce positive coping strategies to deal with the 
experience. 
 
Risks Associated with fMRI Scanning: 
 
(4) Discomfort or anxiety (occasional, not serious). There is a minor risk of discomfort or anxiety/panic 
from being in the confined space of the MRI scanner. 
 
Minimization of Risk: 
 
• The risks of discomfort and anxiety will be minimized by custom pads and pillows to make 
the subject as comfortable as possible. The subject can communicate with the machine 
operator via an intercom and may trigger an audible alarm at any time.  
• Before the subject rolls into the bore of the magnetic, he or she is always reminded that they 
are free to stop the study at any time if they become uncomfortable. 

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(5) Peripheral nerve stimulation (rare, not serious). Fast imaging sequences, such as those employed in this 
study, have the potential to induce peripheral nerve stimulation (PNS). PNS can be described as a light 
touching sensation on the skin surface and may cause mild discomfort but is not harmful to the subject.  
 
Minimization of Risk: 
 
• The MRI machine is operated within FDA guidelines so the potential for inducing PNS is 
low. 
 
(6) Slight dizziness, light-headedness or nausea (rare, not serious). Sometimes subjects report these 
symptoms during or immediately after the scanning session.  
 
Minimization of Risk: 
 
• If a subject feels light-headed, we will have them get up from the scanner bed very slowly, 
resting with the feet dangling for several seconds or more before attempting to stand. 
 
(7) Incidental finding: Magnetic resonance image will reveal a minor or significant lesion in the brain, e. g. 
a tumor, previously unknown to the subject, and requiring additional follow-up. (rare, serious). 
 
Minimization of Risk: 
 
• Subjects will be made aware of the risk of learning about an anomalous finding in the study 
that might require further evaluation with a clinical MRI study. We will also inform the 
subject that many abnormalities will not be picked up in this study, since the scanning 
sequences we use are not sensitive to many forms of brain pathology. However, in the event 
that we find something that is very obvious, such as a large tumor, the PI will personally 
inform the subject by phone call, or in person.  
• A neuroradiologist is available through the fMRI laboratory to review suspicious findings 
and provide guidance about the urgency and advisability of clinical follow-up. No diagnosis 
will be offered, but the P.I. may recommend that the subject pursue a follow-up study with 
their primary care clinician.  
• The PI and study team will facilitate referrals and may provide copies of the brain image if 
these would be deemed helpful. 
 
(8) Hearing damage - from loud, vibrating noises made by the scanner (very rare, serious). 
 
Minimization of Risk: 
• All subjects will wear earplugs and/or earphones throughout the procedure, which attenuate 
high decibel sounds, but still enable a subject to hear the intercom and respond to questions 
from the investigator while they are in the scanner. 
 
(9) Injury (very rare, serious). Because the strong electromagnetic fields can move metal objects and cause 
heating, there is a risk that loose objects (jewelry, keys) outside the body could be accelerated by the 
magnetic field, striking and injuring a subject. There is also a risk that the magnetic fields could disturb 

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a metal fragment in the body, interfere with an implanted device, such as a pacemaker or 
neurostimulator, or cause metal (including foil-backed medication patches) on or in the body to heat up, 
causing harm. 
 
Minimization of Risk: 
• The MRI suite is kept clear of all objects that could be picked up by the magnetic field, and 
all subjects complete a comprehensive MR screening form prior to entering the scanner, 
which is reviewed by the MRI technologist (trained in clinical MRI) before scanning begins.  
 
9. Quality Assurance and Audits 
 
9.1 Audits and Inspections 
 
A regulatory authority (e.g. FDA) may wish to conduct an inspection of the study, during its conduct or 
even after its completion. If an inspection has been requested by a regulatory authority, the study staff must 
immediately inform IRB, Medical School Regulatory Affairs, MIAP, etc.  
 
9.2  Event Windows, Missed Assessments, Missed Sessions and Protocol Deviation Reporting 
 
Any safety-related assessments (AE Questionnaire, etc.) which are missed will be reported to the IRB as a 
protocol deviation. For the other assessments, missing assessments will not be reported as protocol 
deviations unless they constitute > 10% of the total assessments. The time elapsed between the initial 
assessment and sessions are intended to be approximately 1 week, but scheduling logistics may mean this is 
not possible for all subjects, and may be longer for some (~ 30 days). These deviations are expected to be 
minor and will not be reported, although they will be recorded. These allowances should affect neither the 
scientific integrity nor the safety monitoring provisions of the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PRINCIPAL INVESTIGATOR: Stefanie Russman Block, Ph.D.  
 
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