Treating Phobia With Multivoxel Neuro-reinforcement
Phase: NA
Conditions: Phobia
Sponsor: University of California, Los Angeles

 
 
 
 
 
 
 
 
 
Treating Phobia With Multivoxel Neuro-reinforcement 
 
March 23rd, 2022 
NCT03655262 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Treating Phobia With Multivoxel Neuro-reinforcement 
Protocol and Additional Information 
 
The objective of this study is to use the novel approach of neuro-reinforcement based on decoded 
fMRI information to reduce fear responses to fearful stimuli (e.g., spiders, heights) in individuals 
with phobias, directly and unconsciously in the brain, without repeatedly exposing participants to 
their feared stimuli. 
 
Specific Aims 
 
(1) confirm that our method engages the neurobiological target (amygdala reactivity to images of 
a feared object) in a population of individuals with specific phobia; and (2) to determine dosage-
response optimization. 
 
The investigators aim to enroll a total of 30 patients. The investigators seek female and male 
participants in equal proportions. The age range of the subjects will be between 18 and 65. The 
investigators will work to achieve an ethnic and racial distribution that is consistent with the very 
diverse community found in the Los Angeles area and the UCLA campus: Hispanic/Latino 
56.4%, African American 7.7%; Asian/Filipino/Pacific Islander 15.8%; White (non-Hispanic) 
17.5% (California Health Interview Survey). 
 
Potential research participants' eligibility will be confirmed at the beginning of the first session, 
but eligibility criteria will also be listed in recruitment materials. A research assistant or other 
personnel possessing current CITI and HIPAA certification will conduct an eligibility screening 
interview in a private room. Following onset of the study, subjects who are unable to attend to or 
respond to stimuli as required by the experimental protocol will be excluded. 
 
Anxiety disorders, the most common group of mental disorders in the United States, represent a 
major mental health problem. Phobias, in which fear and anxiety are triggered by a specific 
stimulus or situation, are the largest category of anxiety disorders and affect 5 - 12% of the 
world's population. The treatment of anxiety disorders represents almost one third of mental 
health costs annually. Specific phobias and other anxiety disorders, such as PTSD, represent a 
significant driving force in seeking mental health-related treatment. These disorders present a 
major challenge, and researchers have previously explored various ways to address this 
challenge. One of the most effective psychotherapy methods for the treatment of phobias 
involves exposure, or repeated approach towards feared stimuli, often in a hierarchy of least to 
most anxiety-provoking distances or situations. Exposure-based therapies are effective in 
reducing symptoms, but their effectiveness depends on the individual's capacity or willingness to 
consciously confront their feared object. The associated distress can be so extreme that it 
prevents patients from seeking treatment, and contributes to attrition from exposure once 
treatment begins: estimated dropout rates can top 70%, with three out of five refusing to even 
begin treatment, meaning that as low as 12% of patients receive adequate treatment. Even other 
therapies that require conscious engagement with the aversive stimulus, such as cognitive 
therapies, show high dropout rates. As a result, there is an unmet need for treatment that 
minimizes attrition and subjective patient discomfort, especially for clinical populations for 
whom conventional exposure-based therapies are prohibitively aversive. This problem has led 

some researchers to develop less aversive exposure-based therapies—for example, by showing 
the phobic stimulus very briefly, and immediately following it with a visual mask. However, in 
general, learning effects are weak and short-lasting when stimuli are fully masked because 
masking greatly reduces the signal strength of neural representation in the visual system. It 
would seem ideal if the investigators could capitalize on the potential benefits of fully 
unconscious presentation without sacrificing neural signal strength of the relevant visual 
representation. 
 
In the R61 phase, the investigators will enroll 30 patients, who will be required to meet the 
DSM-5 criteria for specific phobias. Patients will be assessed by trained clinical personnel using 
the Anxiety and Related Disorders Interview Schedule (ADIS) for DSM-5 - Adult version, a 
structured clinical interview based on the DSM-5 criteria (Brown & Barlow 2014) and the Fear 
Survey Schedule (Wolpe & Lang 1964). Participants presenting with post-traumatic stress 
disorder (PTSD), Obsessive Compulsive Disorder, Substance Use Disorder, Current Major 
Depression, Bipolar Disorder, Psychosis, neurologic diagnoses or unstable serious medical 
conditions will be excluded. Participants will also be excluded if they are currently prescribed 
psychotropic medication. 
 
Roles and Responsibilities Our study procedures and results will be monitored by the Principal 
Investigator Michelle Craske, the UCLA Institutional Review Board, and an independent Data 
Safety and Monitoring Board. 
 
Dr Craske will monitor adherence to the confidentiality rules, the quality of the data, their 
timeliness, and the correctness of their entry into computer files. This is a routine part of their 
supervision of postdoctoral fellows, graduate students and assistants. Every two weeks, data 
safety will be reviewed. 
 
Trial Safety Specific Events That Would Preclude a Participant from Continuing the 
Intervention A participant will be precluded from continuing the intervention in the event of an 
adverse event rated 3 -5 according to the scale in the Reporting Adverse Events section below. 
Such events could include an injury or other event resulting in hospitalization or a persistent or 
significant disability or incapacity, a life-threatening or disabling event, or a fatal event. 
 
Potential Risks and Protections Against Risk (see Human Subjects for more details) There are 
no known physical, social, legal, or other adverse effects associated with participation in this 
study. The risks from this study to the subject are minimal. At all times, participants will be 
informed that they are welcome to stop any part of the procedures at any time without penalty 
and to discuss their concerns or ask questions of the research staff at any time. Subjects will be 
informed that they should contact the PIs if they experience a research-related injury. 
 
It is possible that some participants may become uncomfortable revealing personal information 
when completing questionnaires and/or become fatigued and bored during the experimental 
procedures. Participants may become physically uncomfortable with the electrodes attached to 
their person and/or with sitting for long periods of time during the psychophysiological 
procedures. They also may become anxious when exposed to the psychophysiological equipment 
and procedures. It is possible that participants may experience emotional distress when presented 

with feared stimuli at the outset of the study. All on-site study personnel will be clinicians who 
will be available to address participants' needs in this regard. 
 
Clinical interviewing will be conducted by trained advanced clinical psychology PhD students or 
staff who are sensitive to the potential discomfort that participants may have while discussing 
personal matters. All diagnostic procedures will be conducted by staff members experienced in 
performance of similar clinical studies, with appropriate Human Subjects and HIPAA 
certifications. Interviews will be conducted in sound protected rooms. All of the procedures, 
including fear conditioning, have been used extensively in prior studies without adverse events. 
Our instrumentation for psychophysiological recordings meets all standards for non- invasive 
recordings, is well maintained, and has approval from the US Food and Drug Administration. 
Standard application procedures are observed to minimize risk of infection. Subjects will be 
protected by: a) respecting their right to refuse to attempt or continue any task, b) providing 
reassurance or intervention if needed, and c) terminating the experimental procedures for 
participants that become acutely distressed during a session. To minimize the risks of fatigue, all 
participants appearing fatigued during the procedures will be allowed to take a break. 
 
There are no known significant side effects associated with MRI procedures. The magnetic 
fields, at the strengths used, are assumed to be without harm, as our MRI scanning procedures 
fall within the FDA guidelines for radiofrequency electromagnetic field exposure. The 
investigators feel these are safe levels and are less hazardous than a comparable X-ray computed 
tomography examination. Exceptions include if a person has electrically, magnetically, or 
mechanically activated implants (such as cardiac pacemakers), clips on blood vessels in his or 
her brain, or other metallic objects in his or her body such as shrapnel, bullets, buckshot, or metal 
fragments; subjects with such attributes will not be allowed to participate. Although there are no 
known risks of an MRI scan to the unborn fetus, the investigators will not permit anyone who is 
or is suspected to be pregnant to participate. Subjects will thus be given an MRI screening 
questionnaire prior to participation, and will be excluded from participating in brain imaging 
studies if they indicate any risk factors on this questionnaire. The most serious potential risks are 
related to the possibility of ferromagnetic objects in the vicinity of the high- field magnet in the 
scanner. These objects could conceivably become projectiles due to the powerful magnetic field. 
Therefore, subjects will be asked to place all metallic and magnetic objects in their possession 
(e.g., keys, jewelry, credit cards) in a locker outside the magnet room. Most people do not find 
magnetic resonance scans uncomfortable, although mild discomfort has been reported on some 
occasions: 1. Some subjects may experience claustrophobia (fear of enclosed spaces) as they will 
be lying on a table in a horizontal cylinder that is only slightly wider in all directions than their 
body, and extra movement will be minimized as their head is secured. They will be instructed to 
notify the researcher in charge of the scan beforehand if they are prone to claustrophobia. 2. The 
MR scanner makes loud knocking or beeping sounds during imaging; earplugs will be provided 
to help reduce this noise. 3. Due to the rapid rate of change in magnetic gradients during 
imaging, the possibility exists for peripheral nerve stimulation. If this happens, subjects may feel 
creeping or tingling sensations, typically along their arms or lower back. 4. Dizziness and nausea 
may occur if the subjects move their head quickly in the bore of the magnet. 5. Finally, there 
may be some heating from the radio frequency coils, the cables to the coils, or response and 
physiological monitoring devices. The machine will be calibrated so that this heating will be no 
more than one degree of body temperature. Subjects will be instructed to immediately notify the 

investigators if they feel uncomfortable at any time, for whatever reason. Subjects will be able to 
contact the research staff at any point in the study via a microphone mounted on the MRI 
scanner. They will also be instructed on how to use the emergency handheld device to inform the 
operator if they wish to immediately stop scanning and be removed from the magnet. The MRI 
can be stopped at any time at their request. 
 
There is no known radiological risk of MRI scanning. Subjects will be screened in a standard 
fashion for magnet sensitive substances (metal prosthesis, etc.), for claustrophobia, and for other 
medical and psychiatric conditions prior to the study. In addition, any participant who has been 
told he or she has cardiovascular disease, or who is pregnant or nursing will be excluded. 
Participants will also be screened for neurological, psychiatric and substance abuse problems and 
a history of other medical problems or medical treatment related to cerebral metabolism and 
blood flow. Because the magnetism of the fMRI machine attracts certain metals, people with 
these metals in them (specifically pacemakers, infusion pumps, aneurysm clips, metal prostheses, 
joints, rods, or plates) will be excluded from the study. The "metal" in dental fillings is less 
susceptible to magnetism and is therefore allowed. Procedures that will minimize discomfort 
during the scanning include the option of an MRI simulation laboratory and for an initial 
familiarization session in the scanner. Also, the use of headphones and video systems will 
minimize the potential discomfort of the scanner environment. Participants will be encouraged to 
ask questions about the equipment and procedures. Experimental procedures will be terminated 
if participants become overly distressed. A protocol outlining the specific steps on how to act if 
patients become overly distressed during these tasks will be available to all staff members. To 
ensure safety during MRI sessions, every researcher in the lab will complete a safety training 
course, every year. Subjects will be carefully screened to make sure they do not have any metal 
before being taken into the room with the MRI scanner. Subjects will wear earplugs to protect 
their hearing while in the MRI scanner. Volunteers who exhibit contraindications for MRI 
exams, such as pacemakers, surgical aneurysm clips and known metal fragments embedded in 
the body including eyes, will be excluded. Women of childbearing age will not be included in 
this study if they are or think they might be pregnant. Subjects with suspected cerebrovascular or 
pulmonary disease or a history of such will be excluded. Subjects who have experienced 
claustrophobia, or who have a history of migraine, arterial hypertension, coronary heart disease, 
asthma, or anemia will be excluded. Based on our current ethics protocol approved by UCLA, in 
all MRI studies the investigators will also exclude subjects with any history of epilepsy or other 
neurological disorders. Subjects will be carefully screened for these conditions prior to scanning, 
using a standardized form/checklist. Subjects will also be instructed not to use any recreational 
drugs (e.g., marijuana, cocaine) within 48 hours before participating, nor consume more than 3 
units of alcoholic beverages within 24 hours before taking part in the study. Subjects will receive 
these instructions a week before participating, and their compliance will be checked again on the 
day of the experiment. 
 
Consent Procedures and Subject Privacy Signed consent will be obtained from each 
participant. Member(s) of the study staff will meet with the prospective participants in a private 
room to review the consent documents and/or provide an oral explanation of the study. Any 
experiments involving MRI scanning will be undertaken in compliance with the safety guidelines 
for MRI research, and prior to participating in the study, subjects will be informed of the risks 
and benefits of the study, and will fill out and sign the screening questionnaire and informed 

consent form. Individuals will be given a chance to ask questions before making a considered 
decision about whether or not to participate in the study. Subjects will be given as long as 
necessary to decide whether they wish to participate in the study. The investigator or study team 
member(s) will confirm that subjects understand the information conveyed during the consent 
process. Study procedures and consent forms will be reviewed and approved by the UCLA 
Institutional Review Boards. Participants will be provided a copy of the consent form and the 
original will be maintained in laboratory files. 
 
Trial Stopping Rules Please see the procedures described in the Reporting Adverse Events 
section below. 
 
Management of Incidental Findings Dr. Craske will follow a detailed, written action plan if the 
participant discloses suicidal intent/plan. 
 
There is a small chance that the MRI scan will discover a brain injury, such as a brain tumor. In 
that case, the investigators will send the participant's scan to a radiologist, who will check the 
scan. If the finding is confirmed to be a clinically relevant abnormality that can be treated, this 
information is passed on to the participant's general practitioner. Each participant will be 
required to provide the name and address of his or her general practitioner. 
 
Data Security Please see the data security measures described in the Data Management, 
Analysis, and Quality Assurance section below. 
 
Reporting Adverse Events Per UCLA IRB requirements, the investigators will report any 
Adverse Events (including Serious Adverse Events) that meet the definition of an Unanticipated 
Problem to the IRB within 10 working days of PI/Co-PI awareness, with the exception of 
unexpected internal (on-site) death, which would be reported within 3 working days. The 
investigators will comply with the NIMH Reportable Events Policy. 
 
In addition to Unanticipated Problems Involving Risks to Subjects or Others, the following 
adverse events will be monitored: deaths, suicide attempts, study dropout, psychiatric 
hospitalizations, and clinical deterioration, defined as emergent suicidal ideation or suicidal plan, 
development of serious substance abuse, or emergence of a new psychiatric or medical diagnosis 
or behavior posing significant risk to the subjects of others. 
 
The following grading system will be used to assess the seriousness of any adverse events: 
 
0 No adverse event or within normal limits 
 
Mild adverse event 
Moderate adverse event 
Severe adverse event resulting in hospitalization or a persistent or significant 
disability/incapacity 
Life-threatening or disabling adverse event 
Fatal adverse event The Ph.D. level project coordinator will be trained in what events to look for 
and to report any such events to Dr Craske. If the event is graded 2-4, Dr. Craske, a licensed 

clinical psychologist, will interview the participant and take the appropriate action. The UCLA 
IRB and NIH will be notified within 24 hours of any serious adverse events (SAEs), in the 3-5 
range. All SAEs will be reported to the DSMB within 2 days of their occurrence. Within a week 
of any SAEs, the DSMB together with Dr Craske will determine whether the adverse event 
affects the Risk/Benefit ratio of the study and whether modifications to the protocol (at Risks to 
Subjects) or consent form (at Risks and Inconveniences) are required. Furthermore, the DSMB 
shall have the discretion and responsibility to recommend that the study be terminated. 
Dr Craske will conduct a review of all non-serious adverse events at least quarterly. They will 
evaluate the types, frequency, and severity of the adverse events and determine if modifications 
to the protocol or consent form are required. A summary of the non-serious adverse events will 
be reported to the IRB and DSMB periodically or, at minimum, when yearly re-approval of the 
IRB protocol is sought. The summary will include number of Participants enrolled, treatment 
retention and reasons for drop-out, and a description of graded adverse events to date. Dr or 
Craske or the IRB has the authority to stop or modify the study. 
 
Data Management, Analysis and Quality Assurance All data will be specifically obtained for 
research purposes during individual test sessions. Sources of material obtained from participants 
will include amygdala reactivity, skin conductance response (SCR), and subjective fear ratings in 
both the R61 and R33 phases. In the R33 phase the investigators will also assess spontaneous 
recovery with the Behavioral Approach Test (BAT) and Anxiety and Related Disorders 
Interview Schedule (ADIS). The identifying information that will be collected from study 
participants includes all information required to create a GUID: sex, first name, last name, 
middle name, date of birth, and city/municipality of birth. The investigators will also collect 
email addresses. 
 
A member of the research team with current CITI and HIPAA certification will assign a code 
number to each data file. The key pairing each code number with each participant's name and 
other identifying information will be stored separately from the data files themselves, in a locked 
filing cabinet to which only declared research personnel have access. All of the interviews and 
study procedures will be conducted in private, locked room where only the experimenter and 
participant are present in order to protect each participant's privacy. The data collected will be 
used only for this study. Upon completion of the study, all data files will be stripped of personal 
identifiers and/or the key to the code destroyed. The investigators agree to follow the OHRPP 
Data Security in Research guidance and procedures. 
 
The investigators will recruit subjects through community outreach. Patients meeting the DSM-5 
criteria for specific phobias will be recruited through the UCLA Anxiety and Depression 
Research Center and advertising in the local community. In order to maximize the fidelity and 
reliability of the between-subjects decoder for fearful objects, it is necessary to establish a pool 
of hyper-realigned brain activity patterns from control subjects matching the demographics of the 
patient population. Therefore, the investigators will attempt to achieve a high level of diversity in 
our sample by placement of advertisements and flyers in local community recreational centers 
and religious centers in areas more densely populated by Asians, Hispanics, and African 
Americans as well as through Internet-based advertisements. Every month, the investigators will 
monitor the ethnic and racial distributions in the recruited sample. If the investigators observe 

that the investigators are not reaching the targeted level of diversity, the investigators will make 
further outreach efforts.