A Novel Neuromonitoring Guided Cognitive Intervention for Targeted Enhancement of Working Memory
Phase: NA
Conditions: ADHD
Sponsor: Stanford University

 
A Novel Neuromonitoring Guided Cognitive 
Intervention for Targeted Enhancement of Working 
Memory 
NCT04002167 
October 26, 2021 
 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
The purpose of the study is to develop a cognitive training method 
that is short, effective and engaging. 
b. 
Objectives 
We hope to learn how NIRS-based neurofeedback enhance the effectiveness of cognitive 
training. 
c. 
Rationale for Research in Humans 
The purpose of this study is to examine how human subjects can control their cognitive 
functions using real-time neurofeedback. 
2. 
STUDY PROCEDURES 
a. 
Procedures 
Trained students and staff will screen, consent, enroll, assess, and monitor participants 
through every step of the process. 
 
Neuroimaging includes functional MRI, anatomical MRI, and NIRS. Participant’s 
physiological responses including heart rate and breathing rate, may be measured inside 
and/or outside of an MRI scan. This may require a belt around the chest or abdomen (to 
measure respiration), a pulse oximeter to be worn on the finger. Wearable or standalone 
eye-tracking devices may be used to track participant's eye movement pattern during the 
training. Particpant's head movement will be recorded during NIRS measurements using 
an accelerometer in order to improve the quality of neurofeedback. 
 
VR googles may be used for presenting computerized tasks and/or training. 

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Demographic data will be collected including education level, ethnicity, socioeconomic 
status and occupational history. Neuropsychological testing includes measures of IQ, 
executive functioning, memory, language processing and visual-motor integration. We 
will also include the Tanner staging assessment - which is a self report scale of physical 
development to assess where the child is in terms of puberty. Psychiatric assessment will 
also be done to assess for current and previous emotional and behavioral problems. 
 
Participants will undergo the following procedures: 
 
1) Screening: Potential subjects will be screened via telephone interview (see attached 
Screen document) or email questionnaire (see eScreen). The screening will involve only 
questions relevant to this study including certain demographic information, medical and 
developmental history to establish eligibility status. 
 
2) Consent: All eligible participants will undergo informed consent procedures. 
 
3) Neuropsychological Assessment: All participants will be administered a battery of 
standardized neuropsychological tests as stated above. 
 
4) NIRS and MRI measurements: Participants will undergo functional near- infrared 
spectroscopy (NIRS) and magnetic resonance imaging (MRI) measurements. No 
injections or other invasive procedures will be utilized. NIRS and MRI will be used to 
provide subjects with real-time feedback about their brain activity during cognitive 
training as well as to measure the participants' brain activity. 
 
5) Intervention: All participants will either undergo cognitive training with 
neurofeedback via NIRS or be waitlisted. Participants will have 50% chance to undergo 
the cognitive training with neurofeedback; those in the waitlist group have the option to 
receive complimentary cognitive training with neurofeedback after completion of the 
study. 
b. 
Procedure Risks 
Neuropsychological assessment is a very low risk procedure and represents the only 
objective, valid and reliable method for accurately measuring cognitive function in 
humans. Neuropsychological assessment represents the standard of care for diagnosing 
cognitive impairments in children and adults. 
 
Neuroimaging assessments using magnetic resonance imaging scans and NIRS are the 
most accurate and non-invasive, low-risk methods for determining neurobiological 
function in humans. Near-Infrared Spectroscopy has the additional benefit of not 
requiring the subject to endure loud noises or confined space for any period of time. This 
study will not employ any invasive neuroimaging techniques such as injection of contrast 
agents. MRI scans and NIRS measurements represent the only existing methods for 
obtaining accurate, in vivo measurements of the human brain. 
c. 
Use of Deception in the Study 

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N/A 
d. 
Use of Audio and Video Recordings 
Video recording will occur. We will archive the data on the CIBSR server, which is 
housed in the CIBSR facility in the Department of Psychiatry and Behavioral Sciences. 
We will occasionally use images or footage in scientific presentations, but in such 
instances all identifying information will be eliminated or occluded. In such 
presentations, the recordings will be used to demonstrate the nature of the task and of our 
study procedure. The recordings will remain on the CIBSR secure server in archived 
form. 
e. 
Alternative Procedures or Courses of Treatment 
N/A 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
N/A There are no treatments involved. 
g. 
Study Endpoint(s) 
N/A There are no treatments involved. 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
Cognitive training is an emergent approach for interrogating brain systems and 
mechanisms (such as neuroplasticity) that are associated with certain cognitive skills and 
the practice of cognitive skills. Cognitive training promotes several neuroplastic 
mechanisms in the brain and has been shown to improve cognitive functioning in healthy 
individuals. While the mechanism underlying these plasticity- related changes in the 
brain is still unclear, it is speculated that cognitive training enhances individual’s 
cognitive reserve (i.e. brain’s ability to perform cognitive tasks) by recruiting either an 
alternative brain network or through a more efficient utilization of brain networks. 
 
The main goal of cognitive training is to boost a specific cognitive ability/brain 
mechanism by employing a set of cognitive training paradigms that target a specific 
cognitive function. In order for the cognitive training to be effective, individuals are 
usually asked to perform a set of cognitive training paradigms for a long period of time (1 
to 6 months, 10 to 300 hours). The question that we arise here is whether we can make a 
more efficient cognitive training program that is short and effective. This will be realized 
by designing a training program that assures subjects will use the targeted brain regions 
during the training. 
b. 
Findings from Past Animal Experiments 
Other groups have shown that cognitive training enhances brain activity in animals. 
4. 
DEVICES USED IN THE STUDY 

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a. 
Investigational Devices (Including Commercial Devices Used Off-Label) 
Investigational Device 1 
Name: 
Customized MRI Scan Equipment 
Description: 
Some of the RF imaging coils, imaging software and other devices used to 
conduct scans at the Lucas Center and CNI (Stanford Center for Cognitive 
and Neurobiological Imaging) are not approved by the FDA. 
Significant Risk? (Y/N) 
No 
Rationale for Non-Significant Risk 
The customized equipment does not currently exist in the market, hence 
our characterization of it as investigational. However, it has been tested 
for safety by highly trained Lucas personnel. 
Investigational Device 2 
Name: 
W-NIRS 
Description: 
An investigational, custom-built NIRS system that is wearable/portable 
and more cost-effective than commercially available NIRS systems. The 
engineering collaborator moved from Stanford to Vanderbilt and they 
keep providing with next iterations of the device. Vanderbilt will not be 
involved in our study and they will not receive data collected at Stanford. 
Significant Risk? (Y/N) 
No 
Rationale for Non-Significant Risk 
There is no known risk associated with functional NIRS. The LED 
sources used in the system operate under IEC/ANSI standards. Theses 
LEDs expose participants to much less light compared with commercially 
available laser-based NIRS systems. 
 
b. 
IDE-Exempt Devices 
IND-Exempt Device 1 
Name: 
ETG-4000 (Hitachi) 
Description: 
NIRS technology uses specific wavelengths of light, introduced at the 
scalp, to enable the noninvasive measurement of changes in the relative 
ratios of deoxygenated hemoglobin (deoxy-Hb) and oxygenated 
hemoglobin (oxy-Hb) in the capillary beds during brain activity.   
IND-Exempt Device 2 
Name: 
NIRSSport (NIRx Medical Technologies) 
Description: 
NIRS technology uses specific wavelengths of light, introduced at the 
scalp, to enable the noninvasive measurement of changes in the relative 
ratios of deoxygenated hemoglobin (deoxy-Hb) and oxygenated 
hemoglobin (oxy-Hb) in the capillary beds during brain activity.   
IND-Exempt Device 3 
Name: 
ETG 2.0 (SMI) 
Description: 
SMI Eye Tracking Glasses 2 Wireless (SMI ETG 2w) are a glasses-type 
eye tracker with full wireless control and live annotations. Instant 
calibrationless setup and 4+hrs mobile operation with the SMI ETG 2w 
smart recorder ensure outstanding productivity for mobile eye tracking 
research.   
IND-Exempt Device 4 
Name: 
VIVE (HTC) 
Description: 
Commercially available VR Goggles and related cameras for presenting 
the computerized exercises/games in an immersive VR environment.   
IND-Exempt Device 5 
Name: 
Gear VR 
Description: 
Commercially available VR Goggles and related cameras for presenting 
the computerized exercises/games in an immersive VR environment.   
IND-Exempt Device 6 
Name: 
NIR Scout (NIRx Medical Technologies) 
Description: 
NIRS technology uses specific wavelengths of light, introduced at the 
scalp, to enable the noninvasive measurement of changes in the relative 
ratios of deoxygenated hemoglobin (deoxy-Hb) and oxygenated 
hemoglobin (oxy-Hb) in the capillary beds during brain activity.   

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5. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
This research study is looking for 160 participants with ADHD. 
b. 
Age, Gender, and Ethnic Background 
Participants (males and females) ages 7-11 years of all ethnic backgrounds will be 
recruited. 
c. 
Vulnerable Populations 
We have already tested the efficacy of the proposed cognitive training in healthy young 
adults in previous phases of the study. We will be studying minors because, in the future, 
neurofeedback and cognitive control paradigms are likely to benefit still-developing 
minors most, due to the increased plasticity associated with early neurodevelopmental 
processes. Thus, we hope to specifically address the applicability of neurofeedback 
scenarios in developing populations. We will be taking special precautions to protect the 
rights of these minors, including following well-established protocols for parental 
consent and assent. 
d. 
Rationale for Exclusion of Certain Populations 
N/A 
e. 
Stanford Populations 
Laboratory personnel and students may be subjects in piloting phases. 
f. 
Healthy Volunteers 
Participants will be children with ADHD. 
 
Parents and subjects will be asked to notify research staff immediately if they encounter 
any problems and participation can be discontinued at any time.. 
g. 
Recruitment Details 
Subjects will be identified using established recruitment measures used at the Center for 
Interdisciplinary Brain Sciences Research. These procedures include advertising online, 
including on ResearchMatch, or in local newspapers and posting notices in public places. 
These procedures also include email messages to email lists and to potential participants. 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
Meeting diagnostic criteria for ADHD, determined by a BRIEF Working Memory 
score >=65. Age range: 7 years - 11 years. 
ii. 
Exclusion Criteria 

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Presence of contraindications for MRI (orthodontia, vascular stents, metallic ear 
tubes, metal implants, pregnancy, etc) for those participating in an MRI scan. History 
of serious medical, neurological or psychiatric illness (except disorders of interest) or 
sensory impairment. 
i. 
Screening Procedures 
Potential participants will be screened for inclusion and exclusion criteria via an online 
and/or telephone screen (see attachments). Only information necessary to ascertain 
eligibility will be requested. Because the screening will include questions involving 
medical history to determine diagnosis of ADHD, a limited waiver of authorization will 
be requested in section 15. 
j. 
Participation in Multiple Protocols 
The screening questionnaire will include a question regarding other study participation. 
Participants can be enrolled in other studies that do not involve medications or substances 
which would affect the MRI and NIRS measurements or cognitive interventions. Each 
case will be evaluated individually prior to enrollment. 
k. 
Payments to Participants 
Participants will be provided with up to $300 for their participation. If the participant 
does not complete the all study visits, he will be reimbursed $20/hr for the portion of the 
study that he has completed. 
l. 
Costs to Participants 
None 
m. 
Planned Duration of the Study 
The study will require approximately 5 years to complete. Total time per participant: 10-
15 minutes for screening, 30 minutes for consent, 30-60 minutes for each 
neuropsychological testing session, 1 hour for NIRS (or MRI) measurements. Analysis of 
participant data will require approximately 18 hours per participant. 
6. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
For MRI scans, there is a minimal non-significant risk associated with use of the custom-
developed imaging coils, imaging software and other non-FDA approved devices used at 
the Lucas Center. 
 
For NIRS scans, there is also a minimal non-significant risk associated with the use of a 
custom-developed cap for holding infrared optodes in place. 
ii. 
Investigational drugs 
N/A 

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iii. 
Commercially available drugs, biologics, reagents or chemicals 
N/A 
iv. 
Procedures 
Neuropsychological testing 
NIRS measurements 
MRI measurements 
Eye Tracking 
VR-based cognitive assessments and training 
v. 
Radioisotopes/radiation-producing machines 
N/A 
vi. 
Physical well-being 
See notes about MRI and NIRS risks above. Otherwise N/A 
vii. 
Psychological well-being 
There is a slight risk that subjects will experience some anxiety, frustration or distress 
during the neuropsychological testing and/or NIRS/MRI procedures. However, this will 
be minimized by training and preparation by clinicians. Any anxiety or distress will be 
brief and transient and the neuropsychological testing will involve rest breaks to 
minimize discomfort and the NIRS/MRI measurements can be stopped at any time by the 
participant. 
viii. 
Economic well-being 
There is no known risk to subjects' economic well being. 
ix. 
Social well-being 
There is no known risk to subjects' social well being. 
x. 
Overall evaluation of risk 
Low 
b. 
International Research Risk Procedures 
N/A 
c. 
Procedures to Minimize Risk 
The consent form for all participants lists all possible risks of the procedures. Research 
staff administering neuropsychological testing will be trained in clinical assessment 
including how to recognize and deal appropriately with participant distress. Frequent rest 
breaks will be included in the assessment protocol to help minimize frustration, fatigue 
and distress. 
 
Research staff are well trained to use protocols and procedures to ensure that the NIRS 
and MRI equipments are used correctly to minimize any risks. Subjects are instructed that 

October 26, 2021 
 
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they can alert the operator that they need help or need to ask a question by speaking 
directly to the experimenter during the NIRS/MRI scan. 
 
All data handling procedures will follow HIPAA regulations. For each participant, a 
folder is created that contains signed consent forms, screening questionnaires and 
NIRS/MRI logs. This folder serves as a permanent archive of original participant data. 
Extensive precautions are taken to insure the privacy of participants and the 
confidentiality of data. Specifically, participant identity is numerically coded on all pages 
within data folders and in the database. All data folders are kept in confidential, locked 
files at Stanford University. Only personnel directly associated with the grant have access 
to these files. Data are entered into the computerized database using only the participant 
ID number, and without any identifying information that would compromise the identity 
and confidentiality of the participants. Participant background information including 
name, gender, ethnicity, and relevant medical and personal information is kept in a 
centralized, restricted access location. This data handling system is efficient, guarantees 
confidentiality, and serves research needs expeditiously. 
d. 
Study Conclusion 
At the discretion of the protocol director, subjects may be taken out of this study due to 
unanticipated circumstances. Some possible reasons for withdrawing a subject from the 
study include: The subject fails to follow instructions or perform specified tasks; The 
investigator decides that continuation could be harmful to the subject; The subject 
requires treatment not allowed in the study; The study is cancelled; Other administrative 
reasons.   
 
The experiment will terminate when all study procedures have been completed or when 
the participant withdraws from the study. Any Adverse Event will be immediately 
reported to the Stanford University IRB and the Psychiatry department chair. 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
- Consent forms 
- AEs, SAEs, SUSARs 
- Protocol Deviations 
- Progress toward Study endpoint(s) 
 
All AEs will be reported to DSMB, NIMH, and/or IRB in compliance with NIMH 
Reportable Events Policy Schedule. 
ii. 
Person(s) responsible for Data and Safety Monitoring 
Dr. Hosseini (PI) and an independent monitoring committee 
iii. 
Scope and Composition of Monitoring Board 
The proposed data and safety monitoring board consists of senior and junior faculty 
with extensive experience in human subject research and/or clinical practice from 

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Stanford. DSMB members do not have any involvement and financial interests in the 
proposed study. 
iv. 
Frequency of DSMB meetings 
The DSMB will meet twice a year and will provide a written recommendation to 
NIMH after each meeting. 
v. 
Specific triggers or stopping rules 
We do not expect any AE or SAE associated with the proposed cognitive intervention 
and therefore we do not expect any stopping rule related to the intervention. 
vi. 
DSMB Reporting 
To PI and NIMH 
vii. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
No 
viii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
Yes 
f. 
Risks to Special Populations 
N/A 
7. 
BENEFITS 
Participants may benefit indirectly through the information learned in their cognitive and 
behavioral evaluation as well as cognitive training. We believe this research will aid in the 
development of an efficient cognitive training method that can be ultimately used for 
boosting/restoring cognitive functions in individuals with impaired executive functioning. 
8. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health.