Treatment of Word Finding Difficulties and Verbal Retrieval Deficits in Civilians Who Sustain a Chronic Traumatic Brain Injury With High Definition Transcranial Direct Current Stimulation
Phase: NA
Conditions: Traumatic Brain Injury, Word Finding Difficulty, Acquired Brain Injury, Cognitive Change
Sponsor: The University of Texas at Dallas

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Study Title: Treating Civilian Traumatic Brain Injury With High 
Definition Transcranial Direct Current Stimulation (ciTBI-HDtDCS) 
 
    
 
NCT05408975 
 
Date of the document: November 27th, 2024 
 
 
 

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The University of Texas Southwestern Medical Center at Dallas 
Institutional Review Board 
 
Protocol 
 
Using High Definition transcranial Direct Current Stimulation to Treat Verbal Retrieval Deficits 
Secondary to Chronic Traumatic Brain Injury (HDtDCS-CTBI) 
 
1. Introduction and Purpose: 
 
The pre-supplemental motor area (preSMA) has been shown to play a role in memory and word 
retrieval. Prior studies have suggested that neurostimulation targeting this region can improve word 
retrieval as well as other cognitive skills. Entraining the preSMA circuits with 10 sessions of 
neurostimulation could be used to improve cognitive functioning evaluated by EEG-based and 
neuropsychological measures. The purpose of this study is to examine the efficacy of high-definition 
transcranial direct current stimulation (HD-tDCS) to the preSMA region and its influence on EEG and 
neuropsychological measures in patients with chronic TBI. We also use MRI imaging to examine how 
baseline white matter integrity affects HD-tDCS therapeutic effects. The 3 aims of this study are 1) to 
determine HD-tDCS targeting pre-supplementary motor area (pre-SMA) modulatory effects on verbal 
retrieval function and synchronized brain activity using electroencephalography (EEG), 2) to use MRI 
imaging to examine how baseline white matter integrity affects HD-tDCS therapeutic effects, and 3) to 
establish predictive models of HD-tDCS induced changes by integrating baseline EEG and MRI 
measures. 
 
2. Background: 
 
High Definition transcranial Direct Current Stimulation (HD-tDCS) represents a safe, portable, and 
low-cost noninvasive brain stimulation technology to target more focused brain regions and modulate 
dysfunctional brain circuitry underlying neurocognitive symptoms. The pre-Supplementary Motor Area 
(pre-SMA) is part of the neural circuit underlying word retrieval functioning and can be more easily 
modulated by HD-tDCS than other deeper brain structures in the circuit. We have shown in pilot 
studies that adults with word retrieval impairment long after traumatic brain injury (TBI) can have 
enhancement of word retrieval from HD-tDCS targeting the pre-SMA. Immediately following 
stimulation, active HD-tDCS compared to sham was associated with significant improvement on a 
verbal (semantic) fluency task in a small sample of adults (N=25). We later combined 
neuropsychological and EEG measures in a case study of a patient with word retrieval impairment 3 
years after a severe TBI, and found that HD-tDCS to the pre-SMA led to enhancement of verbal 
(phonemic) fluency (named 36 more items than baseline) and improved frontal EEG activity that 
lasted for 2 months. Thus, our preliminary work indicates HD-tDCS may have the potential to improve 
word retrieval functioning in those with chronic TBI and that HD-tDCS induced improvement could 
persist for 2 months 
 
3. Study Procedures: 
 
Overview and design 
 
We plan to recruit at least 24 English-speaking participants aged 18-85 years with a history of chronic 
TBI (> 1 year since injury), all of whom have problems with cognition. Participants will be randomized 
into an active HD-tDCS condition or a sham condition in order to assess the efficacy of HD-tDCS on 
improving cognition. The proposed study will measure response to HD-tDCS treatment over the 
preSMA region when compared to sham. Participants will receive two phases of 10 sessions of active 
stimulation (1 mA anodal HD-tDCS targeting preSMA for 20 min) or sham across 2 weeks. All 
participants will be blinded to their condition. EEG and neuropsychological tasks will be completed at 

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baseline, immediate follow-up after session 10, and a 2-month follow-up. Those participants 
randomized into the active or sham group will have the opportunity to return after 2 months and 
receive sham (if active first) or active (if sham first) treatment and will undergo the EEG and 
neuropsychological tests again immediately following the last HD-tDCS session and at a 2-month 
follow-up. With this design, we expect a 15% attrition rate and plan on enrolling ~30 adults to achieve 
our completed sample of 24. 
 
 
 
 
Sample size justification 
 
Pre-study power analyses were conducted for the most power intensive phase of the study (Phase 1), 
using a clinically relevant effect size (Cohen’s d = 1.20) derived from our prior studies. Holding 1- 
β=0.8, and ɑ=0.05, a sample size of 20 would provide sufficient power to identify true interaction 
effects (treatment * time) across all neuropsychological outcome measures in the magnitude of f=0.27 
(Cohen’s d ≈ 0.54). Given that both our and other’s research without intervention suggests that effect 
sizes tend to be larger in EEG compared to neuropsychological measures, we expect the effect size 
of EEG outcomes to be at least equivalent to neuropsychological outcomes. Still, we will perform an 
interim power analysis based on EEG data once half of the targeted recruitment is reached to ensure 
adequate statistical power. As the proposed sample size provides sufficient power to detect moderate 
effects for all outcomes, our study is well powered. 
 
Below is a table summarizing the study visits followed by a detailed description of the procedures for 
each visit. It is a two Phase study. In Phase 1, participants will be randomized to active stimulation (1 
mA anodal HD-tDCS targeting preSMA for 20 min) or sham and complete 13 visits. Then in Phase 2, 
participants who have been in the active group in Phase 1 will be invited to receive the active 
stimulation condition, and those who have been in the sham group in Phase 1 will be invited to 
receive the sham stimulation condition. Either way would involve 11 additional visits in the study. 
 
TABLE 1. SUMMARY OF VISITS 
Phase 1 
PROCEDURES 
TIME 
Visit 1 
Pre-testing neuropsychological assessment/semantic EEG 
3 hours 
Visit 2 
Pre-testing MRI scan 
1 hour 
Visits 3-11 
HD-tDCS active or sham stimulation 
30 minutes 
Visit 12 
HD-tDCS active or sham stimulation and post-testing neuropsychological 
assessment/semantic EEG 
3 hours 
Visit 13 
8-week follow-up assessments/semantic EEG 
3 hours 
Phase 2 
  
  
Visits 14-22 
HD-tDCS sham or active stimulation 
30 minutes 
Visit 23 
HD-tDCS active stimulation and post-testing neuropsychological assessment/ 
semantic EEG 
3 hours 
Visit 24 
8-week follow-up assessments/semantic EEG 
3 hours 

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Transcranial Direct Current Stimulation (tDCS) is a non-invasive technique that requires the 
placement of several sensors (metal electrodes) on a special cap and saline gel on the participant’s 
head. Very low levels of constant electrical current are delivered to specifically targeted areas of the 
brain via these electrodes. Contact quality and impedance levels (<10 kOhms) will be verified before 
each session. The same preparation is used for both active and sham conditions. After each session, 
subjects will be administered a standard post-treatment symptom questionnaire (e.g., assessing for 
skin irritation). Daily treatment lasting for 20 minutes (total of about 30-40 minutes including 
preparation) will be administered over 2 weeks (5 daily sessions each week), as scheduling allows. 
Session scheduling will depend on participant availability and availability in the lab. All treatment 
sessions will be held in Dr. Hart’s lab at UTDallas. 
 
Assessment sessions, including the neuropsychological test battery and the Semantic Selection and 
Semantic Object Retrieval EEG tasks, will be completed at baseline, after intervention session 10, 
and at 2-month follow-up assessments. Each assessment session lasts approximately 3 hours. 
Specifically, the neuropsychological testing will take approximately 1 hour and will assess skills in the 
areas of word retrieval, episodic memory, processing speed, executive functions, and visuospatial 
organization. Participants will be asked to complete a few questionnaires about emotional state and 
cognitive performance as well as completing computer tasks. These tests might be completed through 
in-person or remote online interviews. In addition, MRI scan will be obtained at baseline that include 
structural imaging and takes place at UTSW advanced imaging research center. Participants will also 
undergo event-related electroencephalography (EEG). The EEG procedure is a non-invasive 
technique that requires the placement of 64 sensors (metal electrodes) and saline gel on the scalp. 
The electrodes will record brain electrical activity while participants sit quietly in a chair and perform 
computer-based tasks. During the event-related EEG participants will be asked to react to visual 
stimuli shown on a screen using a button box. The EEG procedure will take place at the UT Dallas 
Callier Center for Communication Disorders, or Research and Operations Center West, both of which 
are in the laboratory of Dr. Hart. The EEG procedure takes nearly 2 hours. 
 
5. Sub-Study Procedures:  
 
not applicable 
 
6. Criteria for Inclusion of Subjects: 
- Age between 18 and 85 
- Female and male subjects 
- All races/ethnicities 
- Fluent in speaking and reading English 
- Capable of understanding and signing an informed (cognitive screening and questions on 
understanding of the study are included to assess capacity) 
- Has had a TBI: loss of consciousness less than 24 hours, posttraumatic amnesia less than 7 days, 
Glasgow Coma Scale no less than 12 at the time of injury, and Glasgow Outcome Scale-Extended 
(GOSE) of at least 5 at the time of evaluation. 
- Has a subjective complaint of verbal retrieval difficulties evaluated with the following questions. 
Affirmative answers of yes to two or more of these questions is considered indicative of a subjective 
verbal retrieval complaint: 
a. Do you have trouble finding words when in conversations with others? 
b. Do you have difficulty remembering lists of things when these are told to you verbally or if the items 
are written down? 
c. Do you have trouble producing the correct name of an object when referring to it? 
d. Do you have difficulty following the conversation of other people because you do not understand 
what people are saying? Do you have difficulty hearing? (In this case, the answer to the first question 

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has to be yes and the second no for this question to be considered positive for a verbal retrieval 
deficit.) 
- Has a subjective report of word finding difficulty assessed by the Questionnaire for Word Finding 
Complaints, that includes 13 Likert-type questions regarding several aspects of word retrieval. 
 
7. Criteria for Exclusion of Subjects: 
- Lifetime major neurologic syndromes (e.g., stroke, epilepsy, brain tumor) 
- Lifetime major cardiovascular conditions (e.g., heart attack, heart failure) 
- Current substance use disorder 
- Lifetime major psychiatric disorders (e.g., schizophrenia, bipolar disorder) 
- Current sensory or physical impairment that interferes with testing 
- Implanted device such as a pace maker or other neuro-stimulator 
- Has metal fragments in head 
- Pregnancy 
 
If a medical condition becomes apparent during the evaluation or follow-up that indicates an increased 
risk then the subject’s involvement in the study will be discontinued.  
 
8. Sources of Research Material: 
 
Research material from questionnaires and interviews will include data about clinical diagnosis, date 
of birth, sex, race, education level, personal medical history, and contact information including name, 
address, and telephone number. Neuropsychological testing research material will involve results for 
word retrieval, episodic memory, processing speed, executive functions, and visuospatial organization 
that will be for research purposes only. EEG research material will involve (1) latency of the frontal 
and left fronto-temporal ERPs and (2) magnitude (spectral power) of the frontal theta (4-8 Hz) 
oscillatory activity, both of which will also be for research purposes only. MRI data will include 
MPRAGE, T2FLAIR, and DTI images. All data will be stored on password protected computers (digital 
data) or in a locked cabinet in a secure location (physical data) that is password protected and 
accessible only to study personnel. Of note, clinical information may be collected from the subjects if 
they undergo assessments for these in standard clinical care visits at UTSW. 
 
9. Recruitment Methods and Consenting Process: 
 
Recruitment for the civilian TBI cohort will primarily be supported by the UTSW memory, TBI, 
neuropsychology clinics, all following a large population of TBI patients. In addition, we will us several 
strategies to maximize recruitment. These will include 1) providing study-related information with 
colleagues at UTSW via e-newsletters and university presentations, 2) placing flyers in exam rooms 
and waiting areas at UTSW memory/TBI/neuropsychology clinic facilities, and 3) advertising the study 
on the UTSW website, our lab website and social media using e-flyers.  
 
Prospective participants will undergo telephone screening for conditions in their medical history as 
well as current medications to save them time and effort from coming to UTSW to enroll in the study if 
they ultimately will not meet major inclusion/exclusion criteria. 
  
Prospective participants meeting pre-screening inclusion/exclusion criteria (over the telephone) will be 
scheduled an appointment to review the study procedures and Consent Form. Study staff will go over 
the consent form in detail with the prospective participant and answer any questions about the 
procedures. Participants will be asked to sign the Consent Form if they understand the study 
procedures, appreciate potential risks/benefits, and desire to be involved in the study. 
 
If, at any time, the subject wishes to withdraw from the screening and consent process, they will do so 
without penalty. 
 

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10. Potential Risks: 
 
Overall, there is of injury from participating in this research. 
 
Risks from the HD-tDCS: 
Overall, HD-tDCS has been found to be a safe, well tolerated investigational device as well as a 
treatment tool when used within the standard parameters. No serious adverse advents caused by HD-
tDCS have been reported in the scientific literature. The research team will stop the procedure 
immediately if the subject chooses. Common side effects include:  
• 
Possible skin sensations, such as tingling, itching, and burning sensations at the site of 
electrodes, that resolves when stimulation is finished. When experienced, the majority of these 
are mild in nature with fewer than 4% of individuals describing the sensations as intense. 
• 
Very rarely, temporary skin irritation may occur under the electrode. This creates a darkening 
of the skin, which normalizes after a week and heals. The size of such is a few millimeters. 
To minimize risk, all subjects will be monitored with one-on-one direct supervision during HD-tDCS 
sessions. If subjects experience discomfort more than the mild tingling or itching expected during HD-
tDCS and are unable to continue, the HD-tDCS session will be immediately terminated.  
 
Risks from EEG: 
• 
Tiredness 
• 
Emotional discomfort 
 
Risks from MRI acquisition:  
The scanner makes a loud, banging or tapping noise while acquiring images. Participants may 
experience nervousness from confinement in a tight space (claustrophobia). Participants may 
experience some discomfort and fatigue from lying still during scanning. There are no known effects 
from exposure to magnetic fields, unless in the presence of the following: heart pacemaker; heart 
valve replacement, or aortic clips; metal fragments in their eyes, skin, or elsewhere in their body; brain 
clips or pieces of metal used in aneurysm surgery or intracranial bypass; venous umbrella; pieces of 
metal in the body resulting from work as a sheet-metal worker or welder; clips placed in an internal 
organ; prosthetic devices, such as middle ear, eye, joint, or penile implants o joint replacement; 
hearing aid that cannot be removed; neurostimulator; insulin pump; intrauterine device (IUD); shunts 
or stents; metal mesh or coil implants; metal plate, pin, screws, or wires, or any other metal implants 
 
Risks Pertaining to Loss of Confidentiality and Privacy:  
Confidentiality of participants is a priority for research staff and also is presumed and must be 
maintained unless the investigator obtains the express permission of the subject to do otherwise. 
Risks from breach of confidentiality include invasion of privacy, as well as social and economic risks. 
Economic risks include alterations in relationships with others that are to the disadvantage of the 
subject, and may involve embarrassment, loss of respect of others, labeling with negative 
consequences, or diminishing the subject's opportunities and status in relation to others. These risks 
include loss of wages or income, and/or damage to employability or insurability. 
 
Unanticipated risks:  
Any experiment may involve risks that cannot be anticipated. Any identified risks will be reported 
immediately to UTSW IRB for further consideration. 
 
11. Subject Safety and Data Monitoring: 
 
All HD-tDCS sessions will be overseen by the Co-PIs. All safety precautions recommended by 
scientific literature and the UT Southwestern IRB will be carefully followed. All adverse events 
volunteered by the subject or elicited by the research team will be recorded in the subjects’ research 
file. All adverse events will be reported within one week to the IRB. Any severe adverse events will be 

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reported within 24-48 hours to the IRB. Data safety monitoring and review will be performed every six 
months by the research team. 
 
In order to safeguard our participants from a breach in confidentiality, the data is coded with a unique 
semi-random subject identifier (URSI). All data after initial entry into the study is coded based on the 
participant’s number. A digital file containing completed questionnaires and assessments from the 
experimental session will be maintained with the URSI number. These files will be stored on password 
in a locked cabinet in a secure location (physical data) and accessible only to study personnel. The 
people who will have access to the data include members of the research team. Identifiable data will 
not be shared with investigators outside of the research team. The data is also available to the IRB for 
audit purposes. Other investigators at UTSW wishing to do secondary analysis may have access to 
the data as well, but will not have access to any identifiable information associated with the data. 
 
12. Procedures to Maintain Confidentiality: 
 
Confidentiality will be maintained according to the highest standards. All subjects will be assigned a 
unique research identifier number (ID). All data will be deidentified with this ID and recorded on 
subject case report forms. The case report forms and key for linking coded identifiers to personal 
identifiers will be maintained in an encrypted UTSW IRB approved electronic data management 
program and on password protected computers that only designated study personnel have access to. 
Research data created by this study will not become part of hospital or institutional medical records. 
Study personnel are not obligated to share study results with the participant.  
  
The UTSW IRB that oversees human subject research will be permitted to access participant records. 
There may be times when we are required by law to share our study participant's information. 
However, the name of the participant will not be used in any published reports about this study. A 
copy of the consent form will be kept in a locked cabinet in a secure location (physical data) that is 
password protected and accessible only to study personnel. The study data may also be presented at 
meetings, published in journals/books or used in classrooms for training purposes. It is possible that 
these data may be used for testing various future analysis tools, in hopes of finding better ways to 
understand the results. 
 
Finally, the participant will understand that the investigator is not prevented from taking steps, 
including reporting to authorities, to prevent serious harm to himself or herself or to others. 
 
13. Potential Benefits: 
 
The potential benefit of this study to subjects includes the opportunity to contribute to a scientific 
investigation that may benefit others in the future. Benefits to others include: informing a possible new 
intervention for cognitive deficits in TBI. The risks associated with study procedures are no more than 
what would be expected in routine clinical and neuropsychological assessment and HD-tDCS 
applications. Thus, there is a strong benefit to risk ratio. The potential benefits to TBI subjects, 
scientific community, and society outweigh the risks associated with study procedures.  
 
14. Biostatistics:  
 
Mixed effects models will be used to evaluate if active HD-tDCS is associated with significant 
improvements over sham stimulation in neuropsychological assessments. Changes in performance 
from baseline to immediately post intervention (cognition in Hypothesis I) and baseline to the 2 month 
follow-up (Hypothesis II) will be assessed for each neuropsychological outcome measure. To test 
Hypotheses I and II, interaction effects among treatment group (active and sham) and time will be 
examined. Statistical significance will be set at ɑ = .05. Covariates of interest include: age, sex, 
ethnicity, education, use of cholinesterase inhibitors, and assignment phase. Correlation coefficient 
across time is assumed around 0.6-0.7 based on the literature. 

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Specifically, we will model each measure at the jth assessment time post-treatment from an individual 
subject in the ith treatment condition, 𝑦𝑖𝑗, as 𝒚𝒊𝒋=µ𝟎+𝑰(𝒙)⋅µ𝒊𝒋+𝑰(𝒛)⋅d𝒊𝒋+e𝒊𝒋𝟎, where µ0 is the baseline 
mean prior to random assignment to i=1,2 conditions (1- active, 2- sham); µ𝑖𝑗 is the mean change 
from baseline for j=1,2 assessment times (1- immediate- [T1], 2- eight weeks [T2] post-treatment); 𝐼(𝑥) 
is an indicator variable for phase 1; similarly, 𝐼(𝑧) is an indicator for Phase 2 (sham-to-active vs active-
to-sham conversion); and d𝑖𝑗 is the mean change from baseline for j =3,4 assessment times (3- 
immediate- in phase 2, 4- eight weeks [T’2] post-treatment in phase 2). Additionally, e𝑖𝑗0 is a random 
error term with 𝑗0=0,1,2,3,4, indicating baseline, post-assessment times for both Phases 1 & 2. Phase 
1 & 2 errors between subjects are independent but positively correlated within subjects across time; 
additionally, a consequence of Phase 2 is that Phase 2 errors are positively correlated across the 
treatment conditions. Due to expected attrition, which will cause missingness in some (but not all) 
assessment times, and due to the complexity of the constraints, phases, and covariance 
parameterization in the linear mixed effects model above, all fixed-effect parameter estimates will be 
obtained by maximum likelihood and all covariance parameters for random effects will be obtained by 
restricted maximum likelihood (REML). All hypothesis tests will be based on t-statistics from a priori 
hypotheses, which are interaction contrasts of the form (µ𝟏𝒋+d𝟏𝒋)/2− (µ𝟐𝒋+d𝟐𝒋)/2 where j is 
understood to reflect the same assessment time regardless of phase (i.e., immediate post- OR 8 
weeks post-treatment). The interaction contrast, shown above, reflects overall active HD-tDCS effects 
compared to sham. All analyses will be performed in SAS, R, and/or Matlab. 
 
Mixed effects models will be used to evaluate if active HD-tDCS is associated with significant changes 
over sham stimulation in EEG measures. Changes from baseline to immediately post intervention 
(Hypothesis I - latency; Hypothesis II - magnitude) and then baseline to 2 month follow-up (Hypothesis 
III) will be assessed. To test Hypotheses I-III, interaction effects among treatment group (active and 
sham) and time will be examined. Statistical significance will be set at ɑ = .05. Correlation coefficient 
across time is assumed around 0.6-0.7 based on the literature.