Brain and Cognitive Changes After Reasoning Training in Individuals With Cognitive Complaints
Phase: NA
Conditions: Mild Cognitive Impairment
Sponsor: The University of Texas at Dallas

Protocol/Project Summary 
 
Title:   
Brain & Cognitive Changes after Reasoning Training in 
Individuals with Cognitive Complaints 
 
Principal Investigator: 
Sandra Chapman, PhD 
Funding Sponsor: 
 
UT Dallas Institutional Funding 
Version: 
 
Version 3, July 10, 2017 
 
 
 

INTRODUCTION AND PURPOSE: This proposal is to conduct a study to obtain data 
regarding the benefits of different types of interventions (i) reasoning training following 
transcranial direct current stimulation (tDCS) (ii) reasoning training following sham transcranial 
direct current stimulation  (tDCS) on frontal- lobe mediated cognitive measures of executive 
control in adults with memory complaints, in the absence of dementia. In addition to behavioral 
assessment of cognition, the project will employ (i) Magnetic Resonance Spectroscopy (MRS) to 
measure changes in brain energy metabolism and Magnetic Resonance Imaging (MRI) to measure 
global brain blood flow and connectivity and (ii) electroencephalogram (EEG), to evaluate 
intervention outcomes.  
  
The primary hypothesis is that individuals receiving tDCS prior to brain training will have a 
stronger response to brain training than those in the sham tDCS group. We further hypothesize 
that short, intensive dosages of reasoning training will enhance performance in trained area of 
cognition and will generalize to untrained domains as measured by frontal lobe-mediated 
measures of executive control (also referred to as fluid intelligence) of working memory, 
inhibition, switching, fluency, and nonverbal reasoning. 
 
With reasoning training we expect increases white matter integrity between temporal and frontal 
lobe regions as measured by Fractional Anisotropy (FA) in the Diffusion Tensor Imaging (DTI) 
sequences. With MRS we expect to characterize changes in brains with mild cognitive 
impairment which are not seen with conventional MRI imaging，including changes in 
concentration of metabolites (such as phosphocreatine, inorganic phosphate, etc), ATP energy 
production, redox potential and cellular pH. Also, in the EEG assessments, we expected 
changes in N2, P3, and N4 ERP components in the reasoning training groups compared to the 
wait-listed control group. Importantly, we expect these changes to be more prominent in the 
reasoning training following tDCS than the reasoning training group alone.  
 
BACKGROUND: In the United States 67.1 million individuals are age 55 or older (U.S. Census 
Bureau). The negative effects of cognitive decline in seniors will produce an enormous economic 
burden at individual, state and national levels, since this age group is one of the most rapidly 
growing segments of our population. One of the biggest risk factors faced by this population is 
decline in brain function. Interventions that promote functional independence, postpone 
hospitalization, and reduce the need for formal care will not only extend independent living and 
improve quality of life for seniors but will also save health care dollars. Thus far, the majority of 
the studies have focused on interventions that target specific brain functions such as memory, 
problem solving, etc. (Ball et al., 2002; Jobe et al., 2001; Mahncke, 2006). A significant 
potential exists to modify the structure and function of the aging human brain given intensive 
mental stimulation. Age-related cognitive decline has consistently been identified on frontal lobe 
measures of executive control such as reasoning. Concomitantly, a greater vulnerability of frontal 
brain networks, which subserve executive control functions, has also been identified with aging. 
Preliminary evidence highlights the potential of cognitive training to modify and strengthen brain 
and cognitive function in seniors. Evidence from our lab indicates that frontally mediated, gist-
based reasoning (defined as the ability to combine detail information to construct abstract 
meanings) offers a promising cognitive domain to train in both healthy agers and individuals 
who have lower baseline cognitive performance. 

In addition, new findings from cognitive training-induced neuroplasticity reveal a significant 
potential for the human brain to modify its structure and function well into old age via 
intensive cognitive training. Emerging research by our group (Anand, et al., 2011) and others 
indicate that such cognitive training programs may be most useful in individuals who have lower 
baseline cognitive performance. There are emerging, data-driven findings that suggest that we 
will be able to prevent modest decline and strengthen cognitive capacities in seniors. The key 
challenge is elucidating what types of  training will be successful in enhancing cognitive 
function into late life and what are the brain state changes associated with successful training.  
 
Limitations from prior studies of cognitive training in seniors show minimal if any generalization 
effect of cognitive training to untrained cognitive functions (Meron, et al., 2015). That is, 
individuals seem to get better on the specific cognitive area trained, such as memory, 
vocabulary; however, the training does not generalize to achieve a more global cognitive benefit 
(Elder and Taylor, 2014).  
 
Transcranical Direct Current Stimulation (tDCS) is a form of neurostimulation which uses 
constant, low current delivered (2 mA) directly to the brain area of interest via electrodes(size 
electrodes: 35 cm²). TDCS is widely used to evaluate cortical functions (Nitsche et al. 2008; 
Matsumoto et al. 2010; Nitsche and Paulus, 2011; Zaehle et al. 2011; Polanìa et al. 2011; Stagg 
and Nitsche 2011; Brunoni et al. 2012a) and has also been proposed as a therapeutic procedure in 
various diseases (Hoy and Fitzgerald 2010; Zyss; 2010; Benninger et al. 2010; Freitas et al. 
2011; Brunelin et al. 2012; Brunoni et al. 2012b; Berlim et al 2013).  
 
Tests on healthy adults demonstrated that tDCS can increase cognitive performance on a variety 
of tasks, depending on the area of the brain being stimulated. Application of tDCS has further 
been shown to improve verbal speed, fluency and naming with stimulation sites ranging from left 
and right temporal and frontal regions (Elder and Taylor, 2014). Improvement of working 
memory, learning, and long-term memory by tDCS has been demonstrated in healthy subjects 
(Kuo and Nitsche, 2012). Improvement of working memory in patients treated by tDCS was 
reported using the digit-span test and the go-no go task (Fregni et al., 2006; Boggio et al., 2007).  
 
TDCS is also used as a therapeutic procedure to improve functions in adults with Mild Cognitive 
Impairment and Alzheimer’s disease (Kulzoq et al., 2014; Hsu et al., 2015). A review of the 
research supports that individuals with Alzheimer's disease benefited from tDCS suggesting that 
noninvasive brain stimulation may be effective in individuals with cognitive decline due to 
physiological or pathological changes (Elder and Taylor, 2014; Hsu et al., 2015). Furthermore, 
research supports the possibility that tDCS may be able to reverse pathological brain activity and 
thereby delay the progression of disease in MCI. This study hopes to explore the ability of tDCS 
to enhance the cognitive functioning of Individuals with cognitive complaints. 
 
CONCISE SUMMARY OF PROJECT: Up to 50 individuals with memory or cognitive 
complaints between the ages of 50 and 80 years will be recruited for this study and may be 
randomized into 1 of 2 groups. These groups are reasoning training following transcranial 
direct current stimulation (tDCS) and reasoning training following sham transcranial direct 
current stimulation. The primary hypothesis is that individuals receiving tDCS prior to brain 
training will have a stronger response to brain training than those in the sham tDCS group. 

Response to training will be measured by improved cognitive function and neural change as 
measured by standardized and experimental measures of cognition, MRI and EEG. A group 
level comparison will be done to compare the groups.  Each group may consist of up to 25 
participants. Participants will be comprehensively screened to rule out individuals who may 
have cognitive complaints which may be due to other issues such as depression, brain injury or 
possible dementia. Participants will be recruited from Center for BrainHealth database, as well 
as through flyers handed out to members of the community who attend lectures related to brain 
health and express an interest in future and ongoing research studies, and by means of 
advertisements placed in local newspapers, radio, television and magazines, and the Center for 
BrainHealth website. Additionally, some participants may be referred by Dr. Mary Quiceno at 
the Alzheimer’s Disease Center (ADC) of University of Texas Southwestern Medical Center. 
Dr. Quiceno is study personnel who will be reviewing participant criteria for amnestic MCI in 
conjunction with the clinicians, and also oversees the ADC.  
 
STUDY PROCEDURES: The experiments described below will be undertaken with the 
understanding and written consent of each subject. Participants will only include people who 
are fluent speakers of English, as not all of the standardized and experimental cognitive tests 
have been normed for non-English speakers.  Participants may be asked to participate in the 
cognitive screening and/or reasoning training portions of the study. Investigators will be blinded 
to which group the participants are randomized. The procedures for the study are explained 
below: 
 
 Phone Screening (20 minutes) 
A phone screening will consist of a brief medical questionnaire to determine eligibility for 
the study. Individuals who are not native English speakers or who have a history of learning 
disability, stroke, cognitive impairment, epilepsy, brain tumors, major psychiatric illness, 
alcoholism and substance abuse will be excluded from the study. Individuals with 
uncontrolled diabetes, uncorrected hearing, uncorrected vision will also be excluded from the 
study, as well as glaucoma, and macular degeneration. Individuals with a score of four or 
above on the Ohio State University TBI Identification Method (Short Form), or those who 
have incurred a brain injury in the past year will be excluded. The AIRC MR screening 
questions will be asked verbally to ensure potential participant can take part in the imaging 
portion of the study, including certain MR-safe metals should metal be located outside of the 
radio-frequency coil, or deemed safe in the current 7T literature. Metal implants will be 
evaluated on a case by case basis by the AIRC Medical Director, and study PI to determine 
eligibility. Individuals who pass the phone screening will be asked for contact information of 
a family member to complete a memory questionnaire.   
 
 Clinical Dementia Rating Scale (Memory Questionnaire) (30 to 40 minutes) 
The Clinical Dementia Rating (CDR) can be completed on the phone with the potential 
participant’s family member and then completed with the participant. It includes general 
questions about memory, daily function and life engagement. After completing the 
questionnaire, individuals may be invited to schedule a time for the cognitive screening.   
 
 Cognitive Screening and Neuropsychological Assessment (Approx. 180 minutes) 

A clinician from the Center for BrainHealth will consent the participant and answer any 
questions before beginning the screen. The screening will consist of a medical questionnaire 
and MMQ which participants are given to bring into the appointment, the Mini Mental State 
Examination (MMSE), Geriatric Depression Scale, Auditory Selective Learning, Wide 
Range Achievement Test (WRAT), Logical Memory (LM) subtest, and the California Verbal 
Learning Test (CVLT).  Participants will also undergo hearing and vision screening. Further 
testing for neuropsychological assessment will include standard neuropsychological 
measures such as the Boston Naming Test (BNT), Controlled Oral Word Association Test, 
Digit Span Forward and Backward (DSFB), Delis-Kaplan Executive Function System, Trails 
A & B, Similarities, and the Wechsler Test of Adult Reading (WTAR). Testing will also 
include experimental measures such as the Test of Strategic Learning, and Verbal Problem 
Solving, a cognitive and physical activity questionnaire, the Cognitive Reserve Index 
questionnaire (CRIq), and demographic scale numbers as assessed by the NAM-POWERS-
BOYD Occupational Scale. Neuropsychological testing will take place on three separate 
occasions, so that assessment is conducted pre and post reasoning training, and three months 
post training. The testing will be done at the Center for BrainHealth at 2200 W. Mockingbird 
Lane, Dallas, Texas. When a person has been seen at the ADC within the past six months, the 
Cognitive Screen and Neuropsychological Assessment will be shortened. Standardized 
neuropsychological tests will be accessed from the ADC with their permission, in order to 
shorten the assessment time. While participants are not being referred from Baylor AT&T 
Memory Center, if they have undergone testing during the past six months and would like to 
offer consent to have these neuropsychological batteries accessed, they will be able to do so 
at the consent process. At the initial neuropsychological assessment, participants will initial a 
portion of the consent form that indicates their willingness to undergo genotyping, with 
genetic information collected via a buccal swab. This is a simple procedure in which a 
participant’s saliva is collected on a swab similar to a cotton tip swab, and sealed in a 
container identified with them individually and preserved for analysis. No blood sample is 
required. Samples will be sent to Inova Fairfax Hospital for genotyping purposes. Some 
participants who have already participated in the testing will be called back if they indicate 
willingness to the additional procedure. At the reconsent, these participants will indicate that 
they will only be offering a saliva sample at the time of the consent by initialing a statement 
on the new form, in addition to a new HIPAA form. Both consent forms will be kept for 
these participants, based on study procedures that were agreed to at the time of their initial 
consent. 
 
All participants who agree to participate in reasoning training will undergo EEG, and 
Magnetic Resonance evaluation before and after training.  
 
 
 EEG (Approx. 90 Minutes) 
Each participant may undergo up to three EEG sessions, before beginning the study, at 
completion of the study, and three months after completing the study. Each EEG testing 
session session may last from 60 to 90 minutes, depending upon the pace of the participant 
response times. All skin preparation equipment coming into contact with one’s skin is thrown 
away after a single use, and elecrodes and caps are cleaned and disinfected immediately after 

use in accordance with published guidelines. EEG experiments will be conducted at the 
Center for BrainHealth. 
 
o Phase 1 (Approx. 30 minutes). The electrode cap will be placed on the 
participant's head. Though the cap itself causes no more physical discomfort than 
a lycra swimcap, the application process takes time because all electrodes (up to 
128) must be able to read the electrophysiological responses from the participant's 
scalp with a specific level of accuracy (5 kOhms). To achieve this level 
electrolyte gel will be added to the participant’s cap. Once this level is achieved 
for 95% of the electrodes the experiment will begin. 
o Phase 2. (Approx. 30 minutes). The participant will be asked to sit as still as 
possible and attend to the words/pictures that follow. For each task, the participant 
will be given instructions specific to that task. Because of the noise potentially 
recorded with neurological data, participants will see many repetitions of the same 
stimuli. Participants will be instructed to push the yes/no button or button 1/button 
2 on the response box to indicate their response. The stimuli will be presented in 
blocks of 5-10 min. 2-3 minute breaks will be given between blocks for 
participants to rest if desired.  
o Phase 3. (Approx. 5 minutes). Once the experiment has ended, the cap will be 
carefully removed. Participants will be offered a towel to dry their hair, and given 
the opportunity to wash their hair if desired. 
o Debriefing. (Approx. 2-5 minutes). Participants are told about the study, and 
given documents pertaining to the reasoning training, and other appointments. 
They will be given an opportunity to ask the investigator questions about the 
study and their participation. They will then be thanked and debriefed. 
 
 Magnetic Resonance Evaluation (Approx. 75 Minutes) 
 
Participants who clear the MR safety screening will complete two MR sessions per time 
points (i.e. pre and post reasoning training) in the study. The first scan will be conducted at 
3T Philips Acheiva Scanner (30 minutes) and the second scan will be done on 7T Philips 
scanner (about 45 minutes) for a total of 60 minutes. For both scans, the participant will 
be asked to stay still and awake in the scanner, with head placed in a pad-cushioned 
coil. The scanner normally makes a loud noise during the procedure, so the participant 
will wear hearing protection (ear plugs) for the scan. While in the scanner, the 
participant can be heard and seen by the technologist performing the scan. For further 
safety, a rubber socket will be wrapped around one of the fingers of the participant to 
allow monitoring of the heart rate and blood oxygen level during the scan. The scanner 
is located at the Advanced Imaging Center, UTSW, 2201 Inwood Rd., Dallas TX 75390.  
Imaging and testing may be done on separate days to facilitate scheduling and so as not 
to over-tire the participants.  
 
Magnetic Resonance Imaging (MRI) – The MRI session will be conducted on 3T Philips 
Acheiva scanner. The MRI scan protocols include high resolution T1 image (MPRAGE) 
Diffusion Tensor Imaging (DTI), pseudo-Continuous Arterial Spin Labeling (pCASL), 
Phase Contrast (PC) and TRUST MRI. The total scan time will be 30 minutes. 

 
Magnetic Resonance Spectroscopy (MRS) – The MRS session will be conducted on 7T 
scanner. The MR protocols on 7T include a 31P MRS. The scan time will be 45 
minutes.      
 
 tDCS (25 minutes each session, 200 minutes total) 
 
Prior to the reasoning training, participants will undergo tDCS. Participants will receive 
20 minutes of tDCS using 2mA or less targeting the inferior frontal gyrus prior to each of 
their 8 reasoning training sessions for a total of 160 total combined minutes. This time 
does not include set up time which should take no more than 5 minutes each session (an 
additional 40 minutes for all sessions). For the sham tDCS group, the device will be 
turned off after 30s. These parameters for sham stimulation were chosen based on 
previous reports that the perceived sensations on the skin, such as tingling, usually fade 
out in the first 30s of active tDCS (Nitsche et al., 2003b; Paulus, 2003). During 
stimulation, there will be a control task to ensure that participants are all involved in the 
same level of cognitive stimulation during training. During each of the twenty minute 
sessions they will be presented with a section of one of the British Broadcasting 
Corporation (BBC) series entitled Planet Earth. The series is a popular nature 
documentary (https://en.wikipedia.org/wiki/Planet_Earth_(TV_series)) from 2006 which 
is moderately stimulating and entertaining, without requiring high resources and causing 
participants to tire prior to reasoning training. We think it is important than participants 
are engaging the same cortical network while being stimulated, to ensure variance is due 
largely to tDCS group assignment. A different episode will be presented each time, with 
care not to select anything which may be overly arousing for most participants. All 
session will be administered at Center for BrainHealth, 2200 W. Mockingbird Lane, 
Dallas, Texas 75235. 
 
The tDCS and tDCS sham sessions will be delivered for 20 minutes immediately prior to 
each of the 8 separate reasoning training sessions. 
 
 Reasoning Training (60 minutes)  
 
Intervention protocol will encompass reasoning training (described below).  One 
group will receive reasoning training following transcranial current stimulation 
(tDCS), the second group will receive sham tDCS. 
 
o Reasoning training alone: Brain training for this group will be delivered in small 
groups of 3-5 individuals over a four-week period (two 1-hour session per week – 
total 8 hours). The training is strategy based rather than content-based so that the 
focus is not content specific or situation dependent. Furthermore, gist-based 
reasoning has been linked to frontal lobe activation and to measures of executive 
function. Potentially, the learned strategies could be applied across a variety of 
living contexts such as attending lectures, going to the movies, following new 
stories, planning and carrying out a project, and understanding brochures outling 
changes in health care benefits, to name a few. The strategy instruction is 

hierarchical and dynamically interdependent, with each strategy building upon 
previous strategies to transform the concrete meaning into abstracted gist-based 
meanings through reasoning and inferencing. Constructing meaning at a higher 
level of abstraction promotes learning which is more efficient and long lasting.   
Participant will be given homework to complete between each group session. The 
take home activities are to provide opportunities for the participants to practice 
the strategies.Groups will be conducted by trained clinicians at UTD Center for 
BrainHealth or at locations in the community. Participants will be evaluated prior 
to the beginning of the 8 intervention sessions, at its conclusion, and three months 
post.   
 
o Participants will receive either tDCS or sham tDCS for 20 minutes prior to 
reasoning training.   
 
 
CRITERIA FOR INCLUSION OF SUBJECTS: Selection criteria will include healthy male 
and female adults between the ages of 50 to 80 years, with cognitive complaints in the absence 
of dementia. Subjects to be screened and enrolled may be individuals in the community who 
respond to flyers handed out at the lectures related to brain health, and who respond to 
advertisements in local newspapers, radio, television and magazines. Selection criteria may also 
include participants who can tolerate at least hour long training sessions, who can participate in 
tasks involving motor abilities such as use of at least one arm and hand, those individuals with 
a score of three or below on the Ohio State University TBI Identification Method (Short Form), 
provided the injury was not in the last year, and who can safely have an MRI, including certain 
MR-safe metals should metal be located outside of the radio-frequency coil, or deemed safe in 
the current 7T literature. Metal implants will be evaluated on a case by case basis by the AIRC 
Medical Director, and study PI to determine eligibility.. No racial/ethnic groups will be 
excluded, although the patients must be able to speak, read, and comprehend English well 
enough to participate in the testing and training sessions, since the assessments are not normed or 
translated in other languages at this time. 
 
CRITERIA FOR EXCLUSION OF SUBJECTS:  
Subjects will be screened for any condition or illness that would interfere with participation or 
make participation potentially harmful. Individuals who have any significant health, 
neurological, or psychiatric illness, or history of substance abuse will be excluded. Individuals 
are not appropriate for the study if they meet any of the following criteria: someone who is 
left-handed, not proficient in reading, comprehending, and speaking English, has pre-existing 
cerebral palsy, females who are not post-menopausal, mental retardation, autism, epilepsy, 
schizophrenia, pervasive developmental disorder, thyroid diseases, diabetes, claustrophobia, 
pregnancy, non-correctable vision problems. Individuals with major depression, psychosis, 
active behavioral disorder, uncontrolled epilepsy, and individuals with a score of four or above 
on the Ohio State University TBI Identification Method (Short Form), or those who have 
incurred a brain injury in the past year will be excluded. Participants will not be included in 
the absence of cognitive complaints. 
 
In addition, participants will be administered a standard MRI prescreening form (attached as 
UT Southwestern Advanced Imaging Research Center (AIRC) MAGNETIC RESONANCE 

(MR) PROCEDURE SCREENING FORM FOR RESEARCH SUBJECTS) to assess the 
presence of any MR contraindications (i.e., unsafe metal or medical devices within/on the 
body) and to screen for significant health, neurological, or psychiatric illness and for a history 
of substance abuse, including alcohol. Exclusions for metal safety include questionable ferrous 
implants, bullets, BB's, shrapnel, any metal within the volume of the radio-frequency coil 
unless it is currently represented in the literature as safe at 7T levels.  
SOURCES OF RESEARCH MATERIAL: Materials to be obtained for research purposes can 
include cognitive test data, neuropsychological test data, physical assessment data, language 
skills test data, health records, imaging data. Center for BrainHealth at The University of Texas 
at Dallas will obtain IRB approval from their institution and UTSouthwestern. Training 
sessions will take place at the Center for BrainHealth, or through online training sessions. Data 
from these activities will be recorded at Center for BrainHealth and UTSouthwestern Imaging 
Center and housed at BrainHealth. 
 
RECRUITMENT OF SUBJECTS: The Research Coordinators at the Center for BrainHealth 
may distribute flyers to members of the community who attend lectures and state an interest in 
future and ongoing research. In addition, the Center for BrainHealth will potentially place 
advertisements in local newspapers and magazines, and on the Center for BrainHealth website 
and social media accounts to reach other members of the community also interested in future and 
ongoing research. The Center for BrainHealth will schedule assessment and study procedures 
for individuals who respond to the aforementioned flyers and ads. Study coordinators and 
investigators involved in this study will have contact with the participants throughout this study. 
If the patient agrees to participate and meets the preliminary study criteria, then informed 
consent will be obtained during the first meeting at the Center for BrainHealth. The patient must 
be able (of age and cognitively competent) to sign the informed Consent and HIPAA 
Authorization. The subjects will be provided detailed information about the study including 
purpose, procedures, and possible risks and benefits of participating, their time commitment to 
the study, as well as a copy of consent forms, and study coordinator contact information. 
 
POTENTIAL RISKS 
There are no known risks associated with the behavioral and psychological testing other than 
fatigue and frustration. If the participant’s responses to questionnaires or the information they 
provide to study personnel indicate suicidal thoughts or actions, the researchers are obligated 
to notify authorities. They will refer the participant to a psychiatrist. There are no known 
risks or adverse effects resulting directly from exposure to magnetic fields and radio frequency 
energy used in this study other than a feeling of claustrophobia, fatigue or discomfort from 
lying still during the scanning process. Although there is no evidence of any risk to pregnant 
women, we will exclude women who are pregnant or suspect they may be pregnant.  
 
Exposure to high magnetic fields may have effects on the normal electrical activity of the body 
including changes in nerve and heart function. Changes in the heart rate or rhythm could occur. 
Blood pressure, temperature, and pulse rate may change. Studies with an 8 Tesla MRI have not 
shown any significant effects.   
 
The participants will be asked not to move the head quickly in the magnetic field to avoid 
potential sensation of dizziness, occurring in 30% or more of subjects. The participants may 
experience a metallic taste while entering or leaving the scanner. This is also a relatively 

common sensation. The participants may experience a headache during or after the scan. This is 
infrequent and occurs in about 5% of volunteers. Another less common occurring is seeing tiny 
light flashes when the eyes are closed. In studies at 8 Tesla, 1 subject out of 200 has vomited as 
the result of being in the scanner. 
 
Exposure to the rapidly changing magnetic fields could cause twitching of the subject’s muscles. 
This effect, known as peripheral nerve stimulation (PNS), is temporary. 
 
As with all MRI, any metal in the body or in clothing represents a risk.  Metallic objects can 
be accelerated by the magnetic field and become dangerous. A metal implant or foreign 
object in the body could be displaced by the magnetic field. There can be increased heating 
near metal structures. Safety screening for unsafe metals by the PI and AIRC Director in 
conjunction with the 7T development plan will ensure this risk is minimized.Potential risks 
of EEG are possible scalp irritation resulting from the cap of sensors, boredom and fatigue. 
If the participant becomes excessively uncomfortable, the experimenter will stop the 
experiment at any time. 
 
Participants undergoing tDCS may experience the following side effects but such are still 
considered to represent a minimal risk. 1) The most common side effect is temporally local 
redness of the skin direct under the electrode. This disappears within 1 hour. 2) They may 
experience itching at the site of the electrode, which also passes within an hour. 3) A small 
number of patients have a slight feeling of dizziness when starting the stimulation. This lasts 
only a few seconds and does not affect balance after stimulation. 4) Very rarely, temporary 
skin damage, or a burn may occur under the electrode. This gives a darkening or peeling of 
the top layers of skin,which normalizes after a week and heals. The size of such etch is a few 
millimeters. This is harmless, however, with the current that we will handle, this risk is 
minimal. 5) On the safety side, transcranial direct current stimulation is considered safe. 
 
Any time information is collected; there is a potential risk for loss of confidentiality. Every 
effort will be made to keep your information confidential; however, this cannot be 
guaranteed. 
 
SUBJECT SAFETY AND DATA MONITORING: The risks associated with specific study 
procedures will be thoroughly explained to participants. The risks of the cognitive assessment 
will be mitigated by using highly trained personnel who provide encouragement; schedule 
breaks, and provide a supportive environment for the study participant. The project staff will 
explain all procedures, including the time required. Care will be taken to minimize any feelings 
of anxiety and discomfort that may be aroused. The patients will not be pushed to perform 
beyond their capacities. They will be encouraged to take breaks if they become tired or 
frustrated. The participant will have the option to terminate participation at any time during the 
study. Participants will be encouraged to put on scrubs (provided by MR facility) to minimize the 
danger of missed metal items. During the fMRI, subjects will be able to communicate through the 
intercom built into the scanner. The procedure will be stopped if the subject is unable to complete 
the study or shows any signs of intolerance such as frequent movements. Reassurance will be 
provided as needed and they will be reminded that their continued participation in the study is 
completely voluntary. In the event of severe adverse effects (e.g. headache, nausea, ear problem 

due to noise), participants will be removed from the study and appropriate follow-up instituted. 
Potential to heat tissue is present in all magnetic resonance imaging. The amount of power is 
monitored with appropriate built-in instrumentation to assure the specific absorption rate (SAR) 
is under FDA standards. In any event of system failure or problems scanning will stop. 
Participants will be monitored by a clinician during administration of tDCS. Should the 
participant become dizzy or experience other side effects during the procedure, reassurance will 
be provided and they will be encouraged to continue. In the case of a itching or burning 
sensation, participants will be encouraged to move the arm band, and inform researchers of any 
irritation. If necessary, the procedure will be discontinued. If there is a burn which occurs that is 
evident to participant or researchers and warrants treatment, the participant will be referred to 
seek immediate treatment with the Urgent Care center, or follow up with their primary care 
physician. 
 
PROCEDURES TO MAINTAIN CONFIDENTIALITY: Every effort will be made to 
maintain the confidentiality of study records. Only the researchers will have access to any 
personally identifying information, that is, contact information for each participant (i.e., an email 
address or phone number). This information will not be stored with the participant data. An 
identification number will be assigned to each participant so that it will be possible to identify 
information to be shared with other researchers as described in the HIPAA. In data analysis, each 
participant will be identified by this number. All research materials with identifiable data, 
consisting of detailed health questionnaires, neuropsychological testing, and consent and HIPAA 
forms, will be kept in locked cabinets in the Center for BrainHealth at UTD and imaging data 
obtained from UTSW will be stored at UTD following research compliance standards. Genetic 
information will be sent to Inova Fairfax Hospital for genomic analysis to identify candidate genes. 
Participant identifying information, such as name, address, and phone number will not be provided to 
the researcher at this university. Some other testing information may be provided for the purpose of 
understanding genetic protection and risk factors. The data from the study may be published, but all 
information will be deidentified and compliant with research confidentiality standards. The 
confidentiality of the data will be maintained within the legal limits. Only associates listed on the 
study will have access to identifying data. The Research Coordinator, the Principal Investigator, 
and co-investigators will have access to the data and to the codes, along with designated research 
associates. The researchers will destroy the personal identifiers upon completion of data 
collection for the study. 
 
POTENTIAL BENEFITS: Participants may not benefit from enrolling in this study. However, 
they may benefit from the training sessions by improving their thinking ability, memory and 
learning skills and by feeling an increase in self-esteem, as a result. In addition, the information 
obtained from this pilot study may be of benefit to patients in future, as the investigators may 
gather more information about the interventional strategies to help healthy adults, in addition to 
risk and protection factors which may be part of genetic profiles. 
 
RISK/BENEFIT ASSESSMENT: The disadvantages to being in this study include: time 
commitment, travel, and the physical and emotional challenges related to assessments and 
trainings. The maximum time planned for each of the MRI/MRS scan is 1 hour and each of 
neuropsychological and experimental behavioral assessment session is up to 2 hours not 
including time for commuting and scheduling for a total of 6 hours for participating in the study. 
Although the 7T MRI scanner is not FDA approved for clinical use, the scanner will be operated 

within the FDA guidelines for high-field imaging. The procedures and training sessions could 
take less time, but the investigators want to prepare the participants for the possibility of the 
maximum time commitments. TDCS is a non-invasive technique which has been shown to be 
safe in healthy subjects in several research centers in previous investigations, with no impact to 
participant well-being. Individuals with a history of seizures, pregnancy, cardiac history or those 
who have a pacemaker will be excluded as a precaution. A referral plan is in place for those who 
have topical skin damage from tDCS. There is a risk of breach of confidentiality, although 
investigators are taking careful precautions to prevent this. Participants are informed of the risks 
prior to signing the consents. 
 
BIOSTATISTICS:   
Our primary hypotheses for all outcome measures, including imaging and EEG, involve 
interactions of experimental group with pre- and post-assessment time periods. We expect that 
tDCS-SMART will have larger post-training improvements for behavioral outcomes, EEG 
components, and imaging biomarker changes relative to tDCS-SHAM. These will be assessed by 
simple interaction tests in general statistical linear mixed models with concerted efforts to 
control a false positive rate inflation from multiple testing. For the latter we will utilize some 
modality-specific methods (e.g., conditional cluster-level inference for imaging), in addition to 
false discovery rate control. 
Fifty participants will be recruited for this study, 25 in each group. Outcome measures, including 
imaging and EEG will be obtained to assess the efficacy of tDCS for a larger clinical trial. This 
number is based on a relatively large effect size taken from a meta-analysis of tDCS studies 
summarized in Price et al. (2015) Brain Stimulation, wherein some Hedge's g values were in the 
0.9-1.0 range for some verbal memory and fluency measures. Given those values, we obtain a 
power level of 0.8 for single degree-of-freedom interaction tests. For those outcomes having 
lower power, we will obtain accurate effect sizes for a larger trial." 
 
 
 
 

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