Computer Training and Transcranial Direct Current Stimulation for Cognition in HIV
Phase: NA
Conditions: HIV-related Mild Neurocognitive Disorder
Sponsor: Nova Southeastern University

 
 
 
 
STUDY PROTOCOL 
 
 
Computer Training and Transcranial Direct Current Stimulation for 
Cognition in HIV 
 
 
Identifier: NCT03440840 
 
National Institute on Aging grant:  R21AG056256 
 
 
Date: 12/2/2020 

RATIONALE FOR STUDY 
HIV-associated neurocognitive disorders (HAND) continue to develop in persons with HIV, even 
when they are otherwise effectively treated1-3 and include deficits in attention, executive function, memory, 
and psychomotor speed.4 They may have significant impacts on affected persons’ ability to care for 
themselves, remember to take their medication, drive, and enjoy life.5-9 As persons with HIV age, they may 
also experience the same declines in cognitive functioning associated with normal aging10;11 While it is 
not clear whether the effects of HIV and aging are synergistic, it is clear that older persons with HIV experience 
problems in attention, psychomotor speed, and memory that have a negative impact on their lives. Treatments 
for cognitive deficits in older persons with HIV thus are needed but available treatments are limited. 
Computer-based cognitive training may improve function in older persons with HIV, but data from small studies 
suggest that effect sizes, while statistically significant, may be small.12;13 Training software is not widely 
available, can be expensive, and lacks the inherent interest needed to sustain participant involvement. The 
uptake of these programs, even if they were inexpensive and widely available, is thus not clear. 
A possible solution is to use commercial computer games for cognitive training. Commercial games, 
such as first person shooters (using a weapon to shoot enemies) or car racing combine the essential elements 
of active learning14;15 and are fun to play. Research shows that playing games has a positive effect on 
cognition in older persons.16 Although many persons assume that players are mostly young men, Pew 
Research data show that 38% of women and 29% of men over 50 play computer games.17 Our own as 
well as others’ studies18;19 have shown that older persons are interested in computers and can work effectively 
with them when given appropriate training. Even this strategy, though, may have only limited effects on 
cognition in older adults.12 
Transcranial direct current simulation (tDCS) has emerged as a safe20 and inexpensive strategy to 
enhance the effects of cognitive training. Studies show substantial increases in amount and rate of learning in 
healthy young21-24 as well as older persons,25;26 and patient groups27-29 that have included individuals with 
neurological disorders such as primary progressive aphasia or Parkinson’s disease. tDCS may also have 
positive effects on depression,30;31 and was acceptable to participants as a treatment for depression in HIV.32 
tDCS is thus a promising technique to enhance cognitive training in older persons with HIV.   
While tDCS is an emerging treatment, it is the subject of serious investigation. Noninvasive brain 
stimulation technologies, including tDCS, were described as promising at a workshop at the Institute of 
Medicine in 2015,33 and the NIMH Division of Translational Research will have held a workshop on tDCS by 
the time this application is reviewed (scheduled for 9/29-30/16).  
To study tDCS and cognitive training in HIV, we completed a pilot study of computer game based 
cognitive training with and without tDCS in older persons (average age 51 years) with HIV.34 Results suggest 
a positive effect of tDCS on cognition and mood and demonstrate the potential feasibility and 
acceptability of the intervention. Given the preliminary nature of the proposed study, we are seeking support 
under the R21 exploratory/developmental mechanism (“high risk – high reward”) in response to the PAR 15-
282, “Multidisciplinary Studies of HIV and Aging” to further explore the usefulness of cognitive training and 
tDCS in persons with HIV.  
We will complete a randomized, single-blind treatment with blinded outcome assessments study of  
game-based cognitive training with and without tDCS, with an attention control group, recruiting 125 
persons to ensure a total sample of 90 individuals 50 years of age and older with HIV-related mild 
neurocognitive disorder, to evaluate the following: 
AIMS AND HYPOTHESES 
AIM 1) Further explore the acceptability and feasibility of game-based cognitive training with and 
without tDCS in older persons with HIV infection by completing a trial that includes a control as well as 
groups receiving cognitive training with and without tDCS. 
Hypothesis 1: A game-based cognitive training intervention combined with tDCS will be acceptable to 
older persons with HIV infection. 
AIM 2) Evaluate the effects of game-based cognitive training with and without tDCS on cognition in 
older persons with HIV. 
Hypothesis 2: Action game based cognitive training will be superior to attention control, while action game 
training with tDCS will be superior to cognitive training alone (control + sham < training + sham <  training + 
tDCS) on measures of reaction time, attention, and psychomotor speed. 
 
 

A. SIGNIFICANCE 
Cognitive deficits persist in HIV even with viral suppression.  Even though advances in treatment of 
HIV infection have made it a manageable disease, affected individuals continue to develop HIV-associated 
neurocognitive disorders (HAND).1;2 Cognitive deficits have been found across a range of domains, but 
commonly include executive functions, attention, memory, and psychomotor speed.4;35-38  
Cognitive deficits have significant impacts on patients’ self-care, medication adherence, driving, 
and quality of life. Studies have linked HAND to functional status in persons with HIV infection.9;39 Verbal 
memory, for example, has been linked to medication adherence.40 The ability to plan and execute complex 
sequences of actions is essential to complex adaptive behaviors, and has been linked to executive dysfunction 
and cognitive slowing in individuals with HAND.38 Similarly, the ability to multitask, required to complete many 
instrumental activities of daily living (IADLs), was linked to IADL performance.41  
HAND may be compounded by age-related cognitive changes. As persons with HIV infection become 
older, they can develop the same age-related cognitive changes as do uninfected older persons.11 Older 
persons with HIV infection are also susceptible to the same comorbidities that affect cognition in uninfected 
older persons as well, such as cardiovascular disease and diabetes.42-45 Although it is not clear whether the 
relation of HAND and cognitive aging is additive or synergistic,46;47 both are sources of cognitive problems for 
older persons with HIV. 
Effective treatments for HAND are needed. Researchers have studied various strategies to improve 
HAND. One study showed that methylphenidate could improve cognitive slowing.48 Other studies have 
evaluated a number of medications but have found little or no effect on cognition in HAND.49-51 Recently, 
though, Sacktor et al. reported an effect on cognition for the antidepressant paroxetine.52 
Computer-based cognitive training may be useful in treating cognitive deficits in older persons with 
HIV. Vance and colleagues have explored the usefulness of computer-based cognitive training to address 
HAND.53;54 Using commercially available software they showed improvements not only in the task trained 
(Useful Field of View) but also in IADLs (Timed Instrumental Activities of Daily Living). Others have evaluated 
the effects of cognitive training programs to improve cognition in healthy older adults. They found significant 
but modest effects on memory.12;13 One important study, the ACTIVE trial,55 showed positive effects of 
psychomotor speed training that were significant after 5 years.56 The expense and lack of inherent interest in 
training software,57 which may be out of reach of indigent patients, are drawbacks. Cost, availability, and lack 
of inherent interest thus may limit the use of cognitive training interventions. 
 Commercial computer games are effective in cognitive training and address these limitations. 
Gaming has positive effects on cognition.15 Action video games in particular may be effective in developing 
attention and psychomotor speed14 while being readily available and often free. Wu and Spence showed that 
game playing improved visual search via improved ability to inhibit distractors.58;59 First person shooters 
(games that involve targeting enemies with a simulated weapon) improve attention and visual processing.60 An 
extensive meta-analysis on cognitive training of spatial skills showed that the benefits of training persist and 
transfer to other non-game spatial tasks.61 As summarized by Merzenich in Nature Reviews Neuroscience: 
“Video games are controlled training regimens delivered in highly motivating behavioral contexts. 
The documented gains in processing speed, attentional control, memory, and cognitive and social 
control that result from playing specific games are expected. Because behavioral changes arise from 
brain changes, it is also no surprise that performance improvements are paralleled by enduring 
physical and functional neurological remodeling.”14 
What about older persons? Action video games also improve cognition in older (age 50+) persons.16 
Anguera et al., for example, in a paper in Nature, showed that a car racing game improved attention and 
working memory in older adults.62 Basak et al.63 (in Psychology and Aging) suggest that training across 
multiple contexts in games promotes transfer of training to other tasks, and report positive effects of game play 
on executive functions and working memory. The ability of computer game playing to improve psychomotor 
speed is particularly relevant to older adults, as training in this domain has a positive effect on IADLs,64;65 
driving,66 and even the risk for dementia.67 Data thus support the usefulness of computer gaming to 
improve cognitive function in older persons in ways that have meaningful effects beyond laboratory 
measures of cognition. 
Will older persons, and especially older women, play computer games? Data on this question show 
that older persons, including older women, are already playing computer games – in fact, according to Pew 
Research more women (38%) than men (29%) over age 50 play computer games.17 While there are 
differences among games played by men and women (e.g., shooters by men and puzzle solving by women), 
data show that older persons play computer games, and that older women play games with substantial 

frequency. Belchior et al.68 showed that a commercial game engaged older persons more than a cognitive 
training program, and qualitative studies of older gamers show that they enjoy gaming and believe that it helps 
them maintain cognitive function.69-71  
Sex as a biological variable. The importance of understanding the impact of cognitive training 
interventions in older women with HIV is highlighted by data suggesting that neurocognitive function in women 
may be affected more severely by HIV-1 infection than in men.72-75 
Transcranial direct current stimulation (tDCS) shows promise in enhancing the effects of cognitive 
training. Although gaming-based training is promising due to its ability to engage older persons, as with other 
cognitive training strategies its effect may be statistically significant but small. tDCS involves the application of 
a small current (1-2 mA) on the scalp, inducing a current in parts of the brain involved in cognition.76 Training 
studies show that tDCS is associated with significant enhancement of cognitive training,21;23;77 is safe,20 and 
has mild side effects such as redness and a burning or tingling sensation.78;79 An extensive review of safety 
data shows that older persons are not at increased risk for adverse effects,20 and it was acceptable to 
participants in an open-label trial of depression in older persons (mean age 53 years) with HIV.32 
Several authors argue that tDCS could be useful in maintaining and improving cognitive function in 
older adults.80;81 A study that combined functional magnetic resonance imaging (fMRI) and tDCS in older 
adults performing a semantic word generation task showed that a single session of tDCS temporarily improved 
their performance to the same level as younger controls.82 Another study showed that tDCS combined with 
working memory training increased the persistence of training effects.83 Yet another study showed that tDCS 
with working memory training also improved function on ecologically-relevant tasks.84 Two meta-analyses on 
the use of tDCS in older adults supported its effectiveness. The first included 25 studies with 448 participants,25 
while the other included 14 studies with 331 participants.26 A substantial body of research thus the supports the 
utility of tDCS combined with cognitive training in older adults. 
Does tDCS work, and if so, how? It may appear implausible that a small electrical current applied to the 
scalp, inducing an even tinier current in the brain, could have an impact on cognition and mood. An extensive 
body of research, though, shows that tDCS can have positive effects on cognition in healthy young 
persons,21;23;23;77 in older persons,25 and in persons with neuropsychiatric disorders.85 Behavioral observations 
are supported by neuroscience research showing that DC stimulation enhances long term potentiation (LTP, a 
central mechanism of learning and memory86) in rat hippocampus.87;88 tDCS has also been associated with 
increased release of brain-derived neurotrophic growth factor (BDNF) in rat hippocampus.88;89 As BDNF is 
critical in learning and memory90;91 and also is a potential mechanism of antidepressant medication action,92;93 
this finding supports not only the observed cognitive effects of tDCS but also its antidepressant effects.31  
The underlying neural mechanisms of tDCS action have also been explored with respect to its effects on 
neurotransmitter and neuromodulator pharmacology. Amphetamine, for example, enhances the effects of 
tDCS,94 while dopamine receptor blockade abolishes it.95 At a broader level, magnetic resonance spectroscopy 
(MRS) shows chemical changes in the brain during tDCS.96 Meinzer and colleagues showed that tDCS over 
the left inferior frontal gyrus enhanced performance on a semantic retrieval task while improving connectivity 
with other language areas on fMRI.97 Research on the mechanisms of tDCS thus has shown that it has effects 
at the cellular, cortical, and network levels.  
tDCS is safe and inexpensive. Safety data on tDCS were recently summarized.20 Over 33,200 sessions 
and 1,000 participants, no severe adverse events have been reported. Common side effects of tDCS include 
redness and mild irritation at the site of stimulation; these resolve after stimulation is discontinued. tDCS, if 
effective when combined with cognitive training, will be cost-effective. Many tDCS studies have used readily 
available iontophoresis (medication delivery) devices that cost $300 to $500. Powered by nine-volt batteries, 
these simple devices are rugged and can be used by multiple persons over many training sessions. Even a 
short series of treatments can have persistent effects,23;82 and the utility of booster sessions has yet to be 
systematically explored. It may also be possible to train patients to use tDCS at home.98  
B. INNOVATION 
The proposed study is innovative in its use of a computer-based game for cognitive training in HIV and its 
combination of cognitive training with tDCS. No readily identifiable study has examined gaming or tDCS to 
improve cognition in persons with HIV infection; this study will allow an evaluation of an action game requiring 
quick reactions, sustained attention and psychomotor speed, and the combination of an action game with tDCS 
as well as provide a contrast with computer-based learning (attention control). Other researchers have 
examined each of these strategies in healthy older adults and in some patient groups, but this study would be 
innovative in allowing an assessment of the effects of cognitive training with and without tDCS in HAND. 

C. APPROACH 
PRELIMINARY STUDIES  
Pilot study of game-based cognitive training with and without tDCS.34 Participants were 11 individuals 
treated for HIV infection who reported cognitive difficulties and evidenced objective cognitive impairment in two 
neuropsychological domains, meeting Frascati criteria for mild neurocognitive disorder (MND).99 They were 
randomly assigned to training with or without tDCS. We used an off-the-shelf 
computer game that is inexpensive (free to download on Windows™), was of 
an appropriate level of difficulty, and is widely popular thus likely to be 
acceptable to our users. GT Racing 2 (Gameloft SE: Paris, France) requires 
that individuals steer a simulated car over courses that include city streets and 
racetracks. Each course requires that the user achieve a basic level of 
proficiency before moving on to the next. The initial difficulty allows all players 
to be successful while the game becomes increasingly difficult. We chose a car 
racing game because of previous demonstrations of the effects of a similar 
game on cognition in older persons62 and our judgment that a car racing game 
would be more acceptable to women than a first person shooting game. 
Participants were trained to use an Xbox game controller (a popular console 
game device) connected via USB to a laptop computer, with the computer displaying the game on a 23-inch 
screen. Each race lasted from 1 ½ to 2 ½ minutes, with the investigator in control of the computer and starting 
the next trial immediately after completing the previous one. 
Before and after six 20-minute training sessions over two weeks with either active or sham tDCS, 
participants completed a battery of cognitive measures (attention and working memory; verbal learning and 
memory; psychomotor speed) as well as self-report measures of cognitive difficulties and mood. All 
assessments were completed by an evaluator blind to treatment assignment or 
via automated computer-assisted self-interview (ACASI) on a touch screen 
computer with the investigators out of the room.  
Individuals receiving active tDCS received 1.5 mA stimulation for 20 
minutes during training with the anode (positive electrode) located over the left 
dorsolateral prefrontal cortex (DLPFC) and the cathode (negative electrode) in 
the right supraorbital area. The left DLPFC was chosen as stimulation site 
because of its use in other studies that showed effects on attention,100 working 
memory,101-104 executive functions,24;85 and psychomotor speed,105 and the role 
of the DLPFC in motor learning.106  Sham participants experienced the same 
procedures but the tDCS device was only turned on for the first 30 seconds, 
allowing the current to ramp up, and then it was turned off. Six sessions on 
every other day were chosen to represent a plausible training protocol that 
would be acceptable while providing an estimate of training effects.26 
After each session, participants responded to three questions via ACASI that asked how they would rate 
their thinking, mood, and discomfort during training. After all training sessions and follow-up testing, the blinded 
evaluator completed a final interview during which participants were asked to which group they had been 
assigned, whether the intervention was helpful, and whether they would participate in a study of tDCS and 
cognitive training in the future. 
Results. The average age of participants was 51.2 years (SD = 4.71); 
they had completed 6 to 15 years of education (mean 11.18, SD = 2.27). Two 
women, and two whites were participants; the majority were thus African-
American men. As correlations of age, gender, education, race, and immune 
status (viral load and CD4 count) with cognitive variables were substantial and 
judged to be potentially meaningful, we included them in analysis of 
covariance (ANCOVA) models assessing differences in performance before 
and after training with or without tDCS. 
As we were primarily interested in exploration of preliminary results via 
graphing and effect sizes, analyses focused on the extent to which the 
interactions between time and treatment condition might represent an effect of 
tDCS on outcomes. Examples of covariate corrected baseline and follow-up 
changes for each group are presented in Figures 1 to 3. Figure 1 (higher scores reflect better performance) 
Fig. 2. Mood
Sham
tDCS
Happy . . . . Sad
Sessions
Fig 3. Cognitive Problems
PAOF Total
Before
After
Sham
tDCS
Sham
tDCS
Digit Span Back
Fig. 1. Working Memory
Before
After

Table 1. Effect sizes 
d 
Digit Span Forward 
0.73 
Digit Span Backward 
3.63 
Digit Span Sequencing 
2.22 
HVLT-R Total 
0.88 
HVLT-R Delayed 
2.58 
Trail Making Test, Part A 
2.66 
Trail Making Test, Part B 
0.84 
Grooved Pegboard 
0.75 
PAOF Total 
1.50 
CESD 
1.07 
Average 
1.58 
presents results for Digit Span Backward (working memory) performance, suggesting that persons in the tDCS 
group may have improved relatively more over the baseline assessment than did those in the sham group 
(effect size, or ES = 1.74). Figure 2 (lower scores reflect better mood) shows mood ratings completed 
immediately after six training sessions. Participants in the active group rated their mood as better over time 
(ES = 1.07). Figure 3 (lower scores indicate fewer problems) shows changes in the Patient Assessment of 
Own Function (PAOF) total107 over assessments. This rating reflects participants’ reports of a range of 
cognitive difficulties, with the active group reporting fewer problems with thinking and memory after training (ES 
= 1.50).  
Effect sizes for treatment by time for all outcome measures are presented in Table 1, for the Wechsler 
Adult Intelligence Scale—IV108 Digit Span subtest (attention and working memory), the Hopkins Verbal 
Learning Test—Revised109 (verbal learning and memory), the Trail Making Test Parts A and B,110 and the 
Grooved Pegboard111 (psychomotor speed). The effect size for Trail 
Making Test Part A was in the reverse direction in favor of the sham 
treatment group. When analyses included change in depressive 
symptoms on the Center for Epidemiological Studies—Depression112 
scale before and after training, the effect size for PAOF was smaller 
(0.83) while that for Digit Span Backward became much larger 
(greater than 10, p = 0.011). As suggested by Cohen,113 effect sizes in 
the range of 0.5 to 0.8 are “medium,” while 0.8 and greater are “large.” 
Results thus suggest that training + tDCS has positive effects 
both on objective measures of attention and psychomotor speed 
and self-report of cognitive problems and mood. 
Success of the blind and participant reactions. We asked 
participants to tell us which treatment group they had been assigned 
to; all stated that they had received active tDCS. Nine of the 11 
participants believed the intervention had been helpful to them 
(including several assigned to sham) while two participants stated they were not sure or believed it had not 
been helpful--they were assigned to sham. Several participants commented: “I got better every visit” (active 
tDCS), “I think it helped my memory” (sham tDCS), “I feel like it helped with concentration and focusing” 
(active), “Helped out a little – to put more thinking about things before I act” (active), and “Now I can think 
longer on more stuff and my memory is somewhat better” (active). All stated they would participate in a similar 
study in the future. Both men and women indicated that they enjoyed the car racing game. 
PLANNED STUDY 
Overview. This will be a randomized, single-blind trial with blinded outcome assessments evaluating the 
effects of computer game based cognitive training with or without tDCS compared to an attention control, 
watching educational videos on a computer (Figure 4). We will enroll 120 participants to obtain a final n of 90 
(allowing for attrition) who will be randomly assigned in 
equal numbers to (1) attention control (educational 
videos + sham tDCS), (2) cognitive training with an 
action (car racing) game + sham tDCS, or (3) cognitive 
training with an action game + active tDCS. The study 
will thus implement the training protocol from the pilot 
study (which participants found enjoyable and 
subjectively helpful) but will now include an attention 
control group to help evaluate nonspecific effects of 
computer use. This study will also expand the assessment battery to include measures of functional status, 
motor function, frailty, driving, and medication adherence. We will ask participants to return for a follow-up one 
month after the final visit to determine if training effects are maintained, laying the groundwork for a larger 
study that could explore strategies to maintain treatment effects if they are obtained. 
Inclusion. Participants will be treated for HIV infection, on a stable regimen of antiretroviral medications for 
at least one month, aged 50 years or older, and meet Frascati criteria99 for mild neurocognitive disorder based 
on report of cognitive difficulties and cognitive deficits in two domains as determined by neuropsychological 
testing. Exclusion. Participants will be excluded if they have conditions that might affect their safety when 
receiving tDCS (e.g., seizure disorder), or on medications that can affect tDCS (psychotropic medications can 
affect how tDCS works) or are severely cognitive impaired. 
 

Recruitment. We have been successful in recruiting for previous studies through contacts with Broward 
House, the largest HIV service provider in Broward County (Fort Lauderdale) Florida. We have also worked 
with Care Resource, a non-profit providing HIV medical care in both Broward and Miami-Dade counties, and 
the HIV clinic at Broward Health, the largest health care provider in Broward County. We will address the need 
to make a special outreach to women by using a female recruiter and specifically addressing potential 
concerns by emphasizing that training and support will be available throughout the study. We will also be able 
to recruit participants in a study completed by Dr. Acevedo (co-investigator) with Hispanics with HIV infection 
over 50 which included a number of women. In a previous study,114 we recruited 124 participants with HIV 
infection over 18 months and retained 120 over 8 weeks. 
Procedures 
Single blind treatment. The rationale for a single- rather double-blind design stems from the nature of 
currently-available tDCS devices. Those that are FDA approved for use with humans have been developed as 
iontophoresis drug delivery devices and do not have the capacity to mask active stimulation from the operator. 
Our design, as discussed above, will employ single-blind stimulation but all assessments will be completed by 
an evaluator who is blind to treatment assignment or via ACASI with the investigator not in the room. As 
reported above, this procedure was successful in our pilot study, and others have reported similar success.30 In 
fact, in one moderately large study Brunoni et al. found that blinding their patients to tDCS assignment was 
effective, while blinding them to active vs. placebo medication was not.30 
Eligibility determination. The same questionnaire and neuropsychological measures of attention, 
working memory, verbal learning and memory, and psychomotor speed used in the pilot study (described 
above) will be used to determine eligibility. As part of eligibility determination participants will provide copies of 
recent laboratory values including HIV-1 RNA (viral load) and CD4 count. 
Baseline assessments.  Eligible participants will then complete a more extensive assessment that 
includes measures of premorbid functioning, reaction time, verbal and visuospatial learning, attention and 
working memory, and executive functioning. A detailed assessment protocol is included as an appendix to this 
submission. Assessments will also measure elements of frailty,115 as it may occur even in middle-aged adults 
with HIV infection116 and is an independent predictor of multimorbidity in HIV.117 The acceptability of the 
intervention to participants will be evaluated with a questionnaire we used previous projects114;118 based on the 
Technology Acceptance Model.119 We will evaluate participants’ satisfaction with the intervention and 
perception of side effects with a questionnaire based on the Treatment Satisfaction Questionnaire for 
Medication (TSQM)120;121 but modified to make it relevant to cognitive training and tDCS. 
In light of the importance of evaluating the practical significance of training effects as well as their impact 
on laboratory cognitive measures, the battery includes a measure of health-related quality of life (SF-36) and a 
self-report measure of instrumental activities of daily living. We will ask participants about their adherence to 
medication and other treatments using a previously validated strategy.122 Given the potential relation of 
psychomotor speed to driving,66 we also include a self-report measure of driving habits123 sensitive to mild 
cognitive impairment.124 
Training. All participants will complete six 20-minute training sessions in our computer lab. Sponge 
electrodes (25cm2) will be placed over the left dorsolateral prefrontal cortex (anode) and the right supraorbital 
area (cathode). In the active tDCS condition, participants will receive 1.5 mA stimulation for 20 minutes while 
they will play the car racing game. In the two sham conditions, the tDCS will be turned on and current allowed 
to ramp up over 30 s to 1.5 mA after which the device will be switched off. The racing + sham tDCS will then 
play the car racing game for 20 minutes, and the attention control group will watch a 20-minute educational 
video with sham tDCS and respond briefly to questions about its content as used in other studies12;13 and our 
own unpublished study. Immediately after each session, participants will respond to rating questions about 
cognitive function, mood, and discomfort. 
Post-test and Follow-up. After completing six training sessions, participants will complete the same 
assessment battery as at baseline, and again one month later (see Appendix and Figure 4). 
POSSIBLE ISSUES 
Age.  While it is true that the age for our participants may be somewhat younger (50 or older) than most 
studies of the elderly, we believe that this range is common in individuals with HIV infection and will include 
persons with age-related cognitive changes. The mean age in a study showing that frailty was associated with 
multimorbidity for example, was 46 years.117 
Game-based cognitive training includes many elements – how to determine what is the active 
ingredient? It is true that action games require a wide range of cognitive skills across a variety of contexts with 

repetition in multiple situations. Bavelier et al.129 argue that it is precisely this aspect of game playing that 
promotes transfer of training from the game to other activities, unlike other cognitive training programs. 
Single blind. Especially given the importance of rigor and reproducibility in NIH-sponsored research, the 
use of a single blind design may raise concerns. This concern is balanced with the need to use devices FDA-
approved for use with humans and the previous success of the single blind strategy in other trials30 as well as 
the pilot study.  
Depression vs cognition. Results of the pilot study as well as other studies show that tDCS may improve 
both cognition and mood. Our pilot study reflects changes in both. Including change in depression in analyses 
reduced the effect size of treatment on self-report of cognitive difficulties, but increased the effect size for 
cognitive measures. We thus will explore the extent to which change in mood affects cognition by examining it 
as a covariate and, if warranted, in a mediation analysis. 
Multiple covariates with small sample. In analyses for the preliminary study, it was judged important to 
include multiple potential covariates (age, gender, race, immune status) to evaluate treatment effects, even 
with a small but heterogeneous sample. Given larger samples in most studies this may seem inappropriate, but 
we note that the in his first presentation of analysis of covariance (ANCOVA) in 1934, Fisher used four 
measurements on four entities (tea producing plots in Ceylon) to demonstrate the technique’s utility.130 
Future studies will examine the impact of ongoing training over a longer period and the usefulness of 
booster sessions. If this study suggests an impact on functional status, a future study might evaluate the 
impact of the intervention on biological markers of illness and actual performance of the activities of daily living. 

 
 
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