Augmenting Cognitive Training In Older Adults
Phase: NA
Conditions: Aging
Sponsor: University of Florida

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Augmenting Cognitive Training In Older Adults 
 
NCT02851511 
 
Document Date: 6/16/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol – IRB # 201600785 
1. Project Title 
Augmenting Cognitive Training In Older Adults: The ACT Study 
2. Investigator(s): 
University of Florida-  
Adam J. Woods, PhD – PI – (Contact PI) 
Ronald Cohen, Ph.D. – Co-PI  
Michael Marsiske, Ph.D. – Co- PI  
Mingzhou Ding, Ph.D., - Co-I 
Christiaan Leeuwenburgh, Ph.D. - Co-I 
Samuel Wu, Ph.D. – Co-I 
Eric Porges, PhD - Co-I 
 
Staff: 
Andrew O’Shea, M.S. 
Roxanne Razaei, B.A. 
Jessica Kraft, M.A.  
Steven DeKosky, M.D. 
Aprinda Indahlastari, Ph.D. 
Yunfeng Dai, Ph.D. 
Yuting Yang 
Kristin Calfee, B.A. 
Alexander Albizu, B.S. 
Daniela Carballo, B.S. 
Michael Gordon, B.S. 
Emanuel Boutzoukas, B.S. 
Nicole Evangelista, B.S. 
Hanna Hausman, B.A. 
Danielle Guess, B.S. 
Joshua Crow, Ph.D. 
Cheshire Hardcastle 
Ayden Dunn 
Claudia Corbo 
Kailey Langer 
Stacey Alvarez Alvarado 
Ruogu Fang 
Skylar Stolte 
Kyle See 
Guanhong Miao 
Crysten Repetti 
Christina Clarke 
Johnna Cesta 
Matthew Garrepy 
Samantha Pedersen 
Nathan Barkdull 
 
 

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3. Abstract: 
The current study will investigate methods for enhancing cognitive training effects in healthy 
older adults by employing a combination of interventions to potentially facilitate neural plasticity 
and optimize readiness for learning. Adults over the age of 65 represent the fastest growing 
group in the US population. As such, age-related cognitive decline represents a major concern 
for public health. Recent research suggests that cognitive training in older adults can improve 
cognitive performance, with effects lasting up to 10 years. However, these effects are typically 
limited to the tasks trained, with little transfer to other cognitive abilities or everyday skills. A two-
phase adaptive randomized clinical trial will examine the individual and combined impact of 
pairing cognitive training with transcranial direct current stimulation (tDCS). tDCS is a method of 
non-invasive brain stimulation that directly stimulates brain regions involved in active cognitive 
function and could enhance neural plasticity when paired with a training task. We will compare 
changes in cognitive and brain function resulting from CT and ET combined with tDCS using a 
comprehensive neurocognitive, clinical, and multimodal neuroimaging assessment of brain 
structure, function, and metabolic state. Functional magnetic resonance imaging (FMRI) will be 
used to assess brain response during working memory, attention, and memory encoding; the 
active cognitive abilities trained by CT. Proton magnetic resonance spectroscopy (MRS) will 
assess cerebral metabolites, including GABA concentrations sensitive to neural plasticity. We 
hypothesize that: 1) tDCS will enhance neurocognitive function, brain function, and functional 
outcomes from CT, with combined CT and tDCS providing the most benefit; 2) Effects of tDCS 
on CT will be maintained up to 12 months following training, and 3) Neuroimaging biomarkers of 
cerebral metabolism, neural plasticity (GABA concentrations) and functional brain response 
(FMRI) during resting vs. active cognitive tasks will predict individual response to tDCS. To date, 
no studies have examined combined intervention strategies using CT or optimization of learning 
and functional status through facilitation of active versus resting brain states in the elderly. The 
present study will provide a unique window into critical mechanisms for combating cognitive 
decline in a rapidly aging US population and possible novel methods for counteracting this 
looming public health crisis. 
4.  Background: 
 
4.1. Public Health / Clinical Significance: 1) Increased life expectancy has resulted in a 
marked increase of the older population. 2) Cognitive changes occur with advanced age that 
affect functional and health status. 3) While Alzheimer’s and related neurodegenerative 
diseases cause the most dramatic cognitive disturbances in the elderly, cognitive aging occurs 
even among people considered to be neurologically healthy. 4) Even mild neurocognitive 
disturbances affect people’s daily functioning, health status, and quality of life. 5) Alterations of 
brain structure and function occur as people reach advanced age, along with cerebral metabolic 
changes, that are associated with neurocognitive decline. 6) Our preliminary data suggests that 
baseline cerebral metabolite (MRS) and functional neuroimaging (FMRI) indices are associated 
with baseline neurocognitive functioning and predictive of subsequent age-related cognitive 
decline and brain disturbances. 7) There is a paucity of preventive and treatment interventions 
for averting cognitive aging and enhancing cognitive function. 8) Certain cognitive training (CT) 
approaches improve specific areas of cognitive performance, although their relative efficacy and 
mechanisms of action are not well understood. 9) Most CT approaches do not generalize well to 
cognitive abilities beyond those being trained or to everyday functional abilities. Efforts are 

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needed to improve the generalizability of CT. 10) Methods exist which could feasibly potentiate 
CT (e.g., tDCS), but they have not been rigorously tested in RCTs.  
 
4.2. Scientific significance. 1) While there is evidence that CT can improve cognitive 
functioning, the underlying mechanisms are not well understood. 2) The efficacy of CT likely is 
dependent on the plasticity of neural systems. 3) Evidence that certain types of neurochemical, 
electrical and behavioral stimulation potentiates synaptic plasticity and enhances learning has 
been demonstrated in laboratory animals. It is important to be able to measure these changes in 
humans during the course of learning such as that occurring with CT. Yet, in vivo human studies 
of these effects are difficult for obvious reasons. 4) Functional (FMRI) and cerebral metabolic 
(MRS) neuroimaging indirectly assess changes in neural plasticity during cognitive tasks. 5) 
Many open questions exist regarding the brain’s structural and functional connectivity in 
relationship to regional cerebral metabolites. Achieving better understanding of these 
relationships is important, since cerebral metabolic alterations may contribute neuropathology 
and perhaps even normal cognitive aging. 6) Extensive research exists for each of these 
neuroimaging modalities in isolation for various diseases, but multimodal studies employing 
these approaches simultaneously are less common, particularly in studies of normal aging or 
CT. 7) Various CT approaches exist, but only a few have been tested and shown to be effective 
in larger scale clinical trials (e.g., UFOV, dual N-back training). RCTs are needed to test the 
relative efficacy of these CT approaches, and whether there is value in using them in 
combination. 8) Brain stimulation may potentiate neural plasticity based on animal studies. Most 
of these approaches have yet to be tested in conjunction with CT in humans. 9) It is unclear 
whether optimal CT benefit is achieved by bolstering activation of brain regions necessary for 
the tasks to be performed. 10) Individual differences exist in the ability of people to benefit from 
CT. 11) State-of-the-art neuroimaging analysis methods may yield insights into interactions 
among brain networks/systems, and ways to optimally integrate structural and functional 
connectivity with cerebral MRS and cognitive outcomes. 12) We will employ state-of-the-art 
statistical methods, extending predictive modeling and causal inference approaches for 
neuroimaging.  
 
4.3. Clinical and scientific background.  
4.3.1. Cognitive aging and dysfunction affects health status, Quality of Life (QOL), and 
functional capacity. Brain dysfunction resulting from neurodegenerative disease or other 
medical condition adversely affects overall health status.7-11 Even mild cognitive deficits affect 
QOL, diet, physical activity and other health behaviors,10,12,13 and are often stronger predictors 
of health outcomes than other physical factors,7 but typically receive less clinical attention. 
Accordingly, cognitive aging has considerable functional relevance.  
4.3.2. Cognitive training. Various CT approaches enhance cognitive functioning in the elderly 
and remediate cognitive disorders. While improvements in cognitive performance are reported 
in many studies, this research suffers from a lack of well-conducted RCTs designed to 
determine the specific factors contributing to cognitive improvements. However, several 
approaches are effective in improving cognitive performance in the context of large RCTs. The 
ACTIVE study showed that CT improved cognitive performance and resulted in some 
generalization to other functional abilities.  
4.3.3. Benefits of cognitive training. Various CT approaches exist with differing degrees of 
demonstrated efficacy. While improved cognitive performance is often reported, this research 
has suffered from a lack of well-controlled RCTs, experimental designs that did not enable the 
basis for effects to be determined, and limited transfer of training.14-18 Yet, findings over the past 
decade (e.g., ACTIVE) suggest that certain CT approaches are effective for enhancing cognitive 
aging.17,19-36 Significant cognitive and functional improvements occur in laboratory and home-
based CT studies.19,23,31,37-41 Effect sizes generally exceed d=1.0 immediately after CT, and 

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even after 10 years (η2 >0.6). In ACTIVE,22,24,32,36,42 people receiving CT outperformed those 
who were untrained, with normal cognitive aging attenuated. We considered and selected CT 
approaches based on consensus of our study team (Woods, Marsiske, Edwards, Czaja, et al.), 
and evidence supporting their effectiveness. Three types of CT training have been particularly 
effective in studies by our group and others: 1) UFOV; 2) N-back Working Memory; 3) Attention-
arousal training, all available in the PositScience BrainHQ suite. Specifically, we will be using 
eight training programs from the PositScience BrainHQ suite described below. 
 
 
 
Attention/Speed of Processing 
1. Hawk Eye- works on visual precision, which helps the brain perceive what is 
seen quickly and accurately so that it can be recalled better. 
2. Divided Attention- requires the brain to focus in on and react to particular 
details—matching colors, shapes, and/or fill patterns—while at the same time 
dismissing competing information. 
3. Target Tracker- is designed to help build divided attention by requiring 
participants to track several items moving around their screen at the same time 
4. Double Decision - requires visual search and selective attention to peripheral 
objects among distractors.20 Difficulty gradually increases relative to object 
similarity, presentation rate, and distractor complexity and eccentricity. 
 
Working Memory 
1. To Do List Training- the brain hears a set of instructions, then uses its memory of 
those instructions to follow them in order. The instructions get longer and more 
complex over time at the task, making greater demands on the working memory 
systems. 
2. Memory Grid - Auditory processing is one of the most important building blocks 
of memory. Only when participants take in information with crystal clarity can the 
brain store it accurately and recall it clearly later. In Memory Grid, the task is to 
match cards representing syllables together. 
3. Auditory Aces- Participant will be presented with auditory information about 
playing cards. The information is presented one card at a time. The task is to 
decide if the current card information matches the card information presented a 
specific number of steps back in the sequence. 
4. Card Shark- N-back working memory task that varies on whether the current 
target matches stimuli presented 0-n steps before and presentation speed, 
leading to increased difficulty,44,45 and age-sensitivity46.  
  
4.3.4. Generalization and functional outcome. Many CT interventions fail to generate transfer 
to functional outcomes. Training transfer has been most studied and shown on UFOV. In 
ACTIVE, ten-year maintenance of UFOV training effects occurred with evidence of substantial 
transfer at 5 and 10 years. UFOV training resulted in fewer self-reported limitations of everyday 
activities,24 higher locus of control 30 and perceived health-related quality of life, 68 better 
subjective health,29 and less depression.27 68 At ten years, UFOV-trained people still reported 
less limitation in daily activities36. Self-reported driving cessation and archival accident records 
indicated lower odds of crashes and driving cessation for UFOV-trained elders at three,25 five,28 
and ten-years post training.35 In other RCTs involving greater sustained adaptive CT dosages 

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(similar to the currently proposed study) superior performance and reaction times were found on 
a driving-simulator and also for instrumental activities of daily living (look up phone numbers, 
read pill bottles, etc.).23 For the other two intervention components, near transfer to other 
cognitive tasks has been shown. N-back training transfers to matrix reasoning44 and to 
sustained attention and self-reported cognitive function in older adults for at least three months 
post training.48 Tonic/phasic attention training transfers to spatial selective attention and the 
temporal distribution of attention (attentional blink).66 
4.3.5. Brain stimulation to potentiate training. Since the pioneering work of Penfield, it has 
been recognized that sensory, motor and cognitive functions could be altered via electrical 
stimulation of specific brain regions. In laboratory animals, brain stimulation represented an 
alternative approach to experimental lesions, enabling both the potentiation and inhibition of 
neural activity depending on where in the brain stimulation was applied. Until recently, most 
human brain stimulation studies involved neurosurgically implanted electrodes, which has 
obvious limitations for general clinical use.  
Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation method that 
alters the sub threshold membrane potential of neurons, facilitates neural plasticity and learning, 
and increases regional blood flow while modulating local GABA concentrations during 
stimulation.69-89 During tDCS, a weak electrical current is applied to the scalp that penetrates 
skin, bone, CSF and the meninges to stimulate underlying cortical and subcortical tissue.90-95 
tDCS applied to dysfunctional cortical regions improves performance on a variety of cognitive 
tasks.96-99 Bilateral tDCS to the frontal cortices improves decision-making, attention and working 
memory performance in older adults.100-103 Improvements from a single session of tDCS have 
been shown to last for up to five years in healthy adults.104-108 Small pilot RCTs (n=20/group) 
pairing CT with bilateral frontal tDCS show significant and lasting improvement in older adults 
experiencing declining cognitive function.108-112 Maintenance of these tDCS and CT effects have 
been shown to last beyond one year. 104,105,107,108,110 These studies demonstrate that CT 
combined with tDCS leads to lasting improvement in CT effectiveness for older adults and 
patients. Research suggests that increased regional blood flow and decreased GABA 
concentrations during tDCS facilitate the brain’s neural plastic response to paired training 
tasks.75,80,83,84,89,113-117 Pairing CT with tDCS to combat age-related cognitive decline may 
potentially hold great promise for older adults.  
 
4.3.6. Age-associated brain changes. It is well known that with advanced age, humans are 
vulnerable to neurodegenerative diseases that cause brain pathology, usually evident on post-
mortem autopsy.118-127 Though less pervasive, neuropathology is also relatively common in 
elderly adults without documented brain disease.128  
4.3.6.1. Age-associated brain change on structural neuroimaging. Changes in structural 
brain volume and morphometry on MRI, along with specific abnormalities, occur with advanced 
age, particularly when there is vascular co-morbidity.129-160  Raz et al. showed cortical and 
subcortical volume loss of .5 -4% per year across different cortical and subcortical regions in 
older adults without overt brain disease.129,133,141,143,161 We have shown cortical and white matter 
volume loss across the lifespan in past large international studies.146,147,162-167 
4.3.6.3. Functional neuroimaging provides a potentially powerful method for assessing 
healthy and abnormal brain functioning (see Cohen and Sweet, for a review168). FMRI is 
noninvasive, can be used in conjunction with structural MRI and MRS, and is sensitive to 
functional brain abnormalities.153,157,169-179 It holds promise as a biomarker of cognitive aging, 
neural plasticity, and cognitive improvements following CT. Age-associated alterations in brain 
activation on FMRI during both rest state and active cognitive tasks have been demonstrated in 
many past studies. Unfortunately, the clinical potential of FMRI has yet to be fully realized, in 
part because many different paradigms have been employed across studies. Furthermore, 
longitudinal change in BOLD response as a function of aging has been examined in relatively 

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few studies, and almost no large RCTs. Reduced cognitive reserve with aging has been linked 
to a number of FMRI effects, including HAROLD and PASA.180-183 Chang et al. showed that 
cognitive reserve influences FMRI activation, with a reduced “dynamic range” of BOLD 
response during tasks relative to rest explaining this effect.184-190 The concept of dynamic range 
is both important and useful, and will be discussed in greater detail when reviewing preliminary 
data (C4).  
4.3.6.4. Cerebral metabolites (MRS): Proton MRS, which is sensitive to chemical compounds 
containing hydrogen, useful for measuring brain metabolites, including N-Acetyl Aspartate 
(NAA), choline (Cho), myo-inositol (MI), creatine (Cr), and glutamate-glutamine complex (Glx). 
Our group and others have shown that MRS abnormalities occur among people with a variety of 
age-related brain disorders, including neurodegenerative disease, cerebrovascular disease, and 
HIV191-206, with reduced NAA and elevated MI associated with cognitive dysfunction and 
conversion to dementia. Elevated Cho and MI reflect inflammatory processes and glial and cell 
membrane disturbances, and are differentially associated with cognitive performance, clinical 
status, and also cortical, subcortical, and white matter volumes on MRI204-211. Thus, MRS is 
predictive of clinically significant neurocognitive dysfunction.206,208-210 
GABA, the brain’s principle inhibitory neurotransmitter,212 is essential for synaptic 
communication and regulation of neuronal excitability,213 and neural plasticity.214-218 It plays a 
key role in learning and memory219-235 and modulates other behavioral and affective functions, 
including executive control and attention.236-238 Decreased cerebral GABA occurs with advanced 
age,219,223,227,230 and GABA dysregulation occurs in neurological and psychiatric conditions.49,239-
267 GABA delivered to the frontal cortex and hippocampus in animals facilitates cognitive and 
working memory performance. GABA can now be reliability measured using proton MRS,5,268-273 
based on seminal work by Edden (consultant).274-278 GABA provides an in vivo biomarker of 
neural plasticity in brain ROIs important for the cognitive functions to be trained in our study. 276 
84 
 
Summary and Conceptual Model. Age-associated 
functional, structural and metabolic brain changes 
occur, even in the absence of frank 
neurodegenerative disease. CT holds promise for 
reducing the adverse effects of cognitive aging, 
enhancing neural plasticity, cognitive efficiency, 
functional capacity, and quality of life. In theory, CT 
benefits could be augmented by coupling it with 
other interventions that either increase neural 
plasticity. Yet, relatively few of these approaches 
have been tested in RCTs, and the mechanisms underlying their effects are largely unknown. 
Even less is known about the combined effects of CT with tDCS. Our preliminary data provides 
strong support for CT to combat cognitive aging, and also for the effects of tDCS on cognition 
and brain function. We hypothesize that CT leads to improvements in neural plasticity (GABA 
MRS) and functional brain response (FMRI). In turn, this can lead to improved cerebral 
metabolic health and structural brain preservation. Coupling CT with tDCS will increase neural 
plasticity in brain areas important for working memory, focused attention, and executive control, 
improve effectiveness of CT, and ultimately cognitive health (see Figure 1 for conceptual 
model).  
5. Specific Aims: 
 
Figure 1 

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Aim 1. Determine whether neurocognitive improvement and longer-term functional outcome (as 
measured by “ecological assessment”) are better when CT is coupled with tDCS, an intervention that 
will increase neuroplasticity and augment training effects.  
H1.1. CT will produce significant improvements on a composite measure of cognitive training 
performance on the POSIT Science BrainHQ tasks (Posit Composite Score) compared to 
the treatment control condition. This aim will be assessed at the end of Phase 1. 
H1.2. tDCS combined with CT will produce significant improvements on a composite measure of 
attention, working memory, processing speed, and executive function (NIH Toolbox Fluid 
Cognition Composite Score, NIHTB FCCS) compared to the sham treatment control 
condition. FCCS will serve as the study primary outcome measure. 
H1.3. Near and far transfer of CT and tDCS will occur, as assessed by the UM Functional Battery 
Composite Index and comprehensive neurocognitive assessment. 
 
Aim 2. Determine whether CT combined with tDCS leads to greater functional and metabolic brain 
changes (FMRI, MRS). Effects will parallel Aim 1.  
H2.1. Compared to TC, CT will decrease activation in working memory and attentional brain 
systems (dorsolateral prefrontal cortex, medial frontal cortex, inferior parietal lobe, 
supplementary motor association cortex), reflecting increased neural efficiency.  
H2.2. Combined CT + tDCS will potentiate these effects.  
H2.3. Cerebral metabolite alterations will occur secondary to CT and tDCS, with long-term 
increases in GABA and N-acetyl aspartate (NAA) concentrations, and decreased choline 
(Cho) and myoinositol (MI) concentrations in the frontal cortex and posterior parietal cortex. 
CT and tDCS will modulate MRS GABA in frontal areas.  
 
Exploratory Aim. Examine which baseline factors (e.g., clinical, demographic, neuroimaging, 
cognitive) best predict individual differences in neurocognitive and functional outcome.  
HE.1.  White matter abnormalities on FLAIR MRI will predict poorer outcome.  
HE.2.  Metabolic-vascular risk factors/disorders (e.g., diabetes) will be predictive of reduced 
outcome.  
HE.3.  Alzheimer’s disease risk factors (APOE4 and familial history) will predict poorer outcome. 
6. Research Plan: 
6.1. Experimental design. This study employs a two-phase randomized clinical trial with 360 
participants total across two sites (University of Florida and University of Arizona; 240 at the University 
of Florida and120 at the University of Arizona). UF will be the parent site for the study. An initial cohort 
of 80 participants collected across the two sites will be assigned to one of four conditions as shown in 
Figure 2. Half of the recruited sample in Phase 1 will undergo CT; the other half will undergo training 
control (TC). The first interim analysis, to be performed when the first cohort of 80 completes 12-month 
follow-up (Phase 1), will investigate whether CT is significantly better than TC thereby enabling 
elimination of the TC condition. CT has previously been established with strong effects on cognitive 
and functional outcomes. If CT and TC are equally effective, groups will be collapsed at initiation of 
Phase 2 for planned assessment of adjunctive tDCS effects. If CT is more effective than TC, as 
previously shown, TC will be eliminated. Data from Phase 1 will also provide important mechanistic 
insight regarding neural mechanisms of CT vs. a well-matched education training control (TC). In 
Phase 2, the remaining 280 participants will be randomized to the two CT arms (i.e., eliminating the 
TC arms). After the remaining 280 participants have completed follow up in the CT arms (including 
those in Phase 1, total n=360) analyses will investigate the benefit of adjunctive 
administration of CT with tDCS. Participants will be assessed at three 
primary time points: 1) baseline pre-training; 2) post-12 weeks of CT/TC + 
stimulation/sham; and 3) one year follow-up after all training (see Figure 3 
for timeline). This design will enable longitudinal analyses of CT and tDCS 
effects individually and in combination. We will examine CT and tDCS effects 
on cognitive performance, functional and metabolic neuroimaging measures, 
and everyday functional abilities. At each assessment, we will obtain clinical and medical history, 
neurocognitive measures, and neuroimaging (structural MRI, FMRI, MRS). All participants will 
undergo neuroimaging at baseline, following CT, and at one-year follow-up.  
 

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6.2. Study participants and randomization procedure. We will recruit 240 older adults 
(women = 120; age: 65-89 years) at UF. Study participants will consist of healthy individuals 
who have expressed an interest in taking part in an intervention aimed at optimizing and 
possibly preserving cognitive functioning and brain health. Web-based permuted block 
randomization (with block size 8) will be used. In phase 1, each block will have two participants 
for each arm. In phase 2, each block will have four participants for each remaining arm. We will 
enroll people with evidence of age-related cognitive decline as defined by performance below 
the 80th percentile on the Cognitive Training assessment. People with pre-existing dementia, 
neurological brain disease, or who meet criteria for a diagnosis of mild cognitive impairment 
(MCI) will be excluded.  
 
6.2.1. Experimental Design Considerations and Limitations: CT Approach. The 
POSITScience BrainHQ treatment program was selected because it 1) provides specific training 
tasks directed at three essential cognitive domains tied to our aims and hypotheses (attention, 
working memory, executive control) that correspond with the neurocognitive and functional 
neuroimaging measures to be studied; 2) is shown to produce significant cognitive and 
functional improvements with good effect sizes in past RCTs (ACTIVE) with up to 10 year 
durability and transfer of training to measures of self-reported everyday functioning; 3) provides 
a “cognitive treatment engine282” which alone has a very highly likelihood of yielding significant 
cognitive and functional improvements, enabling us to test the augmenting effects of tDCS; and 
4) is computerized, well standardized, and efficiently implemented.  
Combined CT. We selected a combined CT approach rather than testing one specific training 
task: 1) This would optimize CT treatment effects for this primary intervention, providing a strong 
and reliable engine of change with which to examine effects of tDCS; 2) This approach enables 
us to affect several related cognitive functions that are strongly dependent on neural plasticity of 
the frontal cortex; and 3) This approach would maximize participants interest and motivation 
versus a single task that could become boring.  
tDCS. Brain stimulation provides a means of directly augmenting CT effects. tDCS was selected 
from possible alternatives (e.g., transcranial magnetic stimulation) based on research and data 
by Woods (PI), including its safety profile, ability to facilitate neural plasticity, and potential for 
application outside of research settings. Frontal stimulation was chosen based on prior and 
preliminary studies demonstrating significant impact on attention, working-memory, and other 
cognitive abilities to be trained during CT. 2mA tDCS was chosen based on prior research 
demonstrating that this parameter excites, rather than inhibits, activity 
in stimulated neurons. 283  
NIH Toolbox. A battery of neurocognitive tests was selected that could 
be completed in 1.5 hrs for all participants. A battery was selected that 
would enable optimal assessment of attention, executive functions, 
and working memory, but would also include some measures of 
learning and memory, and to a lesser extent other cognitive functions. 
We use the NIH Toolbox-Cognitive as a core element of this 
assessment, as it: 1) Can be completed in 30 minutes; 2) Is 
computerized and well standardized with norms from a large national 
cohort of older adults; 3) Provides both accuracy and response time 
measures; 4) Emphasizes the cognitive domains of relevance to the 
study; and 5) Has been the subject of considerable focus and 
investment by NIA. This study provides an ideal vehicle for 
implementing this battery. We supplement the Toolbox with measures 
to provide more coverage of working memory, attention, learning and 
memory.  
Functional outcome. Since important clinical questions remain with 

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respect to the extent to which CT generalizes to other cognitive abilities and everyday 
functioning, a set of functional and ecologically derived outcome measures will be used that 
were developed and used by Czaja (consultant) and her colleagues. Like the NIH Toolbox, this 
battery is computerized, well standardized with good norms on accuracy and response time 
from older adults. It taps into important everyday functions such as using an ATM machine and 
refilling a prescription. See Appendix 2 for detailed manual. 
Neuroimaging measures. We will focus on functional (FMRI) and cerebral metabolic (proton 
MRS) indices for two reasons: 1) These modalities are most linked to and likely sensitive to CT-
associated neural plasticity and brain changes; and 2) Changes in these domains are likely to 
occur over the course of training compared to structural neuroimaging measures. We include 
active FMRI tasks related to the cognitive functions to be trained, as well as a passive resting 
state condition to examine the DMN. With respect to MRS, we use a single voxel method to 
achieve optimal sensitivity and will measure from a single ROI (frontal) corresponding to task 
and resting state associated brain areas. Along with Creatine (Cr), we will examine cerebral 
metabolites sensitive neuronal loss and membrane disturbances (NAA, GLx), and pro-
inflammatory processes (Ch, MI). We will also measure cerebral GABA concentrations using a 
state of art MRS approach that will reflect neural plasticity in ROIs. The MRS indices will be 
examined for Aims 2.  
 
6.3. Procedural sequence. The sequence and flow of the assessments to be conducted at 
baseline and each subsequent assessment is shown in Subject Timeline. 
Screening Visit 
Task  
Estimated Time 
Informed Consent 
45 
Full medical History/rx drugs 
15 
MRI screening form 
5 
NACC UDS 
45 

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WTAR 
5 
BDI 
5 
Computer use questionnaire 
5 
Vision/color vision/hearing 
10 
AD-8 
3 
Cognitive Training assessment 
20 
 
Assessment Visits 
Task 
Estimated Time 
MRI scan 
60 
MRI scan practice 
20 
MRI safety questionnaire 
5 
NIH toolbox 
45 
Computerized functional task 
40 
HVLT 
20 
Stroop 
10 
PASAT 
10 
COWA & Animals 
5 
Digit Span 
10 
Symbol Digit Coding 
5 
Letter-Number Sequencing 
5 
Trails A&B 
5 
BVMT-R 
20 
BDI 
5 
STAI 
5 
PSQI (sleep) 
5 
SF-36 
5 
Apathy scale 
2 
PROMIS 
2 
AUDIT-10 
8 
DAST-10 
5 
UCLA loneliness 
3 
Social Network Scale 
5 
CALCAP 
8 
IADL Questionnaire 
5 
Expectancy Questionnaire 
5 
Driving Questionnaire 
10 
10 meter walk test 
5 
Abbreviated Medical History/rx drugs 
10 
Cognitive Training Assessment 
20 
 

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We will inform potential participants about the study, and facilitate the informed consent process 
using the IRB approved ICF. We will then screen for inclusion/exclusion criteria and schedule 
them for baseline evaluation. All assessments are identical otherwise. Assessment visits will be 
split over a two-day period, to reduce participant burden and ensure quality data collection.  
 
6.4 Cognitive Training. CT will involve sixty sessions over 12-weeks (40 hours total); this 
includes ten daily sessions combined with stimulation for two weeks, then one weekly session 
combined with stimulation for the remaining ten weeks. The remaining 40 sessions will be 
performed by participants at their home on days they do not receive stimulation.  Training 
platform. CT employs an eight component, PositScience BrainHQ suite via its researcher portal 
(described in section 4.3.3). These tasks are web-based and multi-platform (i.e., Windows, 
Mac). Participants will be required to have minimum screen sizes and specific viewing 
distances. The interface masks performance feedback to reduce frustration in the control 
condition. Study interventionists will provide weekly performance summaries. The rationale and 
task demands for each component were described earlier (A.3.3). These CT are commercially 
available (www.positscience.com), with well-documented protocols/manuals (See Appendix 1) 
and thus not described in detail here. Participants will have computers supplied, with training 
and orientation sessions and 24/7 support.  
Training control. The TC condition will serve as a control for the CT condition. TC will involve 
sixty sessions over 12-weeks (40 hours total); this includes ten daily sessions combined with 
stimulation for two weeks, then one weekly session combined with stimulation for the remaining 
ten weeks. The remaining 40 sessions will be performed by participants at their home on days 
they do not receive stimulation.  The duration and frequency of TC will match that of CT. TC 
involves watching educational videos produced by the National Geographic Channel, which 
cover a range of topics such as history, nature, and wildlife. Participants will be asked to 
complete questions on the content of the videos to ensure sustained attention.  
Cognitive Training assessment. An assessment of performance on the 8 cognitive training 
tasks will be given at the screening and assessment visits. The assessment consists of ten 
levels (comprised of the games described in section 4.3.3.) designed to challenge working 
memory, attention, executive function, and speed of processing. The assessment takes 
approximately twenty minutes to complete.   
 
6.5. Transcranial Direct Current Stimulation: Bilateral Frontal tDCS: A Soterix Clinical Trials 
Direct Current Stimulator will apply 20 minutes of 2.0mA direct current through two biocarbon 
rubber electrodes encased in saline soaked 5cm2 sponges (8cc of 0.9% saline solution) placed 
over the frontal cortices at F3 and F4 (10-20 system). Based on our well-established 
computational modeling workflow (C.4.1), F3/F4 stimulation delivers a broad pattern of frontal 
stimulation (see C.4.1d). Current inflow will occur on the right (F4), and outflow on the left (F3). 
Impedance quality will be ≤10kΩ to insure proper stimulation of brain tissue. Sham tDCS: Sham 
stimulation is performed with the same device and all procedures will be identical except for the 
duration of stimulation. Participants will receive 30 seconds of 2 mA of direct current stimulation 
at the beginning of the session. Participants habituate to the sensation of tDCS within 30-60 
seconds of stimulation. This procedure provides the same sensation of tDCS without the full 
duration of stimulation, making it a highly effective sham procedure. Blinding: The device has 
built in RCT double blinding protocols. Soterix will communicate only with Dr. Wu (Co-
I/statistician) to de-identify data for analyses. Physiological Recording: During stimulation 
sessions participants will be asked to wear a special wristband that will be used to record 
physiological information such as pulse. Quality Control: We will take a brief set of pictures of 
the participant’s head after the electrodes are placed to make sure that the electrodes are in the 
correct location.  These photos will be used to create a 3D model of the participant’s head that 
will give us accurate information about where the electrodes were placed.  

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6.6. Neuroimaging Methods. We will conduct neuroimaging on a Siemens 3.0 Tesla research 
dedicated scanner with an existing research agreement. Scanning will take 1 hour to acquire: 1) 
Structural MRI (T1, FLAIR), 2) FMRI (EPI-BOLD), 3) Proton MR Spectroscopy (MRS).  
6.6.1. FMRI paradigms. We will present the two FMRI tasks (2-Back, UFOV) using E-Prime 2 
software (Psychology Software Tools, Inc., Pittsburgh, PA), with the video signal on a screen 
behind the participant’s head. The screen is viewed through a double-mirror attached to the 
head coil. An MR-compatible piano-key response box attached to the stimulus presentation 
computer will collect performance data. We will apply a cushioned-pillow head stabilizer to 
minimize head movement during scanning. 
2-Back. This task will measure brain changes due to our N-back training. We will assess verbal 
working memory on a 2-Back task, as in past studies153,157. 
Consonants are visually presented briefly with a small rest 
period between each. Participants determine if each stimulus is 
the same or different from previously stimuli, responding by 
binary button press (yes vs. no). Executive control, phonemic 
buffering, and sub-vocal phonemic rehearsal are required. 0-back and 2-Back conditions are 
alternated in a block design with two 5-minute runs of eight blocks (consonant lists), with four 
blocks of the 0-Back and four blocks of the 2-Back. 0-Back: Four blocks of nine consonants of 
random case and order (33% targets). Yes-no responses are made if targets that match stimuli 
occurring two earlier. 2-Back: Four blocks of 15 consonants (33% targets) will be 
pseudorandomly presented across the visual field. Accuracy and RT are recorded. 
 
Useful Field of View. This task will measure brain changes due to alterations in attention and 
decision-making processes due to BrainHQ Double Decision and Freeze Frame training. We will 
assess attentional and decision-making processes on a scanner adapted event related UFOV task 
that requires participants to simultaneously apprehend the identification of a centrally located target 
(car or truck) and the location of a target (car) among a parametrically manipulated array of distractors 
(0-47 distractors). Following a visual mask, participants then make a two-alternative forced choice 
(correct or incorrect) decision based on whether both the central target and distal target (without 
distractors) are identical to what was seen in the prior display (Figure 17).Two five-minute blocks of 56 
trials are presented. Accuracy and reaction times are recorded. Jitter prior to stimulus presentation 
and response probe allows contrasts assessing unique activation associated with attentional and 
decision-making brain regions, providing mechanistic insight into cognitive training effects. 
 
 
 
 
 
 
 
 
 
 
Resting State. Participants will also be asked to rest for 6 minutes while functional data is being 
collected to assess resting state activation. 
 
6.6.2. Proton Magnetic Resonance Spectroscopy (MRS): GABA-edited spectra will be 
acquired using the MEGA-PRESS experiment, from a 3x3x3 cm3 voxels (medial frontal). 
Spectra will be analyzed using Gannet and LCModel to assess cerebral metabolites and 
neurotransmitter concentrations.295. 412,413 
 

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6.6.3. Structural MRI. High-resolution whole brain axial gradient-echo MPRAGE 3-D T1-
weighted images will be acquired for volumetric and cortical thickness analyses and FMRI 
localization.  Analyses: Volumetric indices will be obtained for total gray and white matter, 
FreeSurfer ROIs296-298, and a priori ROIs (MRS, FMRI).  
 
 
6.7. Neurocognitive Assessment: Assessments will include a neurocognitive battery (see 
Table 7). The battery consists of standardized, well-established neurocognitive measures with 
strong reliability and validity 304. For cognitive measures with functions assessed see Table 7 
below. Our goal is to assess global cognitive ability (NIH-Toolbox: cognitive module), and 
specifically attention-executive functions, working memory, processing speed, and memory. 
These are domains affected by aging24,31,146,305-314 and will also tap the domains assessed by 
FMRI (Aim 2).  
 
Table 7. Neurocognitive Assessment 
  
HVLT 
Verbal Learning/Memory 
Stroop 
Attention/Executive 
Trail Making A & B 
Executive 
COWA & Animals 
Verbal Fluency 
BVMT 
Visual Memory 
Symbol Digit Coding 
Processing Speed 
Letter Number Sequencing  
Working Memory 
PASAT 
Working Memory 
Digit Span 
Working Memory 
NIH Toolbox Subtests: 
  
*  Dimensional Card Sort 
Executive 
* Flanker 
Attention/Executive 
* Picture Sequence 
Episodic Memory 
* Picture Vocabulary 
Language 
* Oral Reading 
Language 
* Pattern Comparison 
Processing Speed 
* List Sorting 
Working Memory 
 
6.7.1. Functional Outcomes. A touchscreen computer-based functional assessment tool will 
be used to measure tasks like medication management, ATM banking, prescription refill via 
voice menu. Task difficulty can be varied and real-time efficiency and accuracy data are 
collected; the measure is highly correlated with component cognitive abilities targeted in this 
study315,316. See Appendix 2 for a detailed manual. 
 
6.7.2. QOL and PROMIS self-reported health assessment. We will administer the Medical 
Outcomes Study Short Form-36 (SF-36: v. 2.0, a widely used QOL measure), and the PROMIS 
self report measures at each assessment. The PROMIS measures assess change in self-
reported cognitive and physical function. 321 321. Change in self reported physical and mental 
health status correlate with QOL and mental and physical health status. 322,323 324 These two 
measures will serve as important assessments of interventions influence on everyday life. 
 
6.8. Alcohol and Drug Use Questionnaires. We will administer the Alcohol Use Disorders 
Test (AUDIT-10) and Drug Abuse Screening Test (DAST-10). These measures will provide 

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valuable information about how drug and alcohol use may alter the overall efficacy to tDCS, 
cognitive training and education training.  
 
6.9. Driving Record Assessment. Driving records will be requested following the completion of 
the intervention; records will be requested at 5 years post intervention and at 10 years post 
intervention. These records will allow us to examine real world driving outcomes. The driving 
record assessment is optional (the participant choses to consent to this portion or not at 
screening). Participants who do not consent to the driving record assessment can still 
participate in the study.  
 
6.10. Walking assessment. We will administer a 10-meter walk test. This test measures the 
time it takes participants to walk ten meters in a line. Participants are instructed to walk at their 
normal pace, as if they were walking down the street. Participants are instructed to use any 
walking aids they normally use (e.g. cane).  
 
6.11. Quality Control. We will record (with audio and/or video) study procedures for the 
purpose of ensuring quality data collection. Participants will consent (via a checkbox on the 
informed consent form) to this recording. Recording will only be done on participants who 
provide written consent.  
 
6.12. Theft Prevention. This study will be loaning out university computers and other supplies. 
All university equipment must be returned when the participant completes or withdraws from the 
study. In the event university equipment is stolen we will be required to file a police report with 
local authorities. We will make copies of the participant’s driver’s license when they are provided 
university equipment. Having a copy of the driver’s license provides us with needed information 
in the event of lost or stolen university property. This procedure is described in the informed 
consent form. As a driver’s license is protected health information it will be kept separate from 
any de-identified data.  
 
6.13. Transportation. Certain potential participants may lack reliable transportation to the study 
sites. When possible study staff may transport willing participants to the study sites using a 
vehicle owned by the Department of Clinical and Health Psychology. All study staff will follow 
the procedures and regulations for operating University owned vehicles as described by UF 
Environmental Health and Safety at: http://www.ehs.ufl.edu/programs/insurance/automobile/ 
 
To facilitate transportation to and from the study site Uber Health may be used if the participants 
desire to have transportation provided. All costs associated with Uber Health will be covered by 
the study; the participant will not have any cost associated with the Uber Health travel. The 
option to have travel provided will be offered to all potential study participants within a 40 mile 
radius of the study site as costs outside of a 40 mile radius will not be feasible with the current 
travel budget.  
 
Uber Health offers a HIPAA compliant service designed specifically with enhanced ease and 
privacy in mind for those using the service. Participants will not need to have any account 
associated with Uber and study staff will coordinate the whole process. The Uber driver will 
send the participant a text when they are about to arrive at their location, however, the 
participants personal phone number will not be revealed and instead a covert masking of 
numbers is provided by Uber to allow the driver and passenger to communicate without 
revealing their personal phone numbers. If participants do not have or use mobile phones the 
study coordinator can help coordinate the pickup.   

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6.14. Payment. Participants will receive $75 in gift cards at the end of each of the three MRI 
sessions to compensate them for their time and effort.  
If participants are traveling from more than 20 miles away (one-way) to the study location they will 
receive an additional $10 compensation per study visit. If they attend all study visits they will 
receive an additional $270 in compensation for travel. If participants live less than 20 miles away 
they will receive no additional compensation for travel. If participants are utilizing Uber Health for 
transportation they will not receive the additional $10 per visit compensation.  
6.15. Notification of Participants for Cognitive Findings Leading to Study Exclusion. The 
Montreal Cognitive Assessment (MoCA) serves as a brief global dementia screening tool 
commonly implemented in clinical practice. Any participant falling below the 1.5 SD norms 
(adjusted for age and education) would screen fail in the ACT study, as per current 
criteria. If this occurs, the participant will first be contacted via phone call by the study 
physician (Dr. DeKosky) and then provided with a letter from the study team describing 
their reason for screen fail and encouraging them to follow up with their primary care 
physician (the letter and phone call template are submitted in miscellaneous attachments 
in the myIRB system). The procedure for implementation will be built into our RedCap 
data system such that any person meeting this criterion will trigger an email to the site PI 
and site physician alerting the team to follow up with the participant and to provide the 
phone call by the study physician and a letter notifying the participant.  
6.16. COVID-19 Adjunctive Study 
 
6.16.1 Background 
In early 2020 the COVID-19 pandemic reached the United States, and has been 
subsequently spreading rapidly throughout the state of Florida. The pandemic has 
brought about an exceptional number of public health ramifications. The most striking 
public response has been to push for a quarantining of exposed, or likely exposed, 
citizens and a general practice of ‘social distancing’ for the masses. Additionally, public 
places frequented by older adults, such as churches and community centers, have been 
closed leaving an unprecedented number of older adults shuttered in. It has been 
almost unanimously found that social isolation is a major health problem for older adult 
populations living in the general community (Nicholson 2012). There currently is a 
unique opportunity to investigate an enforced social isolation that affects older adults of 
all demographics. In this study we will record and investigate the outcomes of social 
isolation for older adults as well as analyze the individual factors that contribute to 
certain outcomes. 
 
We have a unique set of circumstances where older adults are being forced to remain in 
their home and away from people indiscriminately. This relative uniformity in social 
isolation in response to a significant, state-wide crisis allows us to observe the effects of 
the pandemic on the wellbeing and daily life of older adults, even in adults who might 
otherwise not experience social isolation in their lifetimes. With such a wide array of 
people affected we can investigate individual responses to the crisis by looking at a 
variety of factors as well as track the responses over time. 
 
6.16.2 Specific Aims 

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The following aims will be accomplished using cognitive tests and psychosocial 
questionnaires in an older population during the immediate COVID-19 pandemic and 
aftermath: 
Aim 1—Assess the current consequences of the COVID-19 social isolation in 
comparison to pre- COVID 19.  
H.1.1 Social isolation resulting from the COVID-19 pandemic will result in an 
alteration in cognition, daily living, mental health, and wellbeing in an older 
adult population.  
 
Aim 2—Monitor and record changes in the older adult population throughout and 
following the COVID-19 pandemic and social isolation.  
H.2.1. There will be distinct variations in individual responses to social isolation 
resulting from the COVID-19 pandemic and there will be observable 
characteristics that contribute to the differences in response. 
 
16.6.2 Research Plan 
Study timetable and logistics. Due to the rapidly evolving situation our aim is to 
administer the study measures as soon as possible pending IRB approval. All 
adjunctive administrations will be completed with no in person contact via online 
surveys and telephone calls. At the final COVID-19 assessment time point 
participants will be asked to complete an in person visit where MRI and blood draw 
will be done.  
 
Experimental design. Participants will complete the same set of tasks several times 
starting with acute administration 1, followed by monthly repeats for 6 months, with a 
final assessment at 9 months following the first. A total of 8 assessments will be 
completed. Participants will be asked to complete one in person visit at the final 
COVID-19 time point. At this visit MRI will be conducted to examine possible 
neurological consequences of social isolation from the ongoing pandemic. Only 
resting state functional and structural scans will be done as to not impact functional 
measures of the main study. The MRI will last around 1 hour (see measures section 
below for additional details regarding the MRI). At this final time point we will also 
draw a small amount of blood with the aim of conducting COVID-19 antibody testing. 
COVID-19 antibody testing will allow better classification of previous COVID-19 
positive participants. Blood will be collected by a trained phlebotomist in a biosafety 
level 2 lab at the McKnight Brain Institute and processed in a biosafety level 3 lab. 
Upon request participants will be provided with their COVID-19 antibody results.  
 
Participants. A strength of this proposed adjunctive study is that baseline (pre- 
COVID-19) data has already been collected on the ACT study sample. This adjunct 
will allow us to collect additional information in willing participants without interfering 
with the main study aims. Participation is completely voluntary and in no way affects 
participation in the main ACT study.   
 
Recruitment. Participants who have enrolled in the ACT study will be contacted by 
phone to assess interest in this adjunctive study. Due to the timing of current events, 

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we aim to contact all current participants within 30 days of revision approval. 
However, we will continue to recruit those who we have been unable to make 
contact with until the PI deems that it is no longer fruitful. Only participants who have 
been enrolled in the main study prior to March 16, 2020 will be asked to participate 
in the COVID 19 adjunct. To supplement phone recruitment we will mail letters to 
eligible participants. 
 
Inclusion/Exclusion Criteria. Only participants who have previously provided 
written informed consent to participate in the ACT study will be contacted. The only 
additional inclusion criteria is a willingness to participate in the adjunctive measures. 
Measures.  Adjunctive measures will be conducted via a combination of telephone 
and REDCap online survey responses. Self-Report questionnaire measures will be 
completed by the participants using REDCap. An email will be sent to participants 
with the link to the REDCap survey for them to complete. Cognitive assessments will 
be completed via telephone and entered by research staff into REDCap. For 
participants without internet or computer access an option will be provided to 
complete all measures via telephone.  In total each assessment will last around 1 
hour. See the table below for an estimate of the time each measure will take. All 
measures have been previously approved to be completed in the main ACT study 
with the exception of newly created COVID-19 specific questionnaires. We will be 
conducting an additional MRI at the 9-month COVID-19 time point.  
 
MoCA: A version of the MoCA without visual elements will be completed over the 
phone.  The MoCA is a cognitive screening measure. We will use all three 
versions of the MoCA in a counterbalanced order over the 8 assessments to limit 
test-retest effects.  
 
UDS Number Span: This measure assesses working memory by asking 
participants to remember a series of digits and to repeat them in forward and 
backward order.  
 
Alcohol Use Disorder Identification Test (AUDIT): This measure is a widely 
used self-report questionnaire designed to assess alcohol use. Alcohol use is 
common in adult populations and this measure will allow us to quantify use, 
potential impacts of use, and relate it to stress, individual differences in stress 
and response to the COVID-19 pandemic. 
 
Beck Depression Inventory (BDI):  Symptoms of depression may be a relevant 
factor in response to uncertainty and social unrest.  
 
Pittsburgh Sleep Quality Index (PSQI): Sleep problems are common. This can 
impact emotional status and cognition, including sustained attention. Thus, we 
have selected a measure that assesses sleep quality. 
 

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State-Trait Anxiety inventory (STAI): Subjects may experience increased 
anxiety as a result of the turbulent circumstances surrounding the pandemic.  
 
UCLA Loneliness Scale: Designed to measure one’s subjective feelings of 
loneliness as well as feelings of social isolation.  
 
PROMIS Cognitive Scale: Assesses a person’s perception of cognitive function 
in areas such as concentration, memory, and mental acuity. Cognitive functions 
have been known to diminish in periods of extreme stress, which could be 
aroused as a response to the COVID-19 pandemic. 
 
PROMIS Physical Function Scale: Assesses a person’s perception of their 
ability to perform daily activities of living such as chores around the house or 
carrying groceries.  
 
Social Network Scale: Assesses participants’ social networks, such as the 
frequency, time, and number of people they communicate with on a regular 
basis.  
 
Medical Outcomes Study Short Form-36: Self report questionnaire that 
assesses a variety of functional health outcomes.  
 
Apathy Scale: Measures self-reported feelings of apathy.  
 
COVID-19 Questionnaire: Self report questionnaire that assesses the impact of 
COVID -19 in areas such as a participant’s health behaviors, psychological 
wellbeing, and employment. 
 
Pet Questionnaire: Assesses the influence of animal companions during self-
isolation.  
 
Medical Changes Questionnaire: Assesses any change in medical conditions, 
such as the worsening or appearance of new health problems.  
 
MRI: We will collect structural T1 images, FLAIR (white matter hyper-intensities), 
resting state fMRI, diffusion-weighted imaging (white matter integrity) and 
magnetic resonance spectroscopy (cerebral metabolism). With emerging 
concerns that COVID attacks the central nervous system, these data will be 
important for understanding the impact of COVID on brain health in older adults. 
When compared to each participants most recent ACT MRI, these data will be 
invaluable for quantifying the impact of COVID-19 on brain health. 
 
Estimated time of Online/Phone assessments 
Task 
Estimated Time (Minutes) 
MoCA 
10 
UDS Number Span 
10 

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AUDIT 
8 
BDI 
5 
PSQI 
5 
STAI 
5 
UCLA Loneliness Scale 
3 
PROMIS Cognitive Scale 
2 
PROMIS Physical Function Scale 
2 
Social Network Scale 
5 
SF-36 
5 
Apathy Scale 
2 
COVID-19 Questionnaire 
10 
Pet Questionnaire 
5 
Medical Changes Questionnaire 
5 
Total 
82 
 
 
 
6.16.3 Safety Monitoring. The current pandemic is likely to result in increased mental 
health problems among the general population. If participants indicate suicidality 
on the BDI the study psychologist (Dr. Ron Cohen) will immediately contact them 
for evaluation and referral for treatment.  
 
6.16.5 Adjunctive Study Payment. Participants willing to complete the adjunctive study 
will receive a $20 payment for their time for each assessment timepoint. This payment is 
in addition to any other payment they may receive for the main study. An additional $30 
will be paid for the final visit MRI and blood draw.  
6.17 
Safety procedures for resumption of in person research (June 2020) 
 
Additional COVID precautions for assessment/study visits at the MBI. All surfaces in 
the lab space will be disinfected before and after each participant. Keyboards, mice, ipad 
screens, etc. will be disinfected before and after each session. 6 foot distancing will be 
observed in all sessions. PPE will be worn by the participant and the study staff at all times. 
AMRIS COVID guidelines will be followed for all MRI procedures (MRI compatible PPE, no 
additional visitors or personnel in the MRI suite, etc.). All study activities occur within the 
MBI. The MBI has positioned PPE and sanitization stations throughout the ground floor. 
Participants will be met outside the building by study staff, provided with PPE, if they do not 
arrive with PPE, and escorted directly to the study location on the ground floor.  
 
Additional COVID precautions for tDCS. For the tDCS intervention, we are required to 
apply electrodes on the scalp of the participant. As is already our standard, only disposable 
electrodes are used for each visit to prevent any potential cross participant contact and 
electrodes are disposed of in biowaste containers after each session. All study staff wear 
non-latex exam gloves for all study procedures and gloves are disposed of in bio-waste 
containers after each session. Headstraps to affix electrodes to the scalp will be disinfected 

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with Clorox after each use. Measurement of electrode locations requires placement of small 
marks using either a sharpie or wax pencil to determine the precise location for the 
electrode on the scalp. Thus, the tip of the pen/pencil makes contact with the scalp. Each 
participant will be assigned a single sharpie/pencil and it will only be used on that participant 
(labeled with participant ID). Once the participant has completed all intervention sessions, 
the pen will be disposed of in biowaste. After each session, the pen tip will be wiped with 
Clorox for disinfection.  
 
Additional COVID precautions for Cognitive Training. Participants are provided a laptop 
for completion of cognitive training. The laptop surfaces will be disinfected before being 
provided to the participant. For in lab training sessions, the laptop surfaces will be 
disinfected before and after each session 
6.18 Mechanisms, response heterogeneity and dosing from MRI-derived electric field models in 
tDCS augmented cognitive training 
 
We will leverage existing multimodal neuroimaging and behavioral outcomes data from the ACT 
trial to 1) elucidate mechanism of action underlying response to tDCS treatment with CT, 2) 
address heterogeneity of response in tDCS augmented CT by determining how individual 
variation in the dose of electrical current delivered to the brain interacts with individual brain 
anatomical and lesion characteristics; and 3) refine the intervention strategy of tDCS paired 
with CT by evaluating computational methods for estimating precision delivery of targeted dosing 
characteristics to facilitate tDCS augmented outcomes. We will employ state of the art MRI-
derived computational modeling and machine learning (ML) applied to existing data to 1) create 
precision individualized computational models of electrical current in the brain from tDCS for all 
360 participants in ACT (based in T1 weighted images), 2) determine the characteristics of 
electrical current calculated from electric current models associated with trial outcomes, and 3) 
evaluate a computational method for calculating possible precision dosing of tDCS parameters for 
optimizing trial outcomes in older adults. 
To date, all prior trials of tDCS have applied a fixed dosing strategy (e.g., 2mA for 20 min with 
electrodes at F3/F4 [10-20 measurement system]) in attempts to enhance CT – including ACT. 
However, prior research demonstrates that individual variability in head and brain anatomy (e.g., 
degree of atrophy, skull thickness, etc.) significantly alters the spread and intensity of direct 
electrical current delivered to the brain person to person. The impact of individual variation in 
electrical current delivered to the brain for clinical outcomes has rarely been examined, and 
methods aimed at increasing stimulation effectiveness and optimizing readiness to learn are only 
now beginning to be explored. We will use advanced MRI-derived computational modeling of 
electrical current from existing MRIs to provide a means for accurately estimating individual 
differences in tDCS current delivery to the brain in the largest existing sample of participants 
undergoing tDCS (i.e., ACT) with multimodal neuroimaging data. When combined with state-of-
the-art machine learning approaches and behavioral outcome data (only unblinded once ACT has 
completed all follow-up visits), precision models of tDCS current will be derived to identify critical 
stimulation dosing characteristics (e.g., current intensity, direction/path of current) in specific brain 
regions associated with response vs. non-response to tDCS and CT intervention. These data will 
not only provide much needed information for determining how individual participant 
characteristics impact tDCS efficacy, but will also serve as a foundation for future  precision 
medicine applications of tDCS and CT to remediate cognitive decline in older adults and 
potentially prevent or alter the trajectory towards Alzheimer’s disease.  
 

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Aim 1. Determine inter-individual variability in tDCS current distribution using MRI-derived finite 
element modeling.  
H1.1. Variability in neuroanatomy (e.g. increased atrophy, sulcus depth, skull thickness, etc.) will 
significantly decrease current intensity and alter the pathway/direction of electrical current flow 
induced by tDCS in the brain.  
H1.2. White matter lesions, as measured by white matter hyper-intensities on FLAIR imaging, 
will significantly decrease current intensity and significantly alter the direction of electrical current 
flow induced by tDCS. 
 
Aim 2. Determine critical tDCS current properties and specific brain regions associated with 
responder vs. non-responder to tDCS and CT intervention using machine learning. 
H2.1. Current intensity and direction will significantly predict response vs. non-response to tDCS 
and CT intervention on the NIH Toolbox Fluid Cognition Composite Score (ACT primary 
outcome). 
H2.2. Current intensity and direction within bilateral rostral middle frontal, right superior frontal 
and frontal pole, and left pars orbitalis regions will most strongly predict response vs. non-
response to tDCS and CT intervention.  
H2.3. Current intensity and direction will outperform clinical/demographic characteristics alone 
(e.g., age, sex, comorbidities, mental health, Alzheimer’s disease risk, cognition, etc.) in 
predicting tDCS response. 
 
Exploratory Aim. Evaluate computational methods for achieving precision delivery of dosing 
characteristics in tDCS.  
HE.1. Adjusting tDCS current intensity input into computational models will achieve precision 
delivery of targeted dosing characteristics.  
HE.2. Adjusting electrode locations input into computational models will achieve precision 
delivery of targeted dosing characteristics.  
No new data will be collected from participants to achieve these aims. Only existing data 
collected with consent from participants in the course of the primary ACT study will be used. 
These data will be analyzed using advanced analytic methods (computational modeling and 
machine learning) to achieve all three aims specified in section 6.18.  
 
Aim 1. Dependent measures. The primary dependent measure in Aim 1 is current density 
computed in individual head models from existing MRIs. Current components will be further 
quantified as current intensity and direction. Rationale. Computed current density will provide an 
estimate of tDCS current dose within brain regions unique to each person’s neuroanatomy. 
Outcome analyses. H1.1. The regression analysis between current density (dependent variable) 
and anatomical measures (independent variable) e.g., brain volume ratio, sulcus depth, bone 
thickness will test the hypothesis that unique current density distribution in each person is 
significantly affected by individual characteristics in neuroanatomy. H1.2. Current characteristics 
generated from models will be compared between inclusion and exclusion of white matter lesions. 
A false discovery rate (FDR)-corrected voxel-wise within participants analysis will test the 
hypothesis that inclusion of white matter lesions in computational models significantly alters 
current characteristic predictions.  
Aim 2. Dependent measures. The primary dependent measure in Aim 2 is balanced accuracy. 
This measure provides an overall index of the performance to differentiate responders from non-
responders. Rationale. By using this measure, we provide a single performance indicator upon 
which the heterogeneity of response in tDCS augmented CT can be revealed. Much of our 
preliminary data is based on analyses using this measure. Outcome analyses. All analyses will be 
conducted with the intent to optimize prediction of tDCS outcome. McNemar test at one-tailed 
0.05 significance level will be conducted to determine whether current intensity and direction will 
outperform clinical and demographic characteristics alone in predicting tDCS response. 

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Exploratory Aim. Dependent measures. The primary dependent measure in the Exploratory Aim 
is log-likelihood distance measure. Adjustments of electric current intensity and electrodes 
placement in computational models will be used to minimize the log-likelihood distance measure 
to the Gaussian Mixture Model of the responders’ current distribution.  
Timeline. Construction of the MRI-derived finite element computational models as 
described in aim 1 is estimated to begin in January 2021. We estimate approximately 24 
months will be required to complete this process. By Q3 2022 the ACT study is 
anticipated to be completed and access to the currently blinded randomization conditions 
will be available to complete aim 2 and the exploratory aim.  
The additional analyses described in section 6.18 will not impact study participation in any way. 
The analyses will only use data collected under currently approved study procedures.  
7. Possible Discomforts and Risks: 
Potential Risks.  
There are minimal risks associated with participation in this study. The potential risks are as 
follows:   
Magnetic resonance imaging (MRI). MRI is a procedure that allows doctors to look inside the 
body by using a scanner that sends out a strong magnetic field and radio waves.  This 
procedure is used routinely for medical care and is very safe for most people, but participants 
will be monitored during the entire MRI scan in case any problems occur. The risks of MRI are: 
• The MRI scanner contains a very strong magnet.  Therefore, participants may not be able to 
have the MRI if they have any type of metal implanted in their body, for example, any pacing 
device (such as a heart pacer), any metal in their eyes, or certain types of heart valves or 
brain aneurysm clips.  A MRI technologist will question participants about any 
contraindications before they enter the scanner. 
• There is not much room inside the MRI scanner. Participants may be uncomfortable if they 
do not like to be in close spaces ("claustrophobia").  During the procedure, participants will be 
able to talk with the MRI staff through a speaker system, and, in the event of an emergency, 
participants can tell them to stop the scan. 
• The MRI scanner produces a loud hammering noise, which has produced hearing loss in a 
very small number of participants. Participants will be given earplugs to reduce this risk, and 
headphones for added protection. 
• If an obvious abnormality is discovered during the participant’s MRI scan, they will be 
informed about it by the research team, and will be provided with a copy of the MRI scan and 
we will encourage them to see their primary care physician. MRI will only be done for 
research purposes in this study. 
• Participants will be monitored very carefully while in the scanner, and repeatedly checked to 
ensure comfort. 
Transcranial direct current stimulation. Transcranial direct current stimulation is considered safe 
but a small number of people do experience some side effects.  The most common side effects 
are itching and tingling or mild discomfort at the area of stimulation, and headache.  Other 
possible side effects include dizziness and nausea.  Whenever an electrical stimulation is applied 
to the body, it could possibly cause a seizure or abnormal heartbeat, but this has never occurred 
with the transcranial direct current stimulation parameters used in this study.  

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Cognitive Training. There is a risk participants will find cognitive training on the computer 
challenging, fatiguing, and/or boring.  Research staff will explain what to do and how to perform 
the training tasks tests during an initial study visit. Participants will also have access to a 24-hour 
help line should they have trouble working with the training computer.   
Educational training. There is a risk participants may find ET to be challenging, fatiguing, and/or 
boring. Research staff will be present to address any concerns. Participants are free to skip any 
content they find objectionable and refrain from answering any questions that they find 
uncomfortable. All material presented has been judged appropriate for an educational setting. 
 
Neurocognitive and Functional tests. There is a risk that participants will find cognitive and 
functional tests challenging, because it may be difficult to remember the things that they are 
asked to remember or participants may have trouble hearing or seeing some of the sounds and 
pictures presented on the computer screen. Participants may skip any tests they do not wish to 
complete. Research staff will explain what to do and aid participants during their study visit. 
 
Questionnaires. There is a risk that participants will find questions on the questionnaires 
uncomfortable to answer. Participants may skip any question they feel uncomfortable 
answering. 
  
Participants will be asked questions about previous and current alcohol and drug use with two 
questionnaire measures (AUDIT-10 and DAST-10). These questions are of a particularly 
sensitive nature. There is a risk that participants may feel uncomfortable about answering such 
questions. Like any other part of the study, participants are free to decline to answer anything 
that they are uncomfortable with.  
 
Other possible risks to participants may include fatigue due to the testing. Should this occur, 
participants can take a rest-break at any time or may discontinue the testing at any time.   
 
When being tested some people may develop anxiety. If these tests make participants anxious 
we can stop the testing.  
Researchers will take appropriate steps to protect any information they collect about participants.  
However, there is a slight risk that information about participants could be revealed inappropriately 
or accidentally.  Depending on the nature of the information, such a release could upset or 
embarrass participants, or possibly affect their insurability or employability.  
This study may include risks that are unknown at this time. 
Participation in more than one research study or project may further increase the risks to 
participants. If participants are currently participating in another study using transcranial direct 
current stimulation or transcranial magnetic stimulation, they will not be enrolled in this study until 
all external studies are completed. 
If participants consent to the COVID-19 ancillary blood draw risks associated with phlebotomy 
apply. These include discomfort at the site of puncture, possible bruising and swelling around the 
puncture site, rarely an infection, and uncommonly faintness from the procedure.  
 
Adequacy of Protection against Risks. 
Recruitment and Informed Consent. All study participants will provide written informed consent. 
Persons will be recruited from the CAM-CTRP research registry, advertisements such as 

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newspaper, magazine, and bus ads, community outreach, or community agencies. Participants 
will also be recruited at community events with IRB-approved flyers, and participants will have 
the option to confidentially provide name, phone number, and email if they wish to be contacted 
by the study team to determine study eligibility. Contact information will also be obtained 
through the UF Health Consent2Share registry to identify potential participants. If 
Consent2Share contacts are interested in hearing more about the study, they will be 
administered the phone screening. If we are unable to reach potential participants we will leave 
a phone message (see phone message script) to let them know the reason for our call. If they 
are interested in hearing more about the study they will be directed to call us back and then 
administered the approved phone screening after confirming initial interest and addressing any 
questions they may have.  The contact information will be securely stored during the event and 
immediately stored in the Woods Lab after the event per study data safety management plan. 
People interested in participating in the study will call the CAM-CTRP study recruitment 
coordinator. Potential participants interested in hearing more about the study will be provided 
information about the study. Persons will then indicate their agreement to participate by signing 
the informed consent document.  
 
Our inclusion and exclusion criteria are designed to minimize risks to participants.  
Inclusion criteria:  
1. Age 65 to 89 years; this age group was selected because it is at high risk of age-related 
cognitive decline and have a sufficiently long life expectancy319 to participate in the 
study; 
2. Evidence of age-related cognitive decline in the Cognitive Training assessment defined 
by performance below the 80th percentile.  
3. Ability to participate in the intervention and attend training sessions; willingness to be 
randomized to either treatment group. 
 
Rationale: (1) The age range is selected to include a higher proportion of persons with cognitive 
deficits. (2) Participants will need to show some form of impairment to be included in the study 
in order to avoid biasing the study with extremely high functioning individuals. (3) Participants 
must be willing to perform study activities.  
 
Exclusion criteria: 1) Neurological disorders (e.g., dementia, stroke, seizures, traumatic brain 
injury). 2) Evidence of cognitive impairment (as defined by NACC UDS performance below 1.5 
standard deviations on age/sex/education normative data in at least one cognitive domain). 3) 
Past opportunistic brain infection 4) Major psychiatric illness (schizophrenia, intractable affective 
disorder, current substance dependence diagnosis or severe major depression and/or 
suicidality. 5) Unstable (e.g., cancer other than basal cell skin) and chronic (e.g. severe 
diabetes) medical conditions. 6) MRI contraindications (e.g., claustrophobia, metal implants). 7) 
Physical impairment precluding motor response or lying still for 1 hr and inability to walk two 
blocks without stopping. 8) Currently on GABA-ergic or glutamatergic medications, or on sodium 
channel blockers. 9) Left-handedness. 
 
Rationale: (1) neurological diseases affecting the brain create obvious confounds that would 
obscure the study’s findings or increase risk from non-invasive brain stimulation (i.e., seizures). 
(2) The NACC UDS will be used to exclude people meeting criteria for severe dementia, as this 
study is focused on more mild-moderate cognitive impairment; (3) past opportunistic brain 
infection, and (4) a history of severe psychiatric illness (schizophrenia, chronic intractable 
unipolar or bipolar depression) also would directly affect neurocognitive test performance and 
thus would confound study findings. (5) Unstable (e.g., cancer) and certain chronic medical 
conditions (e.g., severe obesity) may also confound findings and increase study attrition; (6) 

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Given that this study requires MRI imaging to address all aims, factors that make MRI imaging 
unsafe or infeasible for particular study candidates will serve as a basis for exclusion; and (7) 
Physical limitations are a basis for exclusion based on inability to participate in all study 
procedures. Excluding people who cannot walk or sit for an hour will reduce problems in the 
scanner that could confound study findings. (8) GABA-ergic, glutamatergic, or sodium channel 
blocking medications may alter or block the ability of tDCS to facilitate tissue excitability. (9) 
Left-handedness complicates the interpretation of FMRI findings.  
 
Protection against Risk.  
Protection against Risk of confidentiality. Information pertaining to research subjects will be 
obtained from (1) interviews with subjects and (2) procedures described in the "research design 
and methods" section. All data will be considered confidential according to HIPAA guidelines for 
personal health information. All participants will sign a combined consent to participate in 
research and HIPAA compliant confidentiality document approved by the IRB overseeing the 
clinical recruitment setting (i.e. the University of Florida IRB, and the Florida Department of 
Health IRB).  
 
Precautions will be taken to ensure that all research materials are inaccessible to anyone 
other than the investigators, and by ensuring that only qualified and trained individuals conduct 
the study research procedures. Prior to study initiation, procedures for protecting the 
confidential nature of participant data collected will be reviewed and all questions or concerns 
will be clarified at this time. These procedures will be reviewed throughout the study. Staff will 
be trained and certified in handling human subject information to maintain privacy and 
confidentiality. Procedures for allowing access to investigators to use this information for 
research will be under the authority of the PI and will follow HIPAA compliant guidelines for the 
release of PHI.  
 
Contact information for study participants will be kept in separate files and databases from 
the research data. This information will be used by the research assistants to send reminders 
about follow-up times and appointments via phone, email, or mail correspondence depending 
on the participant’s preference. Research assistants may contact study participants via phone, 
email, or mail to provide directions to the study site or answer general questions or concerns 
about the study. In order to avoid participants who are lost to follow up, we will contact study 
participants periodically between their 3 month post intervention visit and their one year follow 
up visit at approximately 3 month intervals. We will send a letter and/or email to participants who 
we are unable to contact via phone to see if their contact information has changed. The 
information will only be kept on computers or devices that are both password protected and 
encrypted.  Any written forms will be kept in locked file cabinets or locked briefcases. None of 
the research data in the central database will have participant identity information. No results 
will ever be reported in a personally identifiable manner. All research data will be entered 
directly into a web-based survey that is maintained by the University of Florida CTSI (REDCap), 
and the data are encrypted as soon as they are sent in a wireless format. The data will be 
transferred and stored on secure servers at the University of Florida, with no identifying 
information. Only de-identified data will be entered into the REDCap database across all sites. A 
data confidentiality agreement will be signed and filed with the UF IRB before any data are 
collected at any site. 
 
No survey data will be labeled with the participant’s name or other identifying information, 
but will instead be labeled with a study ID number. Documents linking study ID numbers to 
identifying information (e.g., name, address, etc) will be stored electronically in a password-
protected file. All paper-data with identifying information will be stored in locked file drawers, 
separate from coded data. Documents linking study ID numbers to identifying information will be 
destroyed at the end of the study. Documents containing data collected on un-consented 

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individuals (i.e., screening logs used to avoid approaching the same individual for study 
enrollment twice) will be shredded daily. All electronic data will be secured and encrypted. 
Identifying information will not be reported.  
 
Protections of risks related to study questionnaires. To minimize any risks related to emotional 
responses to questionnaires, persons will be informed about the types of questions included in 
the surveys, which are similar to the types of questions persons might be asked by their doctor 
in a clinical setting.  
 
Protection of risks related to tDCS. To minimize risk associated with tDCS, participants will be 
monitored throughout stimulation sessions and asked to report any discomfort. If scalp 
sensation is uncomfortable, stimulation will be stopped. In the event of a headache, stimulation  
will be stopped. All tDCS sessions will be administered and continually supervise by a trained 
experimenter. The above symptoms have only been reported when participants are actively 
being stimulated. However, to assess for any symptoms occurring during the 24 h interval 
between stimulation sessions, we will administer a brief symptom screening questionnaire at the 
beginning (symptoms in the past 24 hours) and end of each session (symptoms during 
stimulation). tDCS has not been shown to cause seizures nor lower the seizure threshold in 
animals. There are no reports of seizure induced by tDCS in human participants in the literature. 
However, this may not be true for epilepsy patients, whose seizure threshold rates are likely 
abnormal. Prior history of neurological disorders is an exclusionary criterion for our study and 
thus no participants will have a history of seizure. 
 
 
 
Protection against risks associated with neuroimaging. MRI is widely regarded as a safe, 
noninvasive procedure for visualization of brain tissue in both adults and children. Prior FMRI 
studies by our group and by other groups document the innocuous nature of these procedures. 
Prior to study participation, all participants will be informed of the MRI procedure during the 
informed consent/assent process. The proposed study will be performed on an FDA approved 
Siemens 3 Tesla scanner located at the Advanced Magnetic Resonance Imaging and 
Spectroscopy (AMRIS) research facility at UF. There are no known long-term effects of MRI 
procedures on the body. The FDA Information Sheets, Food and Drug Administration, October 
1995, p. 79, lists as a non-significant risk device, “Magnetic Resonance Imaging (MRI) Devices 
within FDA-specified parameters.”  This study satisfies those parameters. The 3.0 tesla MR 
scanners meets FDA parameters for field strength, gradient switching, and RF power deposition 
for all FDA-approved acquisition schemes including echo-planar imaging. In addition, this 
research protocol involves the use of an FDA-approved acquisition scheme, or the power 
deposition of experimental acquisition scheme proposed meets FDA parameters as verified on 
a phantom using the power monitoring system installed on the MR scanner. Both Dr. Woods 
and trained MRI staff will check for exclusion criteria. The main MRI-related risks include: (a) 
sensitivity to the loudness of the MRI machine - all subjects will be given and must wear ear 
plugs; a squeeze-ball and microphone will be provided so that they may stop the testing if they 
become uncomfortable or anxious at any time; (b) claustrophobia - subjects will have the 
opportunity to practice in a simulator and to become as familiar and comfortable as possible 
before commencing the experiment. In addition, they will be given the opportunity to examine 
the scanner before the tasks starts. The study will be ended early if the space is a problem for 
them; no medications (e.g., benzodiazepines or tranquilizers) will be offered to them; (c) 
lightheadedness when sitting up after lying in the MRI machine - this feeling sometimes occurs 
but has always gone away in a few minutes. Participants will thus be assisted in getting up to 
make sure they do not fall; In sum, the MRI neuroimaging procedures pose no radiological or 
medical risk, given that participants with metal implants susceptible to magnetic heating will be 
excluded based on standard scanner policies. A small number of people may become anxious 

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in the small space of the scanner. These individuals will have the opportunity to terminate the 
scan session. Furthermore, all recruits will be screened for phobias prior to enrollment. There is 
a medical technologist at the imaging site at all times to insure scanner safety, and 
neuroradiologists on call as needed. If an abnormality is noted on the structural MRIs by study 
staff, the PI will provide the participant with a copy of the scan and encourage them to follow up 
with a neurologist. 
 
Protection against risks associated with neurocognitive tests. The neurocognitive assessments 
have minimal risk associated with them. Some participants experience stress associated with 
being tested, though this tends to be quite limited. Breaks will be given in those cases. 
Research staff that collect data have been trained in the conduct of all cognitive function tests 
by other senior staff members. Research staff members will be certified in the conduct of the 
cognitive function tests before they work with study participants.  
 
Data and Safety Monitoring Plan: 
The research team will follow the procedures for data safety and monitoring as required by the 
Institutional Review Board at the University of Florida (UF IRB). The research team will monitor 
participants for any potential adverse events, and all reported events will be forwarded by the PI 
to the UF IRB. 
 
A data and safety monitoring plan (DSMP) has been implemented to ensure the safety of all 
participants involved in the study and to ensure the validity and integrity of the data. The primary 
goal of the DSMP will be to monitor the progress of the study and safety of participants and if 
necessary, recommend modifying the study or terminating the study as appropriate. 
 
• 
The PI’s will be responsible for coordinating activities of the DSMP, including: 
  
o Lab Meetings twice per month, to discuss participant involvement in the study, 
and any issues that have developed or need revision 
o Safety concerns 
o Data Storage and safety 
o Participant safety 
o Outcome data 
o Data quality 
o Integrity 
o Intervention efficacy 
o Recruitment 
o Performance 
 
Both the PI and the study staff will review and examine reports of adverse incidents 
immediately, and make reports to the IRB as necessary for any and all of the following 
situations: 
   
o Serious and non-serious adverse events that may occur 
o Suspicion of scientific fraud or misconduct 
o Any other issues which may warrant protocol changes or modifications. 
 
Procedure for collection and storage of data.  A number of quality control procedures will be 
used to ensure the validity and integrity of the data and the safety of all participants involved in 
the study. Relevant data and safety information obtained on each study participant will be 
verified against the original source documents by the primary study coordinator and any 

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identified discrepancies will be reviewed at these meetings. The primary goal of these meetings 
will be to monitor the progress of the study and safety of participants and if necessary, 
recommend modifying the study or terminating the study as appropriate.  
All identifying information will be archived in Dr. Cohen’s and Woods neuroimaging laboratory 
within the Center for Cognitive Aging and Memory. Imaging data will undergo several levels of 
processing, and all raw and processed data will be archived on a University password-protected 
server in password-protected folders and files. Only study staff will have access to these files. 
The self-report data will be double entered using the RedCap Data System. This system signals 
the user when an out-of-range value is entered. All data entry is then verified via double-entry, 
with the program signaling mismatches with the original entry. Next, computer-generated 
reports of variable frequencies and subject lists will be reviewed, leading to possible corrections 
to coding or entry. After checking for accuracy of data within a given group, data will be stored in 
the password-protected folders along with the imaging data. 
 
 
Location and logistics of data collection. All procedures involving human subjects will be 
performed at facilities of the UF Health Care System. Neurocognitive testing and training will be 
performed at the clinical research unit of the Center for Cognitive Aging and Memory with an 
ancillary location at the Village at Gainesville. Several clinical research examination rooms are 
equipped and dedicated to neurocognitive and functional assessment, and contain all necessary 
computers and test materials. Storage of neuroimaging data backup will occur at the CAM 
Neuroimaging Laboratory. Neuroimaging will take place at the AMRIS facility of the McKnight 
Brain Institute. 
 
Sharing of data from collaborating sites. Due to the multi-center design of the study, data will be 
shared with the University of Florida from a collaborating site, the University of Arizona. The 
collaborating site will send fully de-identified data. Data transfer will take place using the 
secured infrastructure of the University of Florida RedCap system for questionnaire data. De-
identified raw neuroimaging data will be transferred to UF using the Secure File Transfer 
Protocol (SFTP) onto UF Dropbox servers. A data confidentiality agreement will be signed and 
filed with the UF IRB before any data are collected at any site. 
 
Storage of collected data. All electronic data are stored in password protected, secured 
computer systems. All paper data will be stored in a locked file cabinet. Data will only be 
removed when coded, entered, or audited. Only the participant’s study identification number will 
appear on any data forms. Only the PI, the Co-Is, and the RAs will have access to the 
completed data forms and electronically stored data. All data are considered part of the 
participant’s confidential record. Data collected from research participants will be stored in a 
secured, password protected computer file that is separate from network systems. All paper 
data (e.g., subject contact information, consent forms, etc.) will be placed in a locked file cabinet 
within 24 hours of their acquisition as designated by the study's RA. All data will remain 
confidential. Data entry requirements. The data entry system will require a login identification 
and password in order to gain access to the data. Where appropriate, validation and range rules 
will be applied to the actual entry fields. Only the PI and Co-Is will be able to view the data in its 
raw state. 
   
Audit/verification of entered data. All data designated as primary outcome data will be subject to 
a 100% cross-referencing between electronic and paper forms. This audit must have an error 
rate less than 1%. If the verification fails the audit, all data will be re-entered, the original 
computer files discarded, and the newly re-entered data audited. This process will continue until 
the audit no longer exceeds the maximum allowable error rate. All audits will be supervised and 
documented by the PI. 

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Data management and analysis. Our research team has substantial experience in the design 
and implementation of data management procedures that provide accurate recording and 
storage of data, participant confidentiality, and timely analysis. Based on our past experience, 
we believe that our major data management and analysis needs for the proposed project can be 
met by using a high-end PC, equipped with the latest version of SPSS for Windows and 
appropriate spreadsheet programs. All data files are automatically backed-up daily. 
  
Data quality control. All staff involved in data collection will be trained and certified to ensure 
their competence, and re-certified periodically throughout the study as we have done in similar 
trials. Data will be collected and numerically coded using pre-tested electronic entry forms. At 
the time of collection, there will be initial clerical review of all data for accuracy and 
completeness. Every effort will be made to ensure that missing data are kept to a minimum. 
Data entry programs with range checking and response validation will be used for all data 
entered. Under supervision from the PI, the data manager will conduct error checking 
procedures and preliminary analyses on all data to ensure their accuracy. The RAs will be 
trained to avoid omissions in data entry and computer entry protocols will be programmed to 
avoid accidental skipping of question items. We believe that the quality control system to be 
used will ensure a complete and accurate database, and maximize the likelihood that the 
intervention will be delivered correctly and efficiently. As we have done in prior studies, a 
manual of procedures will be developed during the initial study start-up period that explicitly 
describes the specific procedures related to intervention delivery, data collection, and quality 
assurance.   
Frequency of data review. Relevant data and safety information obtained on each study 
participant will be verified against the original source documents by the primary study 
coordinator on a bi-weekly basis. As noted above, any identified discrepancies will be discussed 
with the Principal Investigator and reviewed at weekly meetings. 
  
Measurement and reporting of participant accrual and adherence to eligibility criteria. Review of 
the rate of participant accrual, adherence to inclusion/exclusion criteria will occur weekly during 
the recruitment phase and then every month to assure that participants meet eligibility criteria 
and ethnic diversity goals outlined in the grant proposal.  
 
Safety Review Plan Study progress and safety will be reviewed twice per month (and more 
frequently if needed) by the principal investigator. An annual report will be compiled and will 
include a list and summary of AEs. In addition, the annual report will address (1) whether 
adverse event rates are consistent with pre-study assumptions; (2) reason for dropouts from the 
study; (3) whether all participants met entry criteria; (4) whether continuation of the study is 
justified on the basis that additional data are needed to accomplish the stated aims of the study; 
and (5) conditions whereby the study might be terminated prematurely. The IRB and other 
applicable recipients will review progress of this study annually. 
 
Final storage of paper data. All paper data (e.g., consent forms) may be scanned, and will finally 
be housed at a facility that specializes in the storage of medical/ research information. The 
destruction date of these files will be at least 7 years from the termination of the study and will 
be authorized by the Principal Investigator of the research study. 
Access to cleaned computer data. Once the study is complete, and all data have been 
collected, entered and passed the audit process, the data will be available to the Principal 
Investigator and his designates for analysis. Only the Principal Investigator can give permission 
for the release of aggregated study data. No confidential information may be released without 

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the express written consent of the study participants. Only copies of the finalized data will be 
released. The original data file will remain in its pristine state. 
Description of plan for safety monitoring. Protection of participants from risks related to the 
study is of paramount concern.  
Monitoring physical health and safety. All assessment visits will be conducted at a central 
location and all testing sessions will be conducted and supervised by a trained and certified 
research staff that will monitor potential adverse experiences and symptoms. At each visit, 
participants will be asked to report any adverse events they have experienced since their last 
visit. Immediate medical treatment will be provided for any illness or injury resulting from this 
study. Trained nursing staff members are present in the research center at all times, and a 
physician will also be available to evaluate the participant if needed. 
In addition to the assessments conducted at in-person study visits, participants will be asked 
about any adverse events, including itching, pain, nausea, headache, etc. they have had. 
Participants will also be asked about their mood, including depressive symptomatology, and 
other health related activities (i.e., physical activity), as well as general health status. Based on 
reported symptoms, participants may be asked to come in for an additional follow-up 
assessment visit with one of the healthcare professionals on the study team (i.e., physician or 
psychologist) for further evaluation of their symptoms. Based on information obtained at this 
visit, participants will then be referred for follow-up assessment and/or treatment with the 
appropriate healthcare provider. 
Monitoring mental health and safety. Any participant who endorses clinical levels of any 
psychiatric disorder or who endorses suicidality will be referred to Dr. Cohen, study 
psychologist, for further follow-up assessment. The psychologist will then provide a 
recommendation regarding the appropriate course of follow-up and also advise on whether it is 
safe for the participant to continue in the study. If a participant is found to be actively suicidal 
with a plan and/or intent, they will be escorted immediately to the emergency room at the 
Shands Hospital at the University of Florida. If safety is an issue, UF security or local authorities 
will be called for assistance.  
 
Data and Safety Monitoring Board (DSMB): 
A Data Safety Monitoring Board (DSMB) is established, with responsibility to monitor all 
aspects of the study, including those that require access to any masked data. The DSMB and its 
chair are named and approved by the NIA. It is planned that the DSMB meets by conference 
call as determined by the DSMB and the NIA. The DSMB has access to all deidentified study 
data, documents and progress. The Intervention and Safety Committee, comprised of safety 
personnel from each site, the Chair, and a representative of the DMAQC reports to the 
DSMB for issues related to participant safety.  
The DSMB has the following charges: 
• 
Review the study protocol. 
• 
Review data (including masked data) over the course of the trial. 
• 
Identify problems relating to safety over the course of the study.  
• 
Identify needs for additional data relevant to safety issues and request these data from 
the study investigators. 
• 
Propose appropriate analyses and periodically review developing data on safety and 
endpoints. 
• 
Make recommendations regarding recruitment, treatment effects, retention, compliance, 
safety issues and continuation of the study. 

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• 
At any time, the DSMB may recommend discontinuation of any component/treatment 
group of the study 
 
Finally, the NIA makes the final decision on whether or not to accept the DSMB’s 
recommendation about discontinuation of any component of the study. Any serious adverse 
event that might be due to the study intervention are reported to the DSMB, the IRBs, and to the 
NIA Project Office. The exact timeline for reporting serious adverse events is determined by the 
DSMB, IRBs, and NIA.  
8. Possible Benefits: 
There are well-documented benefits for older adults who participate in cognitive training, 
including improvement in working memory, attention, and executive functions. Deficits in these 
cognitive abilities significantly impact quality of life, financial capacity, medication adherence, 
and mortality in older adults. Those participants randomly assigned to the CT groups may 
benefit from these effects. Participants assigned to the Education Training Control group may 
obtain better knowledge about educational facts from the videos, but are unlikely to have the 
same benefits as those in the CT group. Those participants randomly assigned to the tDCS+CT 
treatment group may experience further benefit beyond that of cognitive training alone. Benefits 
to society will include the contribution of novel data regarding the efficacy of neuromodulation 
methods for enhancing cognitive training effects in older adults. This may help inform treatment 
protocols in a growing segment of the US population (i.e., those 65 years and older). Data 
collected from this study will serve as a foundation for larger clinical studies that examine 
optimized methods for treating aging-related cognitive decline using cognitive training and 
tDCS. Some participants may not benefit from the study at all. 
9. Conflict of Interest: 
None 
 
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