SMART Stimulation: Precision Neuromodulation of Cognition in Older Adults
Phase: NA
Conditions: Aging
Sponsor: University of Florida

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SMART Stimulation: Precision Neuromodulation of Cognition in Older Adults 
NCT05377411 
Document Date: 9/19/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. Project Title 
 SMART Stimulation Study: Precision Neuromodulation of Cognition in Older Adults  
2. Investigator(s): 
Adam J. Woods, PhD 
Ron Cohen, PhD 
Steven DeKosky, MD 
Aprinda Indahlastari, PhD 
Joe Gullett, PhD 
 
Staff 
Andrew O’Shea M.Sc.: Study Coordinator 
Alejandro Albizu, B.S.  
Nicole Baird, B.S. 
Emanuel Boutzoukas, M.S. 
Christina Clarke, B.S. 
Nicole Evangelista, M.S.  
Hanna Hausman, M.S.  
Jessica Kraft, M.S. 
Samantha Pedersen, B.S. 
Crysten Repetti, B.S. 
3. Abstract: 
The current study will investigate methods for enhancing cognitive training (CT) effects 
in healthy older adults by employing a combination of interventions facilitating neural 
plasticity and optimizing 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 pilot 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 enhances 
neural plasticity when paired with a training task. We will compare changes in cognitive 
and brain function resulting from CT combined with active tDCS versus CT combined 
with sham tDCS using a comprehensive neurocognitive, clinical, and multimodal 
neuroimaging assessment of brain structure, function, and metabolic state. A precision 
dosing algorithm will be used to determine the appropriate levels of current and location 
of electrodes to deliver current using tDCS. 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 

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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) Neuroimaging biomarkers of cerebral metabolites, 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 tDCS dose optimization strategies for maximizing 
the learning and functional gains associated with CT. The present study will provide a 
unique window into critical mechanisms for combating cognitive decline in a rapidly 
aging US population and 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 needed to improve the 
generalizability of CT. 10) Methods exist which could 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. Recent developments in 

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MRS enable Gama Amino butyric Acid (GABA), the primary inhibitory neurotransmitter 
and an essential neurotransmitter for synaptic communication and associative 
formation, to be measured from brain regions of interest (ROIs) 1 2. GABA 
concentrations predict attentional control 1 and sensory discrimination 3,4, decrease with 
age5 and yet demonstrate long-term increase with learning interventions.2,6. Functional 
connectivity measured by FMRI provides another potentially powerful approach for 
measuring these changes. Yet, these neuroimaging approaches have been employed 
to only a very limited extent in studies of the mechanisms of CT. Studies employing 
neuroimaging to assess CT outcome are needed. 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. These differences are not 
well understood. We will examine neuroimaging and behavioral factors that predict CT 
outcome and that may account for these individual differences. 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 affect 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. 

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4.3.3. Benefits of cognitive training. Various CT approaches exist. 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 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 (See Miscellaneous Attachments for detailed 
descriptions/samples of each game.) 
Attention/Speed of Processing 
1. Hawk Eye- works on visual precision, which helps the brain perceive what you 
see quickly and accurately so that you can recall it 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 you to 
track several items moving around your 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 of your working memory 
systems. 
2. Memory Grid - Auditory processing is one of the most important building blocks 
of memory. Only when you 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.  
     

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4.3.4. Generalization and functional outcome. 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 (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 holds great promise for 
older adults.  
To date, all prior trials of tDCS have applied a fixed application strategy (e.g., 
2mA for 20 min with electrodes at F3/F4 following the 10-20 EEG system) to target a 
specific brain region (e.g., the dorsolateral prefrontal cortex) in all tDCS recipients. 

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However, prior research demonstrates that individual variability in anatomical structures 
(e.g., brain atrophy, skull thickness, etc.) generates significant variability in the spread 
and amount of delivered electrical current to the brain. To that end, individual 
differences in brain morphology have been found to alter the distribution of delivered 
electrical current in the brain and thus poses a challenge to consistently deliver the 
amount of current needed at the desired brain region across individuals (Indahlastari et 
al., 2020, Albizu et al., 2020). Direct measurements of electrical current distribution 
induced by tDCS are difficult to accomplish. Therefore, computational modeling has 
been employed to estimate current distribution in the human head. With the advent of 
MRI-derived computational models to estimate current dose delivered to the brain at an 
individual level, the ability to systematically quantify the directionality and magnitude 
components of electrical current will create a powerful tool for optimizing stimulation 
outcomes. Advancements in tissue segmentation tools and finite element solvers will 
provide a robust pipeline, albeit computationally intensive, to generate more accurate 
and highly sophisticated models to estimate electrical current flow. Due to the size and 
complexity of these models, traditional univariate methods have been unsuccessful in 
determining the optimal methods to strategically alter brain network communication. 
Alternatively, methods of artificial intelligence (AI) constitute a novel approach in 
neuroimaging to investigate large and complex datasets. AI models (e.g., support vector 
machine, SVM) utilize pattern recognition of information across many features, to gain 
insight on the elements of current delivery that are most important for selectively 
modifying specified functional outcomes.  
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 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 

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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). These measures will provide markers of improvement 
in the temporal processing of information, a key element altered with age. 
 
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 
Edden274-278 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 
A.3.8. 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 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 
Figure 1 

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executive control, improve effectiveness of CT, and ultimately cognitive health (see 
Figure 1 for conceptual model).  
5. Specific Aims: 
Age-related cognitive decline has become a major public health concern. As the 
population ages, the number of older adults experiencing cognitive and functional 
disturbances has increased. There is currently a paucity of effective interventions to 
prevent or treat cognitive decline or to enhance brain function in the elderly. The 
proposed study will recruit a cohort from the state with the highest growth of older 
adults. We will employ an randomized clinical trial (RCT) to test whether the benefits of 
cognitive training (CT) can be enhanced by a combined adjunctive intervention aimed at 
increasing neural plasticity and optimizing readiness for learning: transcranial direct 
current stimulation (tDCS).  
Current CT approaches have been shown to improve performance on trained tasks, 
with effects lasting up to ten years32,33,36,279,280. However, generalization of effects to 
other cognitive domains and everyday functioning has been a problem in the past. 
There is now compelling evidence that the elderly do experience functional 
improvements that persist long after initial training, though peoples’ ability to derive such 
benefits varies. Combined interventions have rarely been examined and methods aimed 
at increasing neural plasticity and optimizing readiness for learning are only now 
beginning to be explored. The proposed study will test one theoretical approach for 
facilitating and optimizing CT effects on functional outcome. We will use an adjunctive 
physiological method to further stimulate task-related brain regions, directly enhancing 
neural responsivity/plasticity and ultimately learning. While theoretical rationales exist 
for each of these approaches, no studies to date have shown whether adjunctive 
administration can optimize learning and functional status in the elderly.  
A randomized clinical trial will enroll 40 participants. Cognitively healthy elderly adults, 
age 65-89 will undergo either a CT intervention in combination with optimized 
transcranial direct current brain stimulation (tDCS) or sham tDCS control. The CT 
intervention will employ a suite of adaptive training tasks from the POSIT Science Brain 
HQ281; a well validated CT method for enhancing cognitive functioning in the elderly. 
Participants will receive tDCS or sham/placebo precision stimulation administered 
during training.  
Participants will be assessed at baseline and after CT (2 weeks). At each time point, a 
comprehensive neurocognitive, clinical and multimodal neuroimaging assessment of 
brain function, metabolic state, and brain structure will be conducted.  
FMRI will be used to assess brain response during working memory, attention and 
memory encoding. Proton magnetic resonance spectroscopy (MRS) will assess 
cerebral metabolites, including gamma-aminobutyric acid (GABA) concentrations, 
sensitive to neural plasticity in task-associated brain regions.   

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The central hypothesis of this proposal is that optimized tDCS will increase 
neural plasticity in task associated brain regions, facilitating effectiveness of CT 
and transfer to everyday function.  
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 neural plasticity and augment training effects.  
H1.1. Active tDCS combined with CT will amplify effects of CT on measures of 
attention, working memory, executive functioning, and learning efficiency, while 
sham tDCS will not. 
H1.2. Active tDCS will enhance near and far transfer of CT, but sham will not 
evidence near or far transfer. 
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. Combined CT + tDCS will potentiate decrease activation in working 
memory and attentional (dorsolateral prefrontal cortex, medial frontal cortex, 
inferior parietal lobe, supplementary motor association cortex) brain systems, 
reflecting increased neural efficiency, while CT + sham tDCS will not.  
H2.2 Cerebral metabolite alterations will occur secondary to CT and tDCS, with 
long-term increase in GABA and N-acetyl aspartate (NAA) concentrations, and 
decreased choline (Cho) and myoinositol (MI) concentrations in the frontal 
cortex. CT and tDCS will modulate MRS GABA in frontal areas. These effects 
will be specific to CT. 
Aim 3. Investigate the performance of optimized tDCS compared to conventional 
application within the literature 
H3.1. Optimized tDCS + CT will generate augmented behavioral gains beyond 
those observed under conventional tDCS application. 
H3.2 Optimized tDCS + CT will also demonstrate greater physiological changes 
of functional connectivity within the working memory network and 
glutamate/glutamine concentrations within the prefrontal cortex compared to 
conventional tDCS application.    
6. Research Plan: 
6.1. Experimental design. This study employs a randomized trial design with 40 
participants. One factor with two levels [Factor 1 = stimulation type (active or sham) 
yields two cells. Thus, participants will be assigned to one of two conditions: 
1: Active tDCS + CT 
2: Sham tDCS + CT 
CT has previously been established with strong effects on cognitive and functional 
outcomes. Some small clinical trials showed small to large effects of tDCS in 
conjunction with CT.  
Participants will be assessed at two primary time points during the study, plus one 
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1) Informed Consent and Screening Visit 
2) Assessment Visit #1- baseline pre-training  
3) Assessment Visit #2- post-2 weeks  
This design will enable longitudinal analyses of CT and tDCS effects. We will examine 
their 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 and following 
training.  
  
6.2. Study participants and randomization procedure. We will recruit 40 older adults 
(age: 65-89 years). 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. We will use web-based permuted 
block randomization to randomly divide participants into the two groups. People with 
pre-existing dementia, neurological brain disease, or meet criteria for a diagnosis of mild 
cognitive impairment (MCI) will be excluded, though people with subjective concerns 
about their cognitive functioning, who do not meet these criteria, may participate. 
Detailed inclusion/exclusion criteria can be found in Section 7. 
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 
Screening 
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Assessment 
Visits 
Activity 
Summary 
 
Informed 
Consent 
Form 
Medical 
History 
Hearing  
and Vision 
Tests 
Memory 
and 
Thinking 
Tasks 
Physical 
and 
Medical 
Self 
Reports 
MRI 
Screen- 
Form 
NIH tool   
box 
MRI 
Brain 
Scan 
Appt.  
Visit #1  
Baseline                
 
 
 
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Visit #2                 
After 2 weeks 
(10 days) of 
Training                 
 
 
 
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Daily Lab 
Visits 
Brain 
Training 
Games  
Brain 
Stimulati
on/Sham 
tDCS 
Sensation 
Questions 
 
 
 
 
 
 
Days 1-10 
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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), Hamilton, and Bikson (consultants), including its 
safety profile, ability to facilitate neural plasticity, and potential for application outside of 
research settings. Recent work from our lab has demonstrated that MRI-derived 
computational models of tDCS-induced current intensity reaching a specific brain region 
important to stimulation gains can reliably predict individual treatment response to tDCS 
(Albizu et al., 2020). Leveraging this information, we can determine the optimal dosing 
strategy to maximize the likelihood of treatment response on an individual level. Thus, 
the location of electrodes where electrical current is applied and the level of current 
intensity (up to 4mA) will vary depending on the individual anatomy of each participant. 
Further, stimulation precision will be enhanced by stereotactic neuronavigation system 
(6.5) as a real-time guidance to ensure accurate and consistent placement of tDCS 
electrodes. These stimulation parameters have been used in previous studies (Khadka 
et al., 2020; Shinde et al., 2021; Workman, Fietsam, & Rudroff, 2020) and, to date, the 
use of conventional tDCS protocols in human trials with parameters ≤40 min, ≤4.0 mA , 
and ≤7.2 Coulombs has not produced any reports of a Serious Adverse Effect or 
irreversible injury (Woods et al., 2016). Theoretical issue damaging levels have been 
estimated to be 25 mA/cm2 and 216 C/cm2 (Sundaram et al., 2009).The current study 
applies well below these levels with 0.114 mA/cm2 of current density and 0.137 C/cm2 of 
total stimulation charge. 
NIH Toolbox. A battery of neurocognitive tests was selected that could be completed in 
approximately 3 hours 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.  
 

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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 one ROI (frontal). Along with 
Creatine (Cr), we will examine cerebral 
metabolites sensitive to neuronal loss and 
membrane disturbances (NAA, GLx), and pro-
inflammatory processes (Ch, MI). We will also 
measure cerebral GABA concentrations using a 
state-of-the-art MRS approach that will reflect 
neural plasticity in ROIs. The MRS indices will 
be examined for Aims 2. We will also collect 
FLAIR imaging data to assess white matter 
hyperintensity load, as a possible predictor of 
treatment response (secondary aim) 
6.3. Procedural sequence. The sequence and 
flow of the assessments to be conducted at 
baseline and each subsequent assessment is 
shown below. We describe participant 
recruitment and retention strategies in the 
Human Subjects section. We will inform potential 
participants about the study, and obtain their 
consent. We will then screen for 
inclusion/exclusion criteria and schedule them 
for baseline assessment visit #1 evaluation. All 
following assessments are identical otherwise.  
6.4 Cognitive Training. CT will involve up to 10 hours of training over 2-weeks (10 
days). At the screening visit and post 2-week intervention participants will complete a 
20-minute composite measure of the cognitive training tasks. Training platform. CT 
employs a PositScience BrainHQ suite via its researcher portal. These tasks are web-
based and multi-platform (i.e., Windows, Mac). Participants will be randomly assigned to 
training on 4 tasks focusing on working memory or 4 tasks focusing on attention/speed 
of processing. Participants will be required to have a specific viewing distances. Study 
interventionists will provide daily performance summaries. The rationale and task 
demands for each component were described earlier (A.3.3). These CT are 
Surveys, Measures, Tasks and Activities 
Screening Visit: 
Informed Consent Process 
Inclusion/Exclusion Screeners 
NACC UDS, Words in Noise (NIH-TB), Visual Acuity (NIH-
TB), Colorblindness, MRI Screener, WTAR (optional: Mock 
MRI, MRI Measuring Device) Drug List review for 
inclusion/exclusion prescriptions 
Baseline Computerized Tasks 
Posit Science Composite Baseline 
Psychological Measures 
BDI, Computer experience survey  
Demographic Information 
Medical History Form 
Assessment Visits: BL, POST 
Neurocognitive Assessment 
Digit Span, Letter Number Sequencing, Symbol Digit 
Coding 
Baseline Computerized Tasks 
Posit Science Baseline, NIH Toolbox 
Psychological Measures 
STAI, BDI, Computer experience survey, Expectations of 
brain training questionnaire, Expectations of brain 
stimulation questionnaire 
Physical Measures 
tDCS Sensation Questionnaire,  
Mulitmodal Neuroimaging 
MRI screener 
MRI Brain Scan Baseline, Post-intervention 
 
Medical History Form 
Training Interventions: 
Cognitive Training 5 hours per week            
(Posit Brain HQ 2 weeks) 
Posit Baseline Measure/weekly 
tDCS Brain Stimulation 
(once per day for 10 days) 
tDCS Stimulation Survey/daily 
Electrode Drift Measurement  

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commercially available (www.positscience.com), with well-documented 
protocols/manuals (See Appendix 1) and thus not described in detail here. (See 
miscellaneous attachments for specific game descriptions.)  Hardware. Participants will 
complete CT on computers located at the McKnight Brain Institute. Support: Participants 
will have the opportunity to ask questions, and will be instructed on the various 
computer tasks. No special technical skills or experience are required. A support phone 
number will be available if participants have questions that arise between study visits.  
 
6.5. Transcranial Direct Current Stimulation: 
Optimized tDCS: Based on our well-established artificial intelligence/computational 
modeling workflow (see figure below), stimulation parameters will be optimized per 
participant to maximize the likelihood of treatment response (Albizu et al. 2021). A 
Soterix Clinical Trials Direct Current Stimulator will apply 20 minutes of up to 4.0mA 
direct current through two biocarbon rubber electrodes covered with at least 5mm-thick 
conductive electrode paste buffer, and placed over the optimized locations based on the 
international 10-20 system by using a combination of 10-20 EEG cap measurement . 
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. Woods 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. 

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Electrode Placement Quality Assurance:  A neuronavigation system equipped with a 3D 
infrared camera (Brainsight, Rouge Research) may be used to register previously 
calculated optimal location for tDCS electrode placement on each participant based on 
their individual structural MRI image with the actual anatomical locations on each 
individual’s scalp to ensure accurate and consistent placement and orientation of 
stimulation electrodes. Prior to registration, head measurement using the EEG 10-20 
cap will be performed for initial markings of electrode location. The initial markings will 
serve as approximate location, which will then be finalized by using the neuronavigation 
system. The procedure on the neuronavigation system starts by capturing known 
anatomical landmarks on the participant’s physical head (e.g., nasion and preauricular 
points) with the 3D infrared camera to align their MRI image with real-world space. The 
optimal electrode locations and orientations within the MRI image can then be 
translated into the real-world space with high accuracy.  
We will also take a brief set of images of the participant’s head after the electrodes are 
placed to make sure that the electrodes are in the correct location. These images 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. Ideally, no electrode displacement 
should occur and thus measurement allows for use of a placement error coefficient in 
statistical analyses of between participant differences in response.  
6.6. Neuroimaging Methods. We will conduct neuroimaging on a Siemens Prisma 3.0 
Tesla research dedicated scanner with an existing research agreement. Scanning will 
take approximately 1 hour to acquire: 1) Structural MRI (T1, FLAIR), 2) FMRI (EPI-
BOLD), 3) Proton MR Spectroscopy (MRS).  
MRI Acclimation Protocol Options:  Participants may have the MRI Measurement Tool 
(See MRI Measurement Tool Appendix in Misc. Attachments) demonstrated for them to 
visually see the size of the inside of the chamber of the MRI Scanner.  Participants may 
be asked to try the device on themselves to gain a greater understanding of the size 
constraints related to the MRI Scan, and to give them a chance to experience the snug 
fit inside the core of the scanner.  If participants cannot fit in the measurement device, 
they will be excluded from the study. 
 
The participant may also be offered to make a visit to the Mock MRI Scanner (See Mock 
MRI Appendix in Misc. Attachments), located in the UF Dental Tower Ground floor, DG-
73) to see if they are completely comfortable with the scanning process, and if they can 
realistically tolerate the size constraints. This can also be a time to discover if 
claustrophobia will be a limiting factor and exclusion for participation. If there is no 
concern regarding fit, or claustrophobia, this part may be skipped. 
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 
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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 for 500ms with an ISI=2500ms. 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 eight blocks (consonant lists), with four blocks of the 0-Back and four blocks of the 
2-Back. Accuracy and RT are recorded. 
The useful field of view (UFOV) fMRI task. Task will involve participants making 
decisions about where on the screen they saw a previously displayed object. 
Participants are presented two images simultaneously, one in a central box, and 
another outside the box. These images disappear very quickly and are replaced by a 
“noise” screen, similar to a scrambled television signal. Then participants are asked 
where they saw the object (a car) outside the box (e.g., up, down, left, right, etc.) and 
what object was inside the box (either a car or a truck). The participants will respond 
using buttons on a response box. After participants have answered they are presented 
a fixation cross and wait until the next trial begins. Time between trials is randomized 
and jittered in accordance with best practice event-related fMRI design. The task 
duration is approximately 10 minutes. Examples of the stimuli are below. 
 
1) Both objects are presented simultaneously 
 
 
2) Noise Screen 
 
 
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 MRS: GABA-edited spectra will be acquired using the MEGA-PRESS 
experiment, from 1 voxel (medial frontal). The scan will last approximately 9 minutes.  
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 

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FMRI. Analyses: Volumetric indices will be obtained for total gray and white matter, 
FreeSurfer ROIs296-298, and a priori ROIs (MRS, FMRI).  
6.6.4. FLAIR. Fluid attenuated inversion recovery (FLAIR) images will be acquired to 
assess white matter hyperintensity load (i.e., white matter damage). Volumetric and 
whole brain analyses of data will be used to look at region specific versus global levels 
of white matter load.  
6.7. Neurocognitive and Psychological Assessments: Assessments will include a 
neurocognitive battery. The battery consists of standardized, well-established 
neurocognitive measures with strong reliability and validity 304. Each is widely used in 
clinical neuropsychology. Our goal is to assess global cognitive ability (NIH-Toolbox: 
cognitive module), and specifically attention-executive functions, working memory, 
processing speed, and learning-memory. These are domains affected by 
aging24,31,146,305-314 and will also tap the domains assessed by FMRI (Aim 1).  
Psychological measures are those commonly used in cognitive training paradigms, such 
as to gain greater understanding of the relation of things like depression, anxiety and 
apathy to the cognitive training intervention, and the resulting effect on memory and 
thinking. The BDI-II has a high risk of identifying severe depression and suicidality.  The 
measure will be monitored carefully to identify and mitigate any risk to persons that are 
identified as at risk.  The PI will be informed immediately, and a referral to Clinical and 
Health Psychology Clinic will be made right away for the participant.  The PI or study 
staff will contact the participant directly to advise them of the concern and assist with 
any intervention that may need to be referred.  The State-Trait Anxiety Inventory (STAI) 
has medium risk to identify anxiety disorders. The National Alzheimer’s Coordinating 
Center Uniform Data Set (NACC UDS), a comprehensive neuropsychological battery 
will be used to assess dementia/MCI in older adults. The NACC UDS is comprised of 
several neuropsychological tests including the Montreal Cognitive Assessment (MoCA), 
Craft Story Immediate and Delayed Recall (similar to the WMS Logical Memory), 
Benton Complex Figure Task Immediate and Delayed Recall, Number Span Forward 
and Backwards, Category Fluency, Trails A & B, The Multilingual Naming Test (similar 
to the Boston Naming Task), and Letter Fluency. The UDS takes approximately 45 
minutes to administer. Score corrections are provided for age, sex and education. 
Self-report questionnaires will be administered electronically via UF Redcap. Items 
marked with an asterisk below will be administered electronically in Redcap rather than 
paper forms.  
 
Screening Visit 
Informed Consent 
MRI Screener 
Medical History/Prescription Drugs * 
Drug Exclusion List Review 
NACC UDS 
Words in Noise (NIH-TB), Visual Acuity (NIH-TB), Color Vision 
WTAR 
Posit Composite Baseline Game Testing  
BDI * 

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Computer and Technology Use Questionnaire * 
 
Assessment Visits #1,2 
NIH Toolbox 
Digit Span 
BDI * 
STAI * 
Expectation of brain stimulation questionnaire * 
Expectation of brain training questionnaire * 
Letter Number Sequencing 
Symbol Digit Coding 
Medical History reassessment * 
MRI Screener 
 
Daily Check In 
tDCS Stimulation sensation questionnaire * 
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 as detailed in the Informed Consent 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.  Someone will 
ask participants questions about this before they have the MRI. 
 
• There is not much room inside the MRI scanner.  Participants may be 
uncomfortable if they do not like to be in enclosed spaces ("claustrophobia").  
During the procedure, they 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 patients. Participants will be given 
earplugs to reduce this risk. 
 
 
• If an obvious abnormality is discovered during participants MRI scan, they will 
be informed about it by the research team, and will be provided with a copy of 

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their MRI scan. We will encourage participants 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.  
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 during participants initial study visit.  
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 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 
help during the study visit. 
Questionnaires. There is a risk that participants will find questions on the 
questionnaires uncomfortable to answer. They may skip any question they feel 
uncomfortable answering.  
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. If requested by the participant, multiple test days are possible.  
When being tested some people may develop anxiety. If these tests make a 
participant 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 them, 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 be 
rescheduled so that their participation in the current study does not overlap with their 
participation in the other study. 

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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, 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. The contact information will be securely stored during the 
event and immediately stored in the Woods Lab 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) Men and women; 2) Age: 65 to 89 years; 3) English speaking; 4) 
Physically mobile; 5) Working memory function between the 0-75th percentile 
determined by screening results on the POSIT Baseline Cognitive Training 
computerized tasks. 
Rationale: (1) The age range is selected to include a higher proportion of persons with 
possible concern about cognitive deficits (2) The language requirement will avoid 
difficulties with interpretation of cognitive results; (3) The mobility requirement is 
required because participants will need to be able to participate in neurocognitive 
testing and MRI testing at different locations; 4) The working memory function 
requirement is needed to avoid randomized groups from being biased by over-
representation of extremely high (e.g., super agers) working memory function in a 
particular group and to include a representative sample consistent with the “typical” 
cognitive aging profile in the US.  
Exclusion criteria: 1) Neurological disorders (e.g., dementia, stroke, seizures, 
traumatic brain injury). 2) Evidence of dementia (NACC UDS scores of 1.5 standard 
deviations below the mean for age, sex and education adjusted norms in a single 
cognitive domain on the task). 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., pregnancy, claustrophobia, metal implants that are 
contraindicated for MRI). 7) Physical impairment precluding motor response or lying still 
for 1 hr and inability to walk two blocks without stopping. 8) Certain prescription 
medications may possibly reduce effects otherwise induced by the tDCS stimulation 
protocol, and are listed on a Drug Exclusion List attached to the Appendices in 
Miscellaneous attachments of this study. 9) Hearing or vision deficits that will not allow 
for standardized cognitive training stimulation; ie colorblindness, inability to hear through 
headphones (with or without hearing aids), macular degeneration or other significant 
diseases that cause severe loss of vision.  If vision is corrected with lenses to 
appropriate levels, then participant will be eligible. 10) Left handedness, as those with 

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left-handedness have a higher percentage rate of atypical functional lateralization for 
brain functions, which would significantly interfere with interpretability of brain data. 11) 
Participants with precision tDCS dosage of >4.0mA required will be excluded due to 
limitations of tDCS device (maximum output of 4.0 mA). The maximum output of 4.0 mA 
reflects a technical limitation of the device design rather than a safety threshold.   
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 cognitive deficits; (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) 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.  
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. 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 data base will 
have participant identity information. No results will ever be reported in a personally 

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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.  
 
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 individuals (i.e., screening logs used to avoid 
approaching the same individual for study enrollment twice) will be removed 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 levels will be decreased to a comfortable 
level or will be stopped. In the event of a headache, stimulation will be decreased to a 
comfortable level (where the headache or nausea is no longer present) or will be 
stopped. All tDCS sessions will be administered and continually supervised 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 
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 

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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 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. FMRI procedures will be supervised by Dr. 
Woods. There is a medical technologist at the imaging site at all times to ensure 
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: 
A data and safety monitoring plan (DSMP) will be implemented to ensure the safety of 
all participants involved in the study and to ensure the validity and integrity of the data. 
The PI will be responsible for coordinating activities of the DSMP, including: arranging 
meetings and communications, and identifying and reviewing relevant participant 
materials. The data and safety information obtained on each study participant will be 
reviewed at weekly meetings. 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. 
Concerns that might dictate modification or termination of the study include: 

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• Participant safety 
• Outcome data 
• Data quality 
• Integrity 
• Intervention efficacy 
• Recruitment 
• Performance 
Both the PI and the study staff will review the study weekly and examine reports of 
adverse incidents and reports of study participant recruitment and follow-up. Throughout 
the course of the study, information regarding issues deemed critical to the study or to 
the safety of research participants will be provided to the PI and primary mentors. As a 
result of receiving this critical information, a meeting to discuss this information may be 
convened. Information deemed critical would include: 
• Serious and non-serious adverse events that may occur 
• Suspicion of scientific fraud or misconduct 
• Any other issues which may warrant protocol changes or modifications. 
Because this is an exploratory study with minimal risk associated with the proposed 
intervention and limited financial resources, there will not be an external data safety and 
monitoring board for this study. The research team, however, 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. 
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 identified discrepancies will be reviewed at these 
weekly 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. Woods’ neuroimaging laboratory within 
the Center for Cognitive Aging and Memory at UF. Imaging data will undergo several 
levels of processing, and all raw and processed data will be archived on a password-
protected server in password-protected folders and files. Only study staff will have 
access to these files. The self-report data will be entered using the Redcap Data Entry 
system. This system signals the user when an out-of-range value is entered. 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. 

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Location and logistics of data collection. Neurocognitive testing and training will be 
performed at the AMRIS/MBI UF facility. Several clinical research examination rooms 
are equipped and dedicated to neurocognitive and functional assessment, and contain 
all necessary computers and test materials. Neuroimaging will take place at the AMRIS 
facility of the McKnight Brain Institute. 
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. A file will 
be maintained that associates the participant’s name with that participant’s study 
identification number. This file will be kept in a locked cabinet separate from the study 
data 
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.  
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.  
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 

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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 and 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 monthly (and more 
frequently if needed) by the principal investigator. Progress reports, including participant 
recruitment, retention/attrition, and AEs will be reviewed. 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) will 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 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. 
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.  
In addition to the assessments conducted at in-person study visits, they 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 

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symptomatology, and other health related activities (i.e., physical activity), as well as 
general health status.  
Monitoring mental health and safety. At each assessment visit, participants will 
complete the BDI to assess for depressive symptom severity. Any participant who 
endorses clinical levels of any psychiatric disorder or who endorses suicidality will be 
referred to Dr. Cohen (a licensed 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. If a participant endorses suicidal thoughts or significant 
psychopathology, participants will be referred to Dr. Cohen for further evaluation. Based 
on this evaluation, he will recommend follow-up assessment and treatment appropriate 
to the situation including treatment at the Psychology and/or Psychiatry Clinics within 
Shands Hospital at the University of Florida. 
Adverse Event Reporting. An adverse event (AE) is defined as any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the intervention irrespective of whether it is considered 
related to the intervention.  
Non serious adverse events. Defined as conditions that may be unpleasant and 
bothersome to the participant that does not require discontinuing the study.  
Serious adverse events (SAEs). Defined as events that may be harmful to the 
participant and/or may be serious enough to warrant either temporary or permanent 
discontinuation of the study intervention, either because they are intolerable or because 
they are judged to be potentially harmful. All serious adverse events require immediate 
reporting and an assessment of the implications for the continuation of the study and/or 
modification of the consent form. The following are considered serious events: 
It is acute or life threatening; 
It results in prolonged, permanent or severe disability; 
It is another severe illness including worsening of a pre-existing condition, injury or 
accidents; 
It is an inpatient hospitalization or surgical procedure, or a treatment to prevent a 
serious event; 
It results in death; 
It is a clinically significant abnormal laboratory or diagnostic test. 

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Classification of AE severity. The principal investigator will evaluate adverse events for 
seriousness, expectedness, severity, and relationship to study intervention at each 
study visit. The primary mechanism for ensuring participant safety will be clinical 
observation of symptoms. The study will be conducted and supervised by trained study 
staff and will monitor potential adverse experiences and symptoms. During each visit, 
participants will log any health-related problems or symptoms they are experiencing. 
These sheets will be reviewed by study staff before allowing the participant to continue. 
Community health services will be contacted immediately if warranted by the 
participants’ symptoms. 
 
All adverse events (AEs) will also be categorized according to the likelihood that 
they are related to the study intervention. Specifically, they will be labeled either 
definitely, probably, possibly or unrelated to the study intervention. The classification of 
potential relationship to the intervention is shown in Table 3. 
 
Effective screening will exclude individuals who would be at increased medical 
risk as a result of participation in this research. FMRI contraindications, such as 
claustrophobia or some metal implants will be assessed by telephone screening and 
again on the day of the scan. Dr. Woods, who has completed MRI safety training and 
has over 10 years’ experience screening FMRI participants, will supervise these 
procedures. The RA who will conduct neuroimaging analyses will be trained in UF 
AMRIS safety procedures and will also be responsible insuring for participant safety. 
Adverse events, although unlikely, may occur as a result of neuroimaging. Such events 
will immediately be reported by Dr. Woods (PI) to the local IRB, with serious adverse 
events reported to both the IRB and NIH. 
SAE reporting. Serious adverse events (SAEs) that are unanticipated, serious, and 
possibly related to the study intervention will be reported within 24 hours of study’s 
knowledge of the SAE to the IRB in accordance with the regulatory requirements. 
Anticipated SAEs or those unrelated to the study intervention will be reported to the 
same individuals/entities in accordance with regulatory requirements. 
 
Minor events will be reported to the IRB at the time of annual review. Both the 
principal investigator and the study staff will review the study weekly and examine 
reports of adverse incidents and reports of study participant recruitment and follow-up. 
Throughout the course of the study, information regarding issues deemed critical to the 

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study or to the safety of research participants will be provided to the principal 
investigator and other study investigators as needed. As a result of receiving this critical 
information, a meeting to discuss this information may be convened. Information 
deemed critical would include: 
• serious and non-serious adverse events that may occur;  
• suspicion of scientific fraud or misconduct;  
• any other issues which may warrant protocol changes or modifications.  
Adverse event (AE) and serious adverse event (SAE) determination and monitoring will 
be achieved via administration of structured questionnaires. Standardized forms for 
referring and treating study participants who experience adverse events will be in place.  
Documentation of Training on Protection of Human Participants. All key personnel 
on the study have successfully completed good clinical practice training.  
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. All participants undergoing CT may benefit 
from these effects. Those participants randomly assigned to the active 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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