Effect of Noninvasive Electrical Brain Stimulation on Memory Performance at Different Times of Day in Younger and Older Adults
Phase: NA
Conditions: Effect of tDCS on Memory in Older and Younger Adults
Sponsor: University of Chicago

 
 
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BSTIM Protocol – Version 4 (December 13, 2023) 
  
 
 
 
 
 
 
Effect of Noninvasive Electrical Brain Stimulation on Memory Performance at Different Times of 
Day in Younger and Older Adults  
   
Study Principal Investigator:  
David A. Gallo, PhD, Professor, Department of 
Psychology University of Chicago  
Supported by: 
The National Institute on Aging  
1R21AG060444 : BRAIN STIMULATION AND TIME OF DAY IN COGNITIVE AGING  
Study Intervention Provided by:   
not applicable  
Sponsor of IND (IDE):   
not applicable  
  
 
 
Originally proposed DSMB protocol, with statistical analysis plan moved to Statistical Analysis File. 

 
 
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BSTIM: 
Effect of Noninvasive Electrical Brain Stimulation on Memory Performance at Different Times 
of Day in Younger and Older Adults  
Objectives   
We have recently found that tDCS has a larger impact on episodic memory in the morning, but 
given the mixed literature on tDCS, we aim here to (1) complete a reliable replication attempt 
of these published tDCS findings, (2) extend this time-of-day tDCS research in new 
directions, including aging, and (3) explore interesting, yet secondary, aging and memory 
questions within our non-tDCS (baseline data) data.   
  
 Aim 1: Determine the extent to which tDCS to left dorsolateral prefrontal cortex (or dlPFC) 
boosts recollection accuracy and working memory performance as a function of time-of-day in 
younger and older adults.  
  
Secondary: Assess the relationship between objectively measured sleep patterns and self-
reported morning-evening preferences on memory performance, and possible interactions with 
tDCS.  
  
Aim 2: Determine the extent that tDCS to dlPFC boosts information-specific processes 
compared to information-general cognitive control processes in younger and older adults. The 
cognitive tasks will experimentally pit information-specific (words, pictures) and cognitive 
control (easy, hard) to test dlPFC tDCS effects in each age group.   
  
Secondary: Determine the regional specificity of tDCS on task performance in younger adults, 
by comparing the impact of tDCS to left dlPFC and left parietal cortex (an active stimulation 
control site, as in Gray et al., 2015).  
  
Aim 3: Determine the extent to which a pre-post between-subjects tDCS design can improve 
the detection of stimulation effects, while also preserving the validity of the sham condition.   
 
Design and Outcomes   
50 Younger Adults will be randomly assigned to three between-subjects tDCS conditions (left 
prefrontal, sham, left parietal control, total YA n=150) and 50 cognitively normal older adults 
will be randomly assigned to two between-subject tDCS conditions (left prefrontal, sham, total 
OA n=100). Each participant will complete 3 sessions: orientation/baseline (no tDCS, time 
varies), AM tDCS, PM tDCS (counterbalancing the order of the AM and PM sessions). 
Primary outcome measures will be cognitive task performance (episodic recollection accuracy 
primary, working memory accuracy secondary) as a function of 3 key factors (age group, tDCS 

 
 
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condition, and time-of-day) and their interaction, and also as a function of secondary factors 
obtained from actigraphy sleep data, sleep diary/log data, and the Morningness-Eveningness 
Questionnaire (aka the Owl-Lark assessment).  
  
Interventions and Duration   
Morning testing sessions will be scheduled at 8 or 9 AM, afternoon testing sessions will be 
scheduled at 3 or 4 PM.  These times were chosen to be similar to those we used in our 
preliminary work that demonstrated time-of-day effects on tDCS in younger adults (9 am vs 1 
pm), except we have shifted the PM session to 3 or 4 PM to be more consistent with aging 
studies that have found AM and PM effects on episodic memory (May & Hasher, 2017; May et 
al., 1993; Intons-Peterson et al., 1998)  
  
Active tDCS will involve 20 minutes of continuous electrical stimulation (2.0 milliamperes, 
mA). Sham tDCS will involve 1 minute of stimulation at the start of the 20 minute period (i.e., 
30 s to gradually ramp up to 2.0 mA, and then 30 s to ramp down), and also 1 minute of 
stimulation at the end of the 20-minute period. As in our prior work, during stimulation 
participants are instructed to sit quietly while remaining awake in preparation for the upcoming 
memory test, but no further instructions are given.  
  
Standard Anodal Procedure. The tDCS technique that we use, modeled after the most 
effective techniques found in the literature (e.g., Nitsche et al., 2008), and aimed at targeting 
left  
prefrontal cortex (for recent electrical models of tDCS, see Opitz, Paulus, Will et al. 
NeuroImage 2015) involves 3 basic steps: (1) the anodal electrode (35 cm2) is placed on the 
scalp over left dlPFC (F3 using the 10-20 EEG system, which typically centers over posterior 
middle frontal gyrus BA 8/9, Herwig et al, 2003), and the cathodal electrode is placed over the 
contralateral supraorbital site, thereby maximizing anodal stimulation of dlPFC and 
surrounding areas; (2) while sitting quietly, the brain is stimulated with mild electrical current 
(2 milliamperes, mA, using gradual ramping) for a total time of 20 minutes (stimulation 
condition), or a few seconds of mild current with no stimulation during most of 20 minutes 
(sham condition); and (3) post-stimulation cognitive task are administered, measuring 
performance enhancements (stimulation > sham). We have found this procedure reliably boosts 
recollection accuracy for at least 25 minutes post-stimulation, and in the literature, dlPFC 
effects on working memory have lasted at least 30 minutes post-stimulation (Ohn et al., 2008). 
Note that the cathodal tDCS electrode has been used to interfere with cognition, but the current 
project focuses on the anodal-based cognitive enhancement technique.  
  
For tDCS, we will use a standard 1x1 tDCS Clinical Trials device (Soterix Medica, NY), 
specialized for double-blinding. Active stimulation will deliver 2 mA of current using 2 

 
 
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electrodes in 5 x 7 cm saline-dampened sponges. The anodal electrode is placed over areas F3 
(left dlPFC) or P5 (left parietal) according to the 10-20 EEG-system, with the cathodal 
electrode on the contralateral supraorbital region. To balance the design for blinding, each of 
the 2 different electrode placements in the active stimulation conditions will be evenly 
represented in the sham condition (younger adults only).  To rule out general arousal effects, 
participants are prompted to make an arousal rating immediately prior to tDCS and 
immediately following tDCS. (Our prior work found that tDCS did not affect arousal, 
compared to sham.)  
 
 
 
 
Sample Size and Population   
Younger adults – Frontal stimulation (n=50)  
Younger adults – Parietal stimulation (n=50)  
Younger adults – Sham (n=50; n=25 frontal placement, n=25 parietal placement)  
Older adults – Frontal stimulation (n=50)  
Older adults – Sham (n=50)  
  
  
 
 

 
 
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STUDY TEAM ROSTER 
Principal Investigator: 
David Gallo  
Department of Psychology  
University of Chicago  
5848 S University Ave  
Chicago IL 60637 773-702-
8829 dgallo@uchicago.edu  
Main responsibilities/Key roles: PI  
Co-Investigators: 
Gabriella Hirsch  
University of Chicago  
5848 S University Ave  
Chicago, IL 60637 805-570-
9165 gvhirsch@uchicago.edu  
Main responsibilities/Key roles: PhD student  
  
Study Coordinator : 
Taylor Chamberlain  
University of Chicago  
5848 S University Ave  
Chicago, IL 60637 443-840-
0043 
tchamberlain@uchicago.edu  
Main responsibilities/Key roles: Study Coordinator  
  
   
  
  
  
 
 
 
 
 
 
 
 

 
 
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1 STUDY OBJECTIVES  
1.1 
Primary Objective  
Test the extent to which tDCS to left prefrontal cortex (compared to sham) impacts different 
aspects of cognitive performance on different cognitive tasks as a function of age group 
(younger, older) and time of day (AM, PM).   
1.2 
Secondary Objectives  
Test the extent that sleep-related measures inform the primary objectives (above), evaluate the 
value of including the pre-tDCS baseline cognitive measures in the analyses, evaluate the 
regional specificity of tDCS effects in younger adults by including a left parietal control site. 
Also, secondary objectives will include interesting memory and aging questions, independent 
of tDCS, described below.  
2 BACKGROUND AND RATIONALE   
2.1        Background on Condition, Disease, or Other Primary Study Focus  
A better understanding of how tDCS impacts cognitive function in younger and older adults 
will have widespread impact. tDCS is the safest and most accessible, non-invasive brain 
stimulation technique available for testing causal links between different brain regions and 
functions, and also for attempting to improve and train cognitive abilities in older adults. By 
identifying key experimental factors that can improve the reliability and robustness of 
stimulation effects on cognitive performance in different age groups, this project should lead to 
the widespread adoption of these design features in future scientific and clinical applications. 
Moreover, we will test the extent that tDCS to dlPFC improves memory performance by 
boosting information-specific processes and/or cognitive control processes that operate across 
different types of information, thereby informing basic theories of how dlPFC contributes to 
memory in younger and older adults.  
2.2        Study Rationale  
Transcranial direct current stimulation (tDCS) to dorsolateral prefrontal cortex (dlPFC) has 
been shown to temporarily improve cognition in younger and older adults. Although the 
current spatial resolution is limited, the technique’s ability to improve cognition by selectively 
stimulating brain regions has significant potential to advance scientific studies of human 

 
 
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cognition. Recently, we have discovered that time-of-day is critical for finding tDCS effects on 
memory in younger adults, an overlooked factor that may be responsible for mixed results in 
past studies. Our results also indicate that prior tDCS studies have had too few participants to 
reliably find the kinds of tDCS effects that we have observed (see also Minarik et al., 2016). 
Motivated by these discoveries, the current project uses a rigorous and well-powered approach 
to determine the importance of time-of-day for detecting tDCS effects on memory in younger 
and older adults, populations that have been targeted in many prior tDCS studies but have 
different optimal times-of-day. We will use the same tDCS stimulation procedures that we have 
used in our prior work, which were based on common tDCS parameters for cognitive studies in 
humans and are noninvasive, minimal risk procedures.  
3 STUDY DESIGN  
● Study Design: Double-blind, sham-controlled, age group x time-of-day tDCS study, 
with secondary analyses on sleep data, within-subjects baseline, and left parietal 
(younger adults only)  
● Study Arms:  50 YA (active frontal), 50 YA (active parietal), 50 YA (sham: 1/2 
prefrontal, ½ parietal), 50 OA (active frontal), 50 OA (sham: all frontal)  
● Study Location: Gallo Memory Lab, Department of Psychology, University of 
Chicago, Hyde Park Campus.  
● Each participant ideally enrolled for 7 days (with flexibility up to 12 days), depending 
on scheduling constraints  
● Intervention: 20 minutes of tDCS to prefrontal or parietal scalp locations, once during 
the  
AM (8 or 9am) and once during the PM (3 or 4 pm)  
● Randomization and double-blinding separately for each age group  
4 SELECTION AND ENROLLMENT OF PARTICIPANTS   
Inclusion and Exclusion Criteria   
Participants must meet all the inclusion criteria to participate in this study, and candidates 
meeting any of the exclusion criteria will be excluded from study participation:  
  
4.1        Inclusion Criteria:  
● 
Right-handed (according to the Edinburgh Handedness Inventory)  
● 
Normal or corrected vision  
● 
Fluent in English (started learning by age 6)  

 
 
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Ability to understand and provide informed consent for study procedures, and to 
comply - with study procedures for the entire length of the study.  
● 
For individuals in the ‘younger adults’ group, must be between 18 and 30 years of age  
● 
For individuals in the ‘older adults’ group, must be between 60 and 75 years of age  
● 
For individuals in the ‘older adults’ group, a score of 23 or above on the Montreal  
Cognitive Assessment (out of 30, education-corrected) is required. This is to minimize  
the inclusion of suspected mild cognitive impairment (MCI) or dementia, targeting 
individuals that score in the normal range according to the recent meta-analysis of 
MoCA’s ability to differentiate normal aging from MCI in Carson et al. (2018, Int. J of 
Geriatric Psychiatry).  
● 
Performance above threshold on the episodic memory task during the baseline session. 
The threshold is defined as having a hit rate that is at least 5% greater than the false 
alarm rate, where hit rate is defined as the number of studied items identified as 
studied, divided by the total number of studied items, and false alarm rate is defined as 
the number of new items identified as studied, divided by the total number of new 
items. We don’t anticipate this threshold to exclude many, if any subjects.  
  
 4.2         Exclusion Criteria:  
● 
Neuropsychological conditions associated with cognitive decline or seizure  
● 
Cochlear implants or metal in the brain/skull (except titanium)  
● 
Psychoactive medications or psychotic diagnoses  
● 
History of excessive use (clinically treated) alcohol or narcotics  
● 
Hospitalization for head trauma (e.g. concussions) in the past 5 years  
● 
Individuals above a threshold score on an assessment of depression, specifically, a 
score of 10 or above on the PHQ-9 (Manea et al., 2012)  
● 
Risk of pregnancy  
● 
Low tolerance of skin irritation  
● 
Prior brain stimulation experience (self-report)  
  
4.3        Study Enrollment Procedures   
● Younger adults will be recruited from the University of Chicago (primarily students) and 
surrounding community, and older adults will be recruited from a database maintained by the 
Gallo lab, as well as newly recruited participants from the Chicago area using word-of-
mouth and advertisements (e.g., Chicago Tribune).   

 
 
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● Study coordinator will maintain a Screening Log including reasons for ineligibility and for 
non-participation of eligible candidates.  
● The Study Coordinator will recruit participants, and if they are eligible and wish to 
participate, use AM/PM Randomization  REDCap database to assign them to have their AM 
session first or their PM session first. The participant will then be scheduled for all 3 
sessions.  
● Participants will give informed consent for all 3 sessions during the baseline/study 
orientation day. All participants must consent for themselves. At this time they are 
considered enrolled.  
5 STUDY INTERVENTIONS  
5.1        Interventions, Administration, and Duration   
Standard tDCS will be used, with 20mA of electricity for 20 minutes during the active 
sessions. This is a minimal risk technique, with potential adverse effects including irritation, 
itching, pain or discomfort under the scalp electrodes.   
For tDCS administration we will use a 1x1 Transcranial Electrical Stimulation (tES) device for  
Clinical Trials purchased from Soterix Medical Inc. (NY, NY). The two stimulation parameters 
(stimulation, and sham) will be pre-programmed into the device by Soterix, using a series of 
codes that are provided to the PI. The PI will use these codes to develop the participant 
randomization scheme for each arm of the study, to achieve double-blinding (see Section 5.2, 
below). Prior to the start of the study, a random sampling of 20 of the factory-provided codes 
will be double-checked by the lab using a digital multimeter (500 codes will be provided by 
Soterix, the study will use 250).  
  
The University of Chicago IRB (Cheri Pettey, Director, SBS IRB) and the PI have determined 
that this NIH clinical trial is classified as a basic research study under FDA guidelines, and 
thus this study does not require FDA approval. The manufacturer of the tDCS device, Soterix, 
has an Abbreviated IDE for the device, but the current study will use the device for research 
purposes only and with minimal (nonsignificant) risk procedures that do not require FDA 
approval.  
5.2        Handling of Study Interventions   
The Study Coordinator will be responsible for collecting a large portion of the data, and they 
will not be privy to the stimulation/sham assignments of each participant. Instead, they will 
only be given access to a soterix stimulation code determined for each participant ahead of 
time to be inputted into the tDCS device at the time of testing. This code will be linked to 

 
 
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either a sham or stimulation testing session, ensuring complete double-blinding regardless of 
the experimenter.   
  
Double-blinding. All participants are informed that they will receive tDCS brain stimulation 
during the 20 m session, with different amounts of electricity and timing depending on the 
experimental condition, and also that the typical sensation of tingling or itchiness might 
habituate. This accurately describes the sensations in the sham condition, because stimulation 
is briefly presented, as well as the sensations in the stimulation condition, as participants do 
often habituate.    
 
Soterix Medical Inc. will create codes in advance for the tDCS device, which, when entered 
into the device, will deliver either active or sham stimulation. A subject will be randomly 
assigned to a code just before the first stimulation session, using REDCap’s randomization 
feature. None of the the study personnel will have access to the spreadsheet that links the codes 
to the active or sham condition. Philip Schumm and Diane Lauderdale will have access to this 
spreadsheet, and will complete the randomization setup in the REDCap databases.  
 
5.3        Concomitant Interventions  
See inclusion/exclusion criteria.  
5.4        Adherence Assessment   
Adherence to the study regimen is defined as participants completing all 3 testing sessions and 
returning the actigraphy watch. Primary analyses will include data only from participants 
completing all 3 sessions.   
  
  
 

 
 
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6 STUDY PROCEDURES  
6.1        Schedule of Evaluations  
  
 
Assessment  
  
Screening:  
ONLINE/ 
PHONE  
Baseline,  
Enrollment, 
Randomization:  
Visit 1 (Day 0)  
AM Visit  
PM Visit  
Safety Inclusion/Exclusion Criteria 
Screening Survey   
X  
   
   
   
Depression Inventory (PHQ-9)  
X  
   
   
   
Edinburgh Handedness Inventory  
X  
  
  
   
Morningness-Eveningness 
Questionnaire  
  
X  
  
  
Subject Information Form  
(Demographics, Medical History)  
  
X  
   
   
Arousal Rating  
  
X  
X  
X  
Substance Use Survey  
  
X  
X  
X  
Shipley Assessment (verbal only)  
  
X  
  
  
Sleep Diary  
  
X  
X  
X  
Post-tDCS Application Survey  
  
  
X  
 X  
Baseline Post-Rest Survey  
  
X  
  
  
Post-Experiment Survey  
   
  
X (if final 
session)  
X (if final 
session)  
Consent Form  
   
X  
  
  
Montreal Cognitive Assessment  
   
X  
  
  
Debrief Form  
  
  
X (if final 
session)  
X (if final 
session)  
Cognitive Tasks  
   
X  
X  
X  
Actigraphy  
  
X  
X  
X  
tDCS Stimulation (active or sham)  
  
  
X  
X  

 
 
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Adverse Events Questioning  
  
  
X  
X  
  
 
  
  
6.2        Description of Evaluations   
 
Cognitive Tasks:  
  
Episodic Memory Task. We will cross stimulus type (words vs. pictures) with a 
recollection difficulty manipulation (items studied once or twice), all within-subjects. 
For the picture study list, participants will study words followed by a corresponding 
picture of the object (half colored pictures, half line drawings). Participants will decide 
if each picture is high or low detail, thereby drawing attention to perceptual features. 
For the word study list, participants will see the names of common objects and will be 
prompted to make one of two semantic judgments (Made in a factory? Found in 
house?), thereby drawing attention to conceptual features. We will give two 
recollection tests alternating across mini-blocks to avoid order effects. On the picture 
test blocks, verbal labels for the studied pictures will be intermixed with non-studied 
items, and participants will make one of three response options (studied as color, line, 
or new) followed by a confidence judgment. The structure of the word test blocks will 
be similar, whereby participants will make one of three response options (studied with 
a factory judgment, a house judgment, or new) in addition to the confidence judgment. 
Within each test, the items studied in the two different picture formats (or semantic 
judgments) will be matched on familiarity, so that participants will need to use 
recollection to make source judgments. Although pictures are typically better 
recollected than words, we have found that discriminating between these two different 
picture formats (namely, color or line judgments during the picture test) and these two 
different semantic judgments (namely, factory or house judgments during the word 
test) can be matched on difficulty with the repetition manipulation (i.e., comparing 
once-presented pictures to repeated words, Sarfan et al., 2014), allowing us to 
disentangle material-specific effects from recollection difficulty. Our primary 
dependent variable (DV) will be source recollection accuracy (the proportion of studied 
items attributed to the correct source, minus the proportion of non-studied items 
incorrectly attributed to that source). During each experimental session, subjects will 
perform the episodic memory task followed by the working memory task (described 
below).  
  

 
 
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Working Memory Task. Similar to the episodic memory task, the working memory 
task will involve a stimulus manipulation (verbal vs. visuospatial working memory) as 
well as a difficulty manipulation, all manipulated within-subjects and across mini-
blocks to control for order effects. Specifically, we will use the N-back task with a 
verbal version (i.e., presenting the numbers 1-9 in a varied sequence) and a matched 
visuospatial version (i.e., presenting a colored square in one of 9 locations on a 3x3 
grid in a varied sequence). Based on neuroimaging work, both tasks rely on bilateral 
PFC regions, but the former relies more heavily on left PFC, and the latter more 
heavily on the right PFC (for meta-analysis, see Owen et al., 2005). Difficulty will be 
manipulated by varying the N in the N-back task into “easy” and “difficult” versions 
for both younger and older adults (1 and 2 back for older adults, 2 and 3 back for 
younger adults). Our primary DV will be proportion of targets correctly identified 
minus the proportion of lures incorrectly endorsed.  
  
6.2.1 
Screening Evaluation  
These evaluations occur to determine if the candidate is eligible for the study. Screening 
evaluations to determine eligibility must be completed within 3 months of study participation.  
  
Consenting Procedure  
The Study Coordinator will oversee the recruitment and screening procedures. Participants will 
have the option to complete the screening procedure via phone interview or an online 
questionnaire, as listed in the study advertisements. The screening procedure will start by 
obtaining informed consent for the screening procedures (verbal consent for phone, electronic 
for online), and then ask questions to verify that inclusion/exclusion factors are met, as well as 
describe the overall procedures of the study to determine eligibility and willingness.  
  
Signed informed consent for the 3-session experiment will be obtained in person, during the 
first session in the lab (orientation/baseline day).  Signed consent forms will be kept under lock 
and key in the Gallo lab.  
  
6.2.2 
Enrollment, Baseline, and/or Randomization  
Enrollment & Randomization  
  
Enrollment begins when the participant signs the informed consent form for the 3-session 
experiment, at the start of the first lab session (i.e., baseline/orientation day).   
  

 
 
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After successful screening, participants will be randomized to either the AM-session-first 
condition or to the PM-session-first condition using the AM/PM Randomization REDCap 
database. Just prior to the baseline session, the participant will be assigned to a cognitive task 
condition using the Task Condition Randomization REDCap database. Finally, just before the 
first tDCS session, the participant will be assigned to a Soterix stimulation code, and to an 
electrode placement (either PFC or parietal), using the Participation REDCap database.   
  
  
Baseline Assessments  
During baseline assessment participants will complete cognitive tasks, demographic 
information, and other forms (Table 6.1).   
  
Morningness-Eveningness Questionnaire (MEQ) online survey - Participants will take the 
MEQ, assessing AM and PM testing preferences, which is correlated with 
physiological measures of circadian rhythms and predicts time-of-day effects on 
cognitive tasks in younger and older adults (Horne & Ostberg, 1976; see May & 
Hasher, 2017). Younger adults are expected to express at least a mild preference for PM 
testing (approximately 70% of younger adults in our prior sample), and older adults at 
least a mild preference for AM testing (typically 75% of older adults, see Yoon et al., 
1999). (See Appendix).  
  
Actigraphy and Sleep Diary online survey - During the initial orientation session 
participants will be equipped with an actigraphy watch and instructions for this and the 
sleep diary, and these data will be collected over a minimum 7-day period. During this 
period, participants will return to the lab for 2 testing sessions (AM/PM, 
nonconsecutively), returning the actigraphy watch and sleep diary on the final testing 
session. These measures will be used to help interpret the differential time of day 
effects (AM vs PM) on cognitive functions that we predict in younger and older adults, 
as well as the predicted interaction with tDCS brain stimulation.  
  
Cognitive Tasks  computerized tasks - During the orientation session participants will 
take baseline cognitive tasks (without tDCS), thereby providing baseline measures for 
some of our analyses and also providing task-initiation practice during this baseline 
stage of the task, thereby minimizing the likelihood that such task-initiation effects 
would impact the subsequent AM/PM testing sessions (i.e., creating practice in the first 
part of the experiment in order to reduce such practice effects between the subsequent 
AM and PM testing sessions). See description above for more information.  
  

 
 
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Montreal Cognitive Assessment. paper/pencil test - We administer the Montreal Cognitive 
Assessment in order to exclude individuals that score outside the range for normal 
aging according to the recent meta-analysis of MoCA’s ability to differentiate normal 
aging from MCI in Carson et al. (2018, Int. J of Geriatric Psychiatry).  
  
Shipley Assessment (verbal only)   online survey - During the second visit only, 
participants are given the verbal portion of the Shipley to test cognitive ability.  
   
Substance Use Survey   online survey - Subjects will be asked not to consume more than 
twice the amount of caffeine and nicotine they normally consume 4 hours prior to each 
session, and not to consume more than twice the amount of alcohol they normally 
consume 24 hours prior to each session, and we have them record their substance use 
in this survey (See Appendix).  
  
Subject Information Form   online survey - Questions regarding demographic information 
and medical history.  
  
Baseline Post-Rest Survey   online survey - Participants are asked about what was on 
their mind during a rest period, to determine if some participants intentionally review 
studied items prior to the memory test.   
  
Arousal Rating    online survey - Participants are asked about their alertness level before 
the encoding portion of the cognitive task and after a rest period.   
  
6.2.3 
Follow-up Visits (AM and PM Visits)  
All participants will be enrolled in the baseline/orientation session, and they then will be 
assigned to active (or sham) tDCS for two follow-up experimental sessions, one in the AM and 
one in the PM.   
● The time between each session will be at least 48 hours (i.e., at least 1 day 
intervening), thereby ensuring at least 1 full day of actigraphy data collected 
outside the lab prior to each tDCS session.   
● The time between the baseline/orientation session and the final tDCS testing 
session should be no less than 7 days and no more than 12 days, thereby 
obtaining at least 7 days of actigraphy data and also providing some flexibility 
in the scheduling of the final session.  
  
Follow up Assessments  
Measures will include cognitive tasks, actigraphy, and the questionnaires listed in table 6.1.  

 
 
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Substance Use Survey  See description above. 
  
  
Arousal Rating  online survey - Participants are asked about their alertness level before 
the encoding portion of the cognitive task adn before and after tDCS stimulation.  
  
Post-tDCS Application Survey  online survey - Participants report sensations during tDCS 
stimulation as well as what was on their mind during the stimulation.  
Cognitive Tasks  computerized tasks - See description above.   
  
Adverse Events Questioning  verbal report - Participants are asked if they have 
experience any after the baseline session. Responses are recorded in the Adverse 
Events Survey (see List of Administrative Logs).  
 6.2.4        Completion/Final Evaluation The final experimental session will be the final     
evaluation, and at the end of this session participants will complete a Post-Experiment Survey
 
 and finally receive a debriefing.   
  
Post-Experiment Survey   online survey -  Participants report their sensations during the 
tDCS procedure, their expectations as to whether and how tDCS impacted 
performance, and also whether and how they believed they performed during the AM 
and the PM testing sessions.  
  
Debrief Sheet  paper info sheet - Participants are given an information sheet about the 
purpose of the study, which includes information about the stimulation and sham 
conditions (but not their own assignment), as well as hypotheses for AM and PM 
testing.  
 
The debriefing sheet also will include citations for further reading. (See Appendix).  
About Early Termination: Participants have the right to end their participation at any 
time. In addition, the PI may terminate participation if a participant is in obvious non-
compliance with the study procedures (e.g., responding randomly or sleeping during 
the cognitive task) or shows signs of moderate or severe adverse events associated with 
the study procedures (e.g., excessive discomfort with the tDCS electrodes).   
  

 
 
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7 SAFETY ASSESSMENTS   
Participant safety will be monitored once an individual is enrolled in the study. The most 
typical negative experiences associated with tDCS include discomfort, tingling, itching, or 
mild burning sensations associated with the electrode application to the skin and/or electrical 
current, as well as headache, fatigue, or transient skin redness. During tDCS participants will 
be asked to report any sensations that become intolerable, so that participation can cease, and 
the Post-tDCS Application Survey administered after each tDCS session will include questions 
on the severity of any uncomfortable experiences during the procedure.  
  
Participants might experience boredom, anxiety, or frustration during the cognitive tests. In 
these cases the researcher will attempt to minimize these risks by encouraging the participant 
and indicating that the tasks are designed to be difficult.  
7.1        Specification of Safety Parameters  
In over a decade of studies using tDCS, in people of different ages and psychological 
conditions, no significant adverse effects have been identified.   
  
In 2011, a review of the adverse effects of tDCS (Brunoni et al., 2011, International Journal of  
Neuropsychopharmacology) identified 209 studies assessing a wide variety of participants, 
including persons from potentially vulnerable populations. Of these 209, only 74 studies 
reported at least one adverse effect (35%), with 43 studies explicitly reporting no adverse 
effects (21%) and 92 studies not reporting the presence or absence of an adverse effect (44%). 
Considering only the 117 studies that explicitly reported the presence or absence of an adverse 
effect, the most common adverse effects reported in the active stimulation groups were itching 
(39%), tingling (22%), headache (14.8%), burning sensation (8.7%) and discomfort (10.4%), 
with no reports of serious adverse effects. Importantly, similar frequencies of each of these 
effects were reported in the non-stimulation sham (placebo) control group (differing by 6% at 
most, for itching), which also requires the presence of an electrode on the skin but no sustained 
electrical stimulation (or only brief stimulation for the first few seconds). Overall, there were 
no unexpected or severe adverse events in over 40 studies with more than 600 older adults 
regardless of cognitive or disease status, and we are unaware of any evidence for increased risk 
of serious adverse effects with aging subjects. A recent meta-analysis indicates that repeated 
sessions of tDCS, separated by 48 hours, should pose no greater risks than those associated 
with a single-session (Nikolin et al., 2018). For further details on the safety of tDCS in human 
trials, see Bikson et al, 2016, Brain Stimulation.   
The Actigraph device captures and records continuous mobility data related to real-world  
activity, mobility and sleep outcomes. There are no risks associated with the Actigraph device 
given it is considered completely noninvasive and comfortable. The experience on behalf of 

 
 
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the participant can be compared to that of a digital wristwatch. The actigraph watch captures 
and records continuous data related to mobility and sleep patterns. For more information on its 
uses and safety, refer to https://www.actigraphcorp.com/.   
  
Other risks are those associated with basic computer or paper tasks, including boredom, mild 
fatigue, test taking anxiety, or breach of confidentiality. The expected frequency of breach of 
confidentiality is never.  
  
7.2        Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters  
This study will only use one stimulation parameter that already is established as minimal risk, 
and highly tolerable for both younger and older adults.  After the tDCS sessions, participants 
will be asked to report their sensations  and rate their unease during the stimulation.  
7.3        Adverse Events and Serious Adverse Events   
Definitions: An adverse event (AE) is generally defined as any unfavorable and unintended 
diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease 
which either occurs during the study, having been absent at baseline, or if present at baseline, 
appears to worsen. Adverse events are to be recorded regardless of their relationship to the 
study intervention.  A serious adverse event (SAE) is generally defined as any untoward 
medical occurrence that results in death, is life threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant disability/incapacity, 
or is a congenital anomaly.  
During the second and third testing sessions, after the cognitive tasks, the participants will be 
asked to report any adverse events that have begun or worsened since the baseline session. 
They will also be asked explicitly describe sensations occurring during the tDCS stimulation 
(see Post-tDCS Application Survey in the appendix), some of which may qualify as adverse 
events. 
 The Study Coordinator will record adverse events reported by participants, and 
the extent that they appear to be related (or unrelated) to the study procedures in the Adverse 
Events Survey.  
7.4        Reporting Procedures  
All adverse experiences will be recorded in the Adverse Events Survey . If the event is 
classified as  a Serious Adverse Event, the PI will be notified immediately. The PI will then 
notify the NIA, the DSMB chair, as well as the IRB with in 24 hours, at which time they may 
ask for additional information.  

 
 
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AEs or SAEs that may occur during the study (regardless of their relationship to the study 
procedures) will submitted in routine reports to the DSMB, prior to DSMB conference calls.  
7.5        Follow-up for Adverse Events  
Any unresolved AE that is possibly related to the study procedures will result in halting the 
subject’s participation in the study. The study is minimal risk and no long-lasting adverse 
events are expected. Any AE that renders the participant ineligible to be in the study (as per the 
inclusion/exclusion criteria) will also be resolved by halting participation in the study.  
7.6        Safety Monitoring  
An NIA-appointed Data and Safety Monitoring Board will review the project, and adherence 
to the Data Safety and Monitoring Plan.  
8 INTERVENTION DISCONTINUATION   
Participates may withdraw voluntarily from participation in the study at any time and for any 
reason. Because the adverse events associated with tDCS are mild and transient, we will not 
continue to follow participants that withdraw from the study. Participants reporting headache 
will be given the option to rest in the lab until the situation resolves.   
  
Data from participants that discontinue without completing both experimental testing sessions 
will be replaced with a new participant assigned to the same condition.  
  
In the event that participation in the study is halted during or following tDCS, the participant 
will be asked to complete the Post-tDCS Application Survey and also will receive debriefing.  
9 STATISTICAL CONSIDERATIONS   
9.1        General Design Issues   
Overall design (from Precis section):  50 Younger Adults will be randomly assigned to three 
between-subjects tDCS conditions (left prefrontal, sham, left parietal control, total YA n=150) 
and 50 cognitively normal older adults will be randomly assigned to two between-subject 
tDCS conditions (left prefrontal, sham, total OA n=100). Each participant will complete 3 
sessions: orientation/baseline (no tDCS, time varies), AM tDCS, PM tDCS (counterbalancing 
the order of the AM and PM sessions). Primary outcome measures will be cognitive task 
performance (episodic recollection accuracy primary, working memory accuracy secondary) as 
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and also as a function of secondary factors obtained from actigraphy sleep data, sleep diary/log 
data, and the Morningness-Eveningness Questionnaire (aka the Owl-Lark assessment).  
  
Rationale for within-subjects AM and PM testing: Each participant will take both an AM and a 
PM testing session. Within-subjects designs are generally preferred over between-subject 
designs, because they reduce the impact of individual variability on performance that is 
unrelated to the AM/PM manipulation, thereby increasing the likelihood of detecting AM/PM 
effects. However, within-subject designs introduce the possibility of practice effects across 
sessions, but we will control for such order effects by counterbalancing the order of the AM 
and PM sessions across participants in each arm. Moreover, collecting a no-tDCS cognitive 
baseline for all participants (during the first session) will give all participants familiarity and 
practice with the cognitive tasks, thereby reducing the impact of such practice effects on the 
subsequent AM and PM tDCS/sham testing sessions.  
  
Rationale for between-subjects tDCS/Sham design: Our previous tDCS work suggests that, on 
average, participants in stimulation and sham conditions do report different kinds of 
sensations. To avoid cross-session learning effects, which would invalidate the sham condition, 
the experiments we propose here will manipulate tDCS between-subjects: Each participant will 
participate in an AM (8 or 9 AM) and PM (3 or 4 PM) testing session (within-subjects), and 
will be randomly assigned to the same tDCS condition in each session (left dlPFC or sham in 
older adults; left dlPFC, left parietal, or sham in younger adults), thereby avoiding any cross-
session learning effects from experiencing different tDCS conditions.   
  
Rationale for cognitive baseline measures: All participants will take a baseline version of the 
cognitive tasks (without tDCS) during the orientation session, serving as a no-tDCS baseline 
(i.e., the “pre” condition in a pre-post design). These cognitive baseline measures are included 
to assess Aim 3: Determine the extent that a pre-post between-subjects tDCS design can 
improve the detection of stimulation effects, while also preserving the validity of the sham 
condition. Our initial analyses will focus on the between-subjects comparisons described 
above, but the statistical power of the between-subjects design to detect group differences 
(stimulation vs sham) is likely limited by individual variability in task performance (unrelated 
to stimulation).  In an attempt to reduce the contribution of individual variability that is 
unrelated to stimulation, and thereby provide a more sensitive test of tDCS effects, we will 
conduct additional analyses that include the baseline performance for all participants as a 
covariate. The primary purpose of this measure is to assess the value of a pre-tDCS baseline in 
detecting tDCS effects, independent from potential time of day effects explored in the other 
aims. Thus, to minimize time constraints on the completion of the project, these orientation 

 
 
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session testing times (and baseline cognitive assessment) will be scheduled at the convenience 
of the participant and experimenter (i.e., baseline sessions can occur outside the AM and PM 
testing windows that are reserved for the tDCS/sham sessions).   
 
2       Sample Size and Randomization  
Power analysis: Our power analysis was based on our most recent and largest tDCS experiment 
with younger adults (Wong et al., in press, n = 30 per each between-subjects condition), which 
yielded a 12% difference in word test accuracy between sham (.23, SD=.21) and active tDCS 
(.35, SD = .21) in the 9 AM group, predicting that we would need 50 participants in each 
stimulation group in order to obtain a similar effect size (Cohen’s d = .57, or a medium effect 
size) with 80% power at p<.05 (2 tailed, calculated with G-Power, v. 3.1.9.3). We therefore 
plan to test 50 younger adults and 50 older adults in each stimulation condition in order to 
detect effects of this magnitude. These sample sizes are considerably larger than most (if not 
all) of the between-subjects tDCS experiments on episodic memory published as of 2017. A 
sample size of 50 per condition also should yield sufficient power to detect the 2x2 interaction 
between brain stimulation (between-subjects) and time-of-day (within-subjects) in each age 
group, if we assume a similar effect size (partial eta squared = .06) for the interaction between 
time-of-day and stimulation we had obtained in younger adults in Wong et al. (in press), and 
also a .25 correlation between the repeated measures during AM and PM (80% power, alpha = 
.05).  
9.2.1 
Treatment Assignment Procedures  
Younger adults will be randomly assigned to one of the three stimulation conditions (active 
frontal, active parietal, or sham: ½ frontal, ½ parietal), and older adults will be randomly 
assigned to one of the two stimulation conditions (active frontal, sham frontal).   
  
Phil  will keep the stimulation codes in a password protected Excel file, which will be shared 
with the DSMB. No other member of the research team will have access to the file.   
Planned breaking of the stimulation codes will occur when the 50 planned participants have 
been tested in each arm of the study, or until the study is terminated in consultation with the 
DSMB.  
The research team and DSMB will have full access to all other data collected throughout the 
study, in order to monitor the quality of the data and allow preliminary analyses of time-of-day 
effects, age group, and other variables (actigraphy, MEQ) on cognitive task performance, as 
well as the exploratory metamemory analysis of baseline cognitive task data (no tDCS).  

 
 
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9.3        Interim analyses and Stopping Rules  
No interim analysis of tDCS/sham differences is planned. We plan a mid-point analysis of the 
baseline cognitive task data (see Exploratory Metamemory Analysis), but this will not involve 
breaking the blinding codes (baseline data are not associated with tDCS). The PI, in 
consultation with the DSMB, will temporarily suspend enrollment in the tDCS portions of the 
study if serious questions arise about efficacy, safety, or poor study performance (e.g., slow 
accrual, high losses-to-follow-up, and poor quality control). In this event, study enrollment 
will only recommence if DSMB and the PI agree that the issue(s) has been resolved, and make 
a designation that the study should (a) continue per protocol, (b) proceed with caution, (c) be 
further investigated, (d) be discontinued, or (e) be modified and then proceed.  
  
Examples of findings that might trigger a safety review are the number of SAEs overall, the 
number of occurrences of a particular type of SAE, severe AEs/reactions, or increased 
frequency of events. Such findings are presented to the DSMB statistician to review the events 
by group to determine whether there are statistical as well as clinical concerns. The statistician 
reports their findings to a closed session of the DSMB or to the Safety Officer and/or NIA. The 
findings are used to determine what steps will be taken.   
9.4        Outcomes   
9.4.1 
Primary outcome   
Our primary dependent variable (DV) will be accuracy on the episodic memory and working 
memory tasks. These will be assessed in each of the 3 sessions (baseline no-tDCS, AM tDCS, 
PM tDCS).  See Section 6: Study Procedures.  
 
10 DATA COLLECTION AND QUALITY ASSURANCE  
10.1 Data Collection Forms   
Information will be collected for each participant by the Study Coordinator, or a research 
assistant under their immediate supervision.  For double-blinding, no member of the PI’s 
research team that will interact with participants will know the stimulation codes that 
differentiate active vs. sham tDCS.  The PI will generate this code list before the study is 
initiated, and then share it with the DSMB. The PI will not refer back to this code list until data 
collection is ended, and the PI will not administer study procedures to study participants. The 
research team will share de-identified data with the PI during the study, to troubleshoot or as 
needed, but no analysis of tDCS vs sham will be conducted until the end of the study. 
Maintaining confidentiality of participant records will be achieved by storing these records in 

 
 
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password protected excel files on a lab computer, backed-up on the University’s protected 
server, and also on external hard-drive in the lab by the Study Coordinator.   
  
  
1. Qualtrics Survey - Adverse events  
○ Contains information about any Adverse Events (both serious and non-serious). 
Data from this survey will be used to generate routine updates to the DSMB 
regarding adverse events. The survey is modeled off of the NIA templates for 
adverse event and serious adverse event logs.  
2. REDCap DB - AM/PM Randomization DB  
○ Enables participant assignment to the AM-session-first or PM-session-first 
condition, prior to the participant’s baseline session.  
3. REDCap DB  - Task Condition Randomization DB  
○ Enables participant assignment to one of 12 task varieties, during the 
participant’s baseline session.   
4. REDCap DB  - Participation DB  
○ Enables participant assignment to active or sham stimulation, and, if the 
participant is a younger adult, to either the dlPFC or parietal electrode 
placement. Will also contain information about each of the participant’s visits.  
5. Spreadsheet - OA Contact Log  
○ Contains information about older adults who have been contacted about 
participating in the study.  
6. Spreadsheet - Screening Log   
○ Contains information about participant eligibility based off the 
Inclusion/Exclusion Criteria Screening Survey.  
7. Paper log - Payment Log   
○ Contains the subject’s name and a place to sign to indicate payment was 
received.  
8. Spreadsheet - Blinding Key   
○ Links a Soterix stimulation code to either the active or sham condition. The 
study personnel will not have access to this file until the close of the study. Phil 
Schumm will maintain the key, and use it to setup the randomization scheme in 
the REDCap databases mentioned above.   
  

 
 
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10.2        Data Management   
● All Administrative Logs in the form of spreadsheets will be maintained in a secure Google 
Drive folder on UChicago’s GSuite, which will be periodically backed up to the Study 
Coordinator’s computer. Note: this excludes the Blinding Key which only Phil Schumm and 
Diane Lauderdale will have access to.  
● Study forms in paper/pencil format (see Description of Evaluations) will be kept in a 
locked file cabinet in the Gallo Memory Lab.  
● Electronic data from online surveys (see Description of Evaluations  ) will maintained on 
the  Study Coordinator’s Lab Computer for backup, which will be automatically backed-up 
on the University server. It will be shared with the research team and the DSMB upon 
request.  
● Electronic cognitive task data (raw and organized in Excel), blinded to tDCS condition 
(active, sham), will maintained on the  Study Coordinator’s Lab Computer, which will be 
automatically backed-up on the University server.  Additionally it will be uploaded to a 
private Open Science Framework project. It will be shared with the research team and the 
DSMB upon request.  
10.3      Quality Assurance   
10.3.1   Training  
The Study Coordinator will be trained in study procedures by the PI, and in tDCS procedures 
by the PIs current research team, who have conducted tDCS research in the lab.  
10.3.2  Quality Control Committee   
The DSMB will review certain blinded data at the midpoint, as described elsewhere, and at 
other times they might request.  
10.3.3 Metrics  
Quality control metrics for outcome measures will be finding the expected effects of age-
group (younger > older) on episodic memory (recollection) accuracy and working memory 
accuracy.  
Moreover, for each participant, we expect hits to be greater than false alarms on these tasks. 
These and other aspects of quality and compliance (study forms, actigraphy) will be 
monitored by the Study Coordinator and PI.  

 
 
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10.3.4 Protocol Deviations  
Protocol deviations will be reported to the PI by the Study Coordinator, and they will be 
documented by the Study Coordinator in the notes section of the Participation REDCap DB  
and made available for review by the DSMB.   
10.3.5 Monitoring  
The Study Coordinator, the PI, and the research team will work together to implement the 
data collection and monitoring procedures described here. They will conduct a pre-review of 
all appropriate materials prior to each DSMB meeting.  
11 PARTICIPANT RIGHTS AND CONFIDENTIALITY   
11.1        Institutional Review Board (IRB) Review  
This protocol and the informed consent documents and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for oversight of the study.   
11.2         Informed Consent Forms  
A signed consent form (younger or older adult versions) will be obtained from each participant. 
All participants must be able to consent for themselves. The consent form will describe the 
purpose of the study, the procedures to be followed, and the risks and benefits of participation. 
A copy will be given to each participant and this fact will be documented in the participant’s 
record.   
11.3        Participant Confidentiality   
No medical records will be accessed or created as part of this study, and as such, no HIPAA 
regulated data will be collected in this study.  
  
Any data, specimens, forms, reports, and other records that leave the site will be identified only 
by a Participant ID to maintain confidentiality.  All paper records will be kept in a locked file 
cabinet. Information will not be released without written permission of the participant, except 
as necessary for monitoring by IRB, the FDA, the NIA, and the OHRP.  
11.4        Study Discontinuation   
The study may be discontinued at any time by the IRB, the NIA, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are protected.   

 
 
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12 ETHICAL CONSIDERATIONS  
The guiding ethical principles being followed by the study are those required by The 
University of Chicago SSD IRB as well as those provided by the NIA.  
13 COMMITTEES  
The Data Safety and Monitoring Board will be responsible for the following:  
● Review the research protocol, informed consent documents and plans for data safety 
and monitoring as defined in this document;  
● Recommend subject recruitment be initiated after receipt of a satisfactory protocol;  
● Evaluate the progress of the trial, including periodic assessments of data quality and 
timeliness, recruitment, accrual and retention, participant risk versus benefit, 
performance of the trial sites, and other factors that can affect study outcome;  
● Review study performance, make recommendations and assist in the resolution of 
problems reported by the Principal Investigator;  
● Report to NIA on the safety and  progress of the trial;  
14 PUBLICATION OF RESEARCH FINDINGS  
Any presentation, abstract, or manuscript will be made available for review by the sponsor and 
the NIA prior to submission.  
  
 
 
 
 
 
 
 
 
 
 

 
 
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