Application of Transcranial Alternating Current Stimulation for Modulation of Sleep and Cognitive Performance
Phase: NA
Conditions: Mild Cognitive Impairment
Sponsor: University of Colorado, Denver

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Official Title: 
Application of Transcranial Alternating Current Stimulation for Modulation of Sleep and Cognitive 
Performance 
NCT03112902 
June 4th, 2019 
 

2 
 
TITLE: Application of transcranial alternating current stimulation for modulation of sleep and cognitive performance.  
 
PROTOCOL VERSION DATE:   04June2019 
 
COMIRB# 16-1875 
 
PRINCIPAL INVESTIGATOR (PI): 
Name: Brice McConnell, MD, PhD 
Address: Department of Neurology 
University of Colorado School of Medicine 
Academic Office 1, Mail Stop B-185 
12631 East 17th Avenue 
Aurora CO 80045 
Telephone: (303) 724-2080 
Email: Brice.McConnell@ucdenver.edu 
 
 
 
I.             OBJECTIVES 
Impaired sleep, in particular fragmented sleep and loss of slow wave activity (SWA) during non-
rapid-eye-movement (NREM) sleep, is known to occur during the physiologic process of aging (1-3). 
Disrupted sleep is particularly pronounced among patients with diagnoses of Mild Cognitive 
Impairment (MCI) and those who progress to Alzheimer’s Disease (AD), and is associated with 
worsening of cognitive impairment with progression of brain pathophysiology (4, 5).  Recent advances 
in non-invasive neuromodulation via transcranial electric stimulation (tES) offer a chance for immediate 
impact on sleep and cognition, with a safe and readily available technology (6, 7). Neurophysiologic 
mechanisms of tES have been elucidated in both animal and human brains, and include local changes in 
cortical excitability (8, 9) and synaptic plasticity (10), with global modulation of cortical networks and 
functional connectivity (11, 12). Transcranial alternating current stimulation (tACS), a type of tES, has 
been demonstrated to modulate sleep architecture and cognitive performance when applied during 
SWA (7, 13). Thus, we propose that application of tACS has the potential to improve sleep quality 
among patients with MCI, and to additionally improve measures of cognitive performance, mood, and 
quality of life.  
 
Hypotheses and Specific Aims:  The purpose of this research is to investigate the utility of transcranial 
alternating current stimulation (tACS) to modulate sleep, cognition, mood, and quality of life among 
normal healthy adults, older adults, as well as individuals with mild cognitive impairment (MCI). We will 
do this with the following Specific Aims: 
 
 
1). Optimize tACS parameters for duration, intensity and frequencies via utilization of EEG data 
recorded during tACS stimulation. 
2). Determine whether recording artifacts introduced by tACS can confidently be removed from 
EEG signals. 
 
3). Determine effects of tACS delivered with nested frequencies(multi-frequency signal) vs single 
frequency tACS, with regard to intrinsic EEG signal, for modulation of SWA coherence and power, 
as recorded in our overnight EEG sleep data. 
 
4). Determine the cumulative effects of tACS delivered in multiple, consecutive nights on 
underlying EEG signals, sleep architecture, sleep quality and cognitive function among  patients 
with MCI. 

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5). Determine if tACS is a viable treatment for disturbances of sleep and cognitive performance 
among patients with MCI. 
 
6). Generate pilot data and manuscripts to support applications for larger randomized placebo-
controlled clinical trials. 
We hypothesize that through multiple and consecutive sessions, there are cumulative effects 
of tACS on sleep architecture, with subsequent impacts on cognitive performance, mood and quality of 
life among normal health adults, older adults, as well as individuals with MCI.  
 
II.            BACKGROUND AND SIGNIFICANCE 
 
Transcranial alternating current stimulation (tACS) is a form of transcranial electrical stimulation 
(tES), similar to transcranial direct current stimulation (tDCS), each of which utilizes scalp electrodes to 
deliver current at low amperage through brain cortex. In the case the tACS this current is set to alternate in 
a specific frequency (14). This transcranial current flow has been demonstrated to alter cellular membrane 
potentials, with subsequent alteration of cortical excitability and synaptic potentiation (10). The use of tES 
in human trials has increased markedly within the last 15 years, and to date hundreds of trials with 
thousands of subjects have been reported without any serious side effects (10, 15). The benefits of tES 
have been demonstrated in treating the cognitive symptoms of many neurological illnesses including 
Alzheimer’s disease, Parkinson’s disease, stroke, depression and epilepsy; notably with exceptional 
tolerability and without any major safety concerns reported (16-22). 
Unique to tACS is the ability to entrain underlying EEG rhythms with subsequent effects on spectral 
power and coherence of specific EEG frequencies (23). tACS has been demonstrated to modulate multiple 
domains of cognition and underlying brain networks, in a mechanism that is dependent on both frequency 
and location of cortical stimulation sites (reviewed in (24)). With respect to sleep modulation, tACS has 
been demonstrated to enhance slow wave sleep duration and quality in healthy adults, with subsequent 
improvement of cognitive performance in memory encoding (7, 13, 25). The use of tACS for such studies 
has until now relied on conventional sleep lab polysomnography for assessment of EEG and delivery of 
tACS. Recent innovations in EEG and tES technology, however, have now enabled both tES studies (26, 27), 
and EEG sleep studies (28) to be performed unsupervised in an at-home protocol. Our proposed study will 
utilize at-home tACS with simultaneous EEG monitoring to demonstrate feasibility in treating and assessing 
sleep impairment and accompanying cognitive impairment. Data and manuscripts from this work will be 
used to support applications for funding larger scale studies using remote treatment and assessment, and 
thus provide a paradigm which is more feasible to translate and implement in clinical settings.  
Sleep impairment is common among patients with MCI and AD, and has been associated with 
worsening cognitive function and progression of the neurodegenerative process (reviewed in (29)). The 
pathological process of Aβ and tau accumulation has been associated with disruption of normal sleep 
physiology (4, 30, 31), and has been more specifically linked with the loss of SWA during NREM that is the 
hallmark of disease progression in MCI and AD (32). The process of memory consolidation occurs during 
SWA, and the loss of SWA in the context of disrupted sleep physiology has been demonstrated to produce 
symptoms of cognitive impairment (3, 32, 33). Further, a causal relationship between disruption of sleep 
and progression of neurodegenerative process has been demonstrated in animal models of AD (34, 35), 
and it has been suggested that a bi-directional relationship exists between sleep disruption and worsening 
AD pathology, with one of the functions of sleep being to clear toxic compounds from the brain  (reviewed 
in (36)). Thus, targeted interventions to improve sleep physiology offer opportunities for clinical 
intervention, which may not only treat symptoms of cognitive impairment, but may also slow or reverse 
the progression of neurodegeneration from MCI to AD.    
Our objectives are to assess the effects of tACS on sleep architecture in EEG recording, as well as 
effects on sleep quality and cognitive function, for the purpose of developing large scale, randomized, 
placebo-controlled clinical trials. We propose that this technology is fundamentally safe, and relatively 
cost effective. Demonstration of successful tACS pilot studies will allow for development of subsequent 
studies with broad application to studies of brain and sleep neurophysiology, as well as to more rapid 

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development of therapeutics for treatment of patients with neurodegenerative disease including MCI 
and AD and potentially neuroprotective trials. 
 
III.          PRELIMINARY STUDIES 
The PI has assisted both planning and execution of tDCS and transcranial magnetic stimulation 
(TMS) experiments with his primary mentor. The mentor has significant experience in the application of 
TMS, has ongoing tDCS experiments (COMIRB 15-1035), and has completed training in the safety and 
use of tDCS in healthy adults and clinical populations at the Berenson-Allen Center for Noninvasive Brain 
Stimulation (Harvard Medical School) and has trained numerous graduate students and clinicians in the 
safe application of noninvasive brain stimulation in clinical and research contexts. 
 
IV.          RESEARCH STUDY DESIGN 
 
1. Optimization of tACS settings during sleep: In this branch of our study we will optimize our tACS 
delivery in normal healthy research subjects by assessing response to EEG signal during stimulation. 
Recent developments in tACS technique allow for analysis of data acquired during tACS,(37) and this 
branch of our study will utilize this novel capability to determine optimal tACS stimulation intensity, 
duration, and frequencies for enhancement of slow wave sleep. This will be a single night tACS treatment, 
and multiple variables of tACS stimulation (different intensities, durations, and frequencies) will be 
applied for each subject. The outcome measures will be slow wave activity power, as well as 
synchronization of EEG signals in our recordings before, during and after tACS. 
The subjects will initially be assigned to receive tACS with frequency, intensity and duration 
parameters in ranges similar to published trials utilizing tACS during sleep (0.75 Hz, five minutes duration, 
0.318 mA/cm2) (7, 25). Each of these tACS variables will be stepwise modulated, with multiple sets of 
parameters used sequentially for each subject night of sleep.  EEG data will be analyzed for each 
stimulation condition to determine optimal response to tACS with regard to frequencies, intensity, and 
duration. Sequential subjects will receive iterations of optimization to allow for refinement of tACS 
response in EEG recorded data. We predict that measurable changes in EEG slow wave power, measured 
between 0.5-2 Hz, can be determined within single subjects via processing EEG data obtained during 
stimulation. This proposal seeks to enroll up to 52 subjects to allow for multiple cycles of optimization and 
repetition of parameters across multiple individuals.  Optimal tACS parameters will then be applied for 
subsequent steps of the experiments outlined below.  
 
2. Optimization of tACS and EEG recording settings while awake: In this branch of our study we will 
optimize our tACS delivery and EEG recording parameters during the awake state in normal healthy 
research subjects. The ability to record and analyze EEG signals during tACS requires successful removal 
of recording artifacts from the EEG signals. In this branch of the study we will record EEG in the MEG 
laboratory setting while subjects are awake to assist optimization of EEG recording and artifact removal.  
The subjects will be assigned to receive tACS with frequency, intensity and duration parameters in 
ranges similar to our sleep optimization steps. The tACS variables will be stepwise modulated, with 
multiple sets of parameters used sequentially for each subject while subjects are awake.  EEG data will 
be recorded with subjects in rest-state, and EEG artifacts will be introduced into the recording 
electrodes to assist in examination of artifacts that are encountered with application of tACS. We 
predict that tACS artifacts can be successfully removed from EEG recordings with a high degree of 
confidence with our optimized recording and stimulating techniques. 
This proposal seeks to enroll up to 15 subjects to allow for multiple cycles of optimization and 
repetition of parameters across multiple individuals.  
3. Assessment of multi-frequency nesting effects in tACS among Healthy 18-50 subjects: In this 
branch of our study we will test healthy 18-50 year old research subjects’ response to tACS applied 
during NREM sleep, with addition of frequency nesting in multiple frequencies which recapitulate 

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intrinsic sleep EEG signals.  Our outcomes will include EEG data, cognitive performance, and assessment 
of sleep quality.  This will be a randomized-controlled cross-over trial with three study arms: a tACS 
treatment group nesting, a tACS single frequency treatment group, and a sham treatment group.  
The subjects will be assigned to one of three treatment groups (tACS nested, tACS single frequency, 
or sham) using block randomization. Computer-generated randomization will place each subject into 
one of the study groups initially, then cross each subject the each other condition subsequent sessions. 
The primary outcome measure is induced EEG power of slow wave sleep of 0.5-2 Hz measured 
immediately before and after each train of stimulation.  To detect a significant change (p<0.05) of EEG 
power increase ≥ 20% above sham, with a power of 0.80, a sample size of 15 subjects will be necessary, 
based on effect sizes from prior studies (7). Subjects will receive 1 session for each stimulation type, in a 
cross-over design with at least 1 week between each stimulation condition for wash-out. This will total 
to 3 sessions for each subject, with a total of 45 sessions for all subjects. Subjects will have up to 24 
weeks to complete all study sessions and complete the trial. The proposed study seeks to enroll 30 
participants to account for participants that may fail our screening criteria, have unusable data or drop-
out of the study before completion. Secondary outcomes will include analysis of slow wave EEG 
coherence, sleep spindle signal, duration of slow wave sleep, total duration of sleep, word-paired 
associates task and finger tapping task (7, 25),  as well as subjective sleep quality reported on the 
Consensus Sleep Diary and Pittsburgh Sleep Quality Index (38, 39). Data collection for this study is 
expected to take 6 months. 
 
4. Assessment of tACS in Older Adult Subjects: In this branch of our study, we will test older adults 
for response to tACS applied during NREM sleep, with outcomes of EEG data, cognitive performance 
assessments, as well as assessment of sleep quality, mood, and quality of life measures.  In addition, 
subjects will be screened for decisional capacity via the UCSD Brief Assessment of Capacity to Consent 
(UBACC), and subjects who are found to have impaired capacity will require a legally authorized 
representative for consent (40). 
In this branch of our study we will test older adults’ response to tACS applied during NREM sleep, 
with addition of frequency nesting in multiple frequencies which recapitulate intrinsic sleep EEG signals.  
Nested tACS will be applied in-phase in reference to underlying EEG signal using closed-loop stimulation.  
Our outcomes will include EEG data, cognitive performance, and assessment of sleep quality.  This will 
be a randomized-controlled cross-over trial with two study arms: a tACS treatment group nesting, , and a 
sham treatment group. Additionally, prior to the two treatment arms, subjects will undergo an 
adaptation night which gives them the chance to practice using and sleeping with the equipment. There 
will be no tACS during the adaptation night but EEG will be recorded. Subjects can begin the treatment 
arms between three days and three weeks after completing the adaptation night.   
The subjects will be assigned to one of two treatment groups (tACS nested , or sham) using block 
randomization. Computer-generated randomization will place each subject into one of the study groups 
initially, then cross each subject the each other condition for subsequent sessions. The primary outcome 
measure is induced EEG power of slow wave sleep of 0.5-2 Hz measured immediately before and after 
each train of stimulation.  To detect a significant change (p<0.05) of EEG power increase ≥ 20% above 
sham, with a power of 0.80, a sample size of 15 subjects will be necessary, based on effect sizes from 
prior studies (7).  Subjects will receive 1 session for each stimulation type, in a cross-over design with at 
least 1 week between each stimulation condition for wash-out. This will total to 2 sessions for each 
subject, with a total of 30 sessions for all subjects. Subjects will have up to 24 weeks to complete all 
study sessions and complete the trial. The proposed study seeks to enroll 35 participants to account for 
participants that may fail our screening criteria, have unusable data or drop-out of the study before 
completion. Subjects will also be required to have a study partner assist them at home during the 
adaptation night and treatment sessions. We are NOT collecting any information about the study 
partner, they are simply required to assist the subjects.  Secondary outcomes will include analysis of 
slow wave EEG coherence, sleep spindle signal, duration of slow wave sleep, total duration of sleep, 
word-paired associates task and finger tapping task (7, 25),  as well as subjective sleep quality reported 

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on the Consensus Sleep Diary and Pittsburgh Sleep Quality Index (38, 39). Data collection for this study 
is expected to take 6 months. 
 
 
5. Assessment of tACS in MCI Subjects: In this branch of our study, we will test individuals with MCI 
for response to tACS applied during NREM sleep, with outcomes of EEG data, cognitive performance 
assessments, as well as assessment of sleep quality, mood, and quality of life measures.  In addition, 
subjects will be screened for decisional capacity via the UCSD Brief Assessment of Capacity to Consent 
(UBACC), and subjects who are found to have impaired capacity will require a legally authorized 
representative for consent (40). 
This will be a randomized-controlled trial with two study arms: a tACS treatment phase and a sham 
treatment phase. The subjects will be assigned to one of two treatment groups (tACS vs sham) in a 1:1 
ratio using block randomization. Stimulation will be applied in-phase, single frequency or nested, if 
indicated based on the results of experiments 1 and 2. Computer-generated randomization will place 
each subject into one of the study groups. The primary outcome measured is EEG power of slow wave 
sleep of 0.5-2 Hz, measured immediately before and after each train of stimulation.  To detect a 
significant change (p<0.05) of EEG power increase ≥ 20% above sham, with a power of 0.80, a sample 
size of 30 subjects will be necessary. Subjects will receive either stimulation type, tACS or sham, each 
night for the one week study period, for up to 7 stimulation sessions pending results of Experiment 2. 
Subjects will have up to 24 weeks to complete all study sessions and complete the trial. The proposed 
study seeks to enroll 35 participants to account for participants that may fail our screening criteria, have 
unusable data or drop-out of the study before completion.  
Secondary outcomes will include analysis of slow wave EEG coherence, slow and fast spindle 
activity, duration of slow wave sleep, total duration of sleep, and subjective sleep quality reported on 
the Consensus Sleep Diary (CSD), Pittsburgh Sleep Quality Index (PSQI), mood assessment by the 
Hospital Anxiety and Depression Scale (HADS), overall function in the Clinical Global Impression of 
Change (CGIC).  
 
Consensus Sleep Diary (CSD) 
The CSD is a sleep journal instrument that is designed to measure sleep and has been validated for 
intervention trials in insomnia (38, 41).  
 
Word Paired-Associate Task 
Our computerized paired-associate task consists of 48 semantically related words selected from a 
normative database with assessment of memory encoding on recollection performance (25, 42) 
 
Finger Tapping Task 
This is a finger sequence tapping task of procedural memory.  Subjects repeatedly finger-tap 
with their non-dominant hand a five-element sequence presented on a computer monitor, e.g. 
4-2-3-1-4, as fast and accurately as possible on a key board (7). 
 
Pittsburgh Sleep Quality Index (PSQI) 
This is a 10 question questionnaire consisting of questions related to usual sleep habits (39).  
 
The Hospital Anxiety and Depression Scale (HADS) 
The HADS is a 14 item self-assessment scale for rapid detection of anxiety and depression (43, 44).  
 
Clinical Global Impression of change (CGIC; for patient, caregiver and clinician)  
The CGIC is a three question assessment that consists of global measures to score severity of illness, 
global improvement, and efficacy index (45). 
 

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V. 
FUNDING 
 
 
The American Academy of Neurology and Rocky Mountain Alzheimer’s Disease Center are paying for 
this study.  
 
VI. 
ABOUT THE SUBJECTS 
 
Subject Population(s) 
Number to be enrolled 
Optimization-Asleep 
52 
Optimization-Wake 
15 
Healthy 18-50 Year Olds 
30 
Older Adult Subjects 
35 
MCI subjects 
35 
 
Optimization-Asleep: 
Inclusion Criteria- The subject population will be individuals between the ages of 18-70 who are 
fluent in English 
Exclusion Criteria-  
• 
brain tumors  
• 
skull defects  
• 
epilepsy  
• 
metal implants/devices above the neck 
• 
eczema or sensitive skin 
• 
severe insomnia that interferes with subject’s ability to sleep 
• 
currently taking sedatives and/or sleeping medications 
• 
sleep apnea that requires CPAP 
• 
REM-sleep behavior disorder  
• 
currently pregnant or trying to become pregnant during the study period 
• 
diagnosis of cognitive impairment.  
 
Optimization-Wake: 
Inclusion Criteria- The subject population will be individuals between the ages of 18-65 who are 
fluent in English 
Exclusion Criteria-  
• 
brain tumors  
• 
skull defects  
• 
epilepsy  
• 
metal implants/devices above the neck 
• 
eczema or sensitive skin 
• 
severe insomnia that limits ability to sleep 
• 
currently taking sedatives and/or sleeping medications 
• 
sleep apnea that requires CPAP 
• 
REM-sleep behavior disorder  
• 
currently pregnant or trying to become pregnant during the study period 
• 
diagnosis of cognitive impairment.  
 

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Healthy 18-50 year olds:  
Inclusion Criteria- The subject population will be individuals between the ages of 18-50 who are 
native English speakers 
Exclusion Criteria-  
• 
brain tumors  
• 
skull defects  
• 
epilepsy  
• 
metal implants/devices above the neck 
• 
eczema or sensitive skin 
• 
severe insomnia that limits ability to sleep at night 
• 
currently taking sedatives and/or sleeping medications 
• 
sleep apnea that requires CPAP 
• 
REM-sleep behavior disorder  
• 
currently pregnant or trying to become pregnant during the study period 
• 
diagnosis of cognitive impairment.  
 
Older adult subjects:  
Inclusion Criteria- The subject population will be individuals between the ages of 51-85 who are 
native English speakers. We will further require older adult subjects to enroll in the study with a 
study partner to help them with the technological aspects of applying equipment and performing 
home-based cognitive assessments.  
Exclusion Criteria-  
• 
brain tumors  
• 
skull defects  
• 
epilepsy  
• 
metal implants/devices above the neck 
• 
eczema or sensitive skin 
• 
severe insomnia that limits ability to sleep at night 
• 
currently taking sedatives and/or sleeping medications 
• 
sleep apnea that requires CPAP 
• 
REM-sleep behavior disorder  
• 
currently pregnant or trying to become pregnant during the study period 
• 
diagnosis of cognitive impairment.  
 
MCI subjects:  
Inclusion Criteria- The subject population will be individuals between the ages of 45-90 who meet 
clinical criteria for diagnosis of amnestic MCI and are native English speakers. We will further require 
MCI patients enroll in the study with a study partner to help them with technological aspects of 
applying equipment and performing home-based cognitive assessments. 
Exclusion Criteria-  
• 
brain tumors  
• 
skull defects  
• 
epilepsy  
• 
metal implants/devices above the neck 
• 
eczema or sensitive skin 
• 
severe insomnia that limits ability to sleep at night 
• 
currently taking sedatives and/or sleeping medications 
• 
sleep apnea that requires CPAP 
• 
REM-sleep behavior disorder  
• 
currently pregnant or trying to become pregnant during the study period 

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VII.         VULNERABLE POPULATIONS 
MCI individuals are considered a vulnerable population due to their cognitive impairment. They are the 
subject of this research study, and thus MCI individuals must be included. Subjects with diagnosis of MCI 
will be screened for decisional capacity via the UCSD Brief Assessment of Capacity to Consent (UBACC), 
and subjects who are found to have impaired capacity will require a legally authorized representative for 
consent (40). 
 
 
VIII.       RECRUITMENT METHODS 
 
Recruitment of subjects will be done through e-mail notifications and through paper flyers placed in 
elevators and on bulletin boards throughout Anschutz Medical Campus. Additionally, community 
outreach will be conducted through paper flyers, Rocky Mountain Alzheimer’s Disease Center 
community newsletters, and/ or email notifications. Flyers will direct participants to contact Nicola 
Haakonsen (Department of Neurology recruitment specialist) via email or telephone if they are 
interested and meet the inclusion and exclusion criteria. Pre-screening will be done via phone or email 
correspondence and will be determined by verifying that they satisfy the eligibility criteria. At this time, 
we will inform the subjects that they cannot consume alcoholic, caffeinated or nicotine products during 
the nighttime portion of the study period. 
 
List recruitment methods/materials and attach a copy of each in eRA 
 
1.   Recruitment flyer 
 
IX.          COMPENSATION 
Subjects will be paid $25 per home visit (or $25 per awake optimization visit) to participate in this 
study. Maximum payment amounts for each study arm are listed below.  
Sleep Optimization= $25 
Awake Optimization= $25 
Healthy 18-50= $75 
Older Adults= $75 
MCI= $175 
 
X.            CONSENT PROCESS 
Consent will be gathered from the subjects prior to the start of the study testing night, in the MEG 
facility of Building 500. Participants will be walked through the form with the experimenter upon 
arrival. All questions from the participant will be answered by the experimenter at this time. 
Additionally, participants will be provided with a copy of the consent form to keep for their records. 
 
XI.          PROCESS TO DOCUMENT CONSENT IN WRITING 
Written consent will be obtained and a copy of the form will be given to the study participant. Since 
English as a primary language is an inclusion criteria, consent forms will only be presented in English. 
 
XII.         PROCEDURES 
 
 
1. tACS FREQUENCY, INTENSITY AND DURATION OPTIMIZATION EXPERIMENTS    
 
INITIAL VISIT 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 

10 
 
Gather informed consent 
Gather consent 
15 minutes 
EEG/tACS Equipment Trial 
Teach subjects proper equipment 
use/adjust for comfort 
45 minutes 
Total time 
60 minutes 
 
HOME PORTIONS 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
tDCS/EEG Stimulation and Recording Gather EEG data before, during and 
after stimulation 
overnight 
Total time 
Overnight x 1 nights  
 
VISIT TWO 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
Post-procedure questionnaire 
Assess for tolerability of device and 
address any safety concerns 
15 minutes 
Collection of Equipment 
Collect and Inventory Instruments and 
Hardware 
15 minutes 
Total time 
30 minutes 
 
 
 
2. tACS and EEG ARTIFACT REMOVAL OPTIMIZATION-AWAKE 
 
STUDY VISIT 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
Gather informed consent 
Gather consent 
15 minutes 
EEG/tACS recordings 
Generate EEG data while tACS is 
applied during awake state for 
optimization of artifact removal  
60 minutes 
Total time 
75 minutes 
 
 
 
3. tACS NESTING EFFECTS EXPERIMENT IN HEALTHY 18-50 
 
INITIAL VISIT 

11 
 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
Gather informed consent 
Gather consent 
15 minutes 
EEG/tACS Equipment Trial 
Teach subjects proper equipment 
use/adjust for comfort 
45 minutes 
Total time 
60 minutes 
 
HOME PORTIONS 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
tACS/EEG Stimulation and Recording Gather EEG data before and after 
stimulation 
overnight 
Complete Consensus Sleep Diary 
Assess Sleep Quality (after each night 
of study) 
10 minutes 
Word Paired-Associate Task 
Assess Memory Encoding (before and 
after sleep) 
20 minutes 
Finger Tapping Task 
Assess Procedural Memory (before and
after sleep) 
15 minutes 
Total time 
Overnight x 3 nights 
(1 week apart for 
washout) 
 
VISITS TWO, FOUR and SIX 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
Post-procedure questionnaire 
Assess for tolerability of device and 
address any safety concerns 
15 minutes 
Collection of Sleep Diary and 
Equipment 
Collect and Inventory Instruments and 
Hardware 
15 minutes 
Total time 
30 minutes 
 
VISITS THREE and FIVE 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
EEG/tACS Equipment Distribution 
Ensure subjects remember proper 
equipment use 
20 minutes 

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Total time 
20 minutes 
 
4. tACS NESTING EFFECTS EXPERIMENT IN OLDER ADULTS 
 
INITIAL VISIT 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
Gather informed consent 
Gather consent 
15 minutes 
EEG/tACS Equipment Trial 
Teach subjects proper equipment 
use/adjust for comfort 
45 minutes 
Total time 
60 minutes 
 
HOME PORTION- ADAPTATION NIGHT 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
EEG Recording 
Gather EEG data before and after 
stimulation 
overnight 
Complete Consensus Sleep Diary 
Assess Sleep Quality (after each night 
of study) 
10 minutes 
Total time 
Overnight 
 
HOME PORTIONS-tACS TREATMENT NIGHTS 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
tACS/EEG Stimulation and Recording Gather EEG data before and after 
stimulation 
overnight 
Complete Consensus Sleep Diary 
Assess Sleep Quality (after each night 
of study) 
10 minutes 
Word Paired-Associate Task 
Assess Memory Encoding (before and 
after sleep) 
20 minutes 
Finger Tapping Task 
Assess Procedural Memory (before and
after sleep) 
15 minutes 
Total time 
Overnight x 3 nights 
(1 week apart for 
washout) 
 
VISITS TWO, FOUR, and SIX  

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Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
Post-procedure questionnaire 
Assess for tolerability of device and 
address any safety concerns 
15 minutes 
Collection of Sleep Diary and 
Equipment 
Collect and Inventory Instruments and 
Hardware 
15 minutes 
Total time 
30 minutes 
 
VISITS THREE, and FIVE 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
EEG/tACS Equipment Distribution 
Ensure subjects remember proper 
equipment use 
20 minutes 
Total time 
20 minutes 
 
5. tACS SLEEP MODULATION MCI EXPERIMENT 
 
INITIAL VISIT 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
Gather informed consent/UBACC 
Gather consent/Screen for capacity 
15 minutes 
EEG/tACS Equipment Trial 
Teach subjects proper equipment 
use/adjust for comfort 
45 minutes 
HADS 
Assess anxiety and depression (to be 
administered for MCI trial) 
5 minutes 
CGIC 
Assess Global Impression (to be 
administered for MCI trial) 
5 minutes 
Total time 
60-70 minutes 
 
HOME PORTIONS 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
tDCS/EEG Stimulation and Recording Gather EEG data before and after 
stimulation 
overnight 
Complete Consensus Sleep Diary 
Assess Sleep Quality (after each night 
of study) 
10 minutes 

14 
 
Word Paired-Associate Task 
Assess Memory Encoding (before and 
after sleep each night) 
20 minutes 
Finger Tapping Task 
Assess Procedural Memory (before and
after sleep) 
15 minutes 
Total time 
Overnight x 7 nights 
 
VISITS TWO, FOUR and SIX 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
Post-procedure questionnaire 
Assess for tolerability of device and 
address any safety concerns 
15 minutes 
HADS 
Assess anxiety and depression (to be 
administered for MCI trial) 
5 minutes 
CGIC 
Assess Global Impression (to be 
administered for MCI trial) 
5 minutes 
Collection of Sleep Diary and 
Equipment 
Collect and Inventory Instruments and 
Hardware 
15 minutes 
Total time 
30-40 minutes 
 
VISITS THREE and FIVE 
Name of 
Instrument/tool/procedure 
Purpose (i.e. what data is being 
collected) 
Time to complete 
EEG/tACS Equipment Distribution 
Ensure subjects remember proper 
equipment use 
20 minutes 
Total time 
20 minutes 
 
Location 
Pre- and post-test sessions will occur in Building 500 of the Anschutz Medical Campus. Testing will occur 
at the subjects’ homes.  
 
tACS Procedure 
tACS or sham will be administered using the StarStim stimulator. Anodes of the tACS stimulator will be 
placed bilaterally at frontal positions on a 10-20 EEG Electrode Placement System and the cathodes will 
be placed bilaterally on the posterior regions. Oscillating stimulation, ranging between 0 mA to 2.0 mA 
(maximum current density 0.515 mA/cm2) will be applied through electrodes in trains up to ten minutes, at 
frequencies between 0 to 500 Hz in the tACS treatment groups while subjects are in stable stage 2 or 
deeper NREM sleep on EEG recording (total stimulation time not to exceed 60 minutes). This is similar 
to prior tACS sleep studies which have safely utilized stimulation protocols within this frequency range 
(7, 46-48). Our maximum current density is within guidelines of established protocols, and is well below 
safety thresholds of 14.29 mA/cm2 from data obtained in animal models (49). All stimulation 

15 
 
parameters are well below currently accepted safety guidelines for tACS (50). Sham condition will be 
application of electrodes, without activation of current stimulation.  The StarStim tACS device is 
designed to turn on and off automatically, without need for subject control.  
 
XIII.       SPECIMEN MANAGEMENT 
There will be no specimens taken in this study. 
 
XIV.       DATA MANAGEMENT 
 
All efforts will be made to protect the confidentiality of research subjects. All electronic data will be 
collected via REDCap, de-identified by the research team, and stored on their servers. Only study 
personnel will have access to the data. The dataset will be stored on a computer that is password- 
protected, virus-protected, and automatically logs the user off after a period of inactivity. The computer 
is located in a locked office. The computer will be password protected when not in use. All written data 
will be stored in a locked file cabinet in a private office, the research office of the Department of 
Neurology. All personnel involved in the study have completed HIPAA training. Any PHI will be stripped 
from data files (or shredded from written records) within 6 months of the end of the data collection 
period such that all PHI will be deleted prior to completion of the final data set. Any publication of data 
will be reported in aggregate.   
 
XV.         WITHDRAWAL OF PARTICIPANTS 
Subjects will be withdrawn if they experience adverse effects due to tACS application or are 
unable to tolerate wearing of equipment. Data from subjects that withdraw will be collected and 
protected, but not utilized in the data analysis.  Follow up will only be performed in the case of 
adverse events to ensure the safety of the patient. 
 
XVI.       RISKS TO PARTICIPANTS 
 
tACS 
 
Over 10,000 research subjects had received tES, including tACS, as of 2014, without any serious side 
effects reported (51). There has been no evidence of seizures, neuronal pathology, edema or 
neuropsychological damage (15). At-home, unsupervised, application of tES has been demonstrated to be safe 
and well-tolerated, without any major adverse events or safety concerns (26, 27). During administration of tES, 
subjects have reported a mild tingling sensation (70.6%), moderate subjective fatigue (35.3%) and a light 
itching sensation (30.4%). After administration of tES, subjects have reported mild transient headaches 
(11.8%), nausea (2.9%) and insomnia (0.98%) (52). Our stimulation parameters (maximum current density 
0.515 mA/cm2) are far below established safety thresholds of 14.29 mA/cm2 (49). All stimulation 
parameters within this proposal are well below currently accepted safety guidelines for tACS (50). 
Independently-constructed and direct-to-consumer tES devices have been utilized in the home 
setting, and in scientific study, without any reported significant adverse events and are considered to be 
safe for use without food and drug administration (FDA) oversight (53, 54). Direct-to-consumer tES devices 
include the Thynk (http://www.thynk.com/ ;©THYNK) and Foc.us (http://www.foc.us/ ;©FOC.US), which 
are marketed for multiple purposes including mood regulation, athletic performance, and cognitive 
enhancement. The Foc.us device is further marketed for sleep enhancement, and is available with a sleep 
kit to apply tACS at home by consumers. Additional  consumer applications include the Halo Sport 
(http://www.haloneuro.com/  ;©HALO NEUROSCIENCE) tES device, which is available direct-to-consumer 
without physician or FDA oversight, has been trialed for athletic training by several athletic organizations, 
including the US Ski and Snowboarding Association (USSA) national Olympic governing body 
(http://ussa.org/ ) (55).  
 
The Starstim device, as detailed below, is considered a non-significant risk device, as defined under 
21 C.F.R. § 812.3(m). Safety features include integrated limited of current intensity, voltage, and impedance 
to assure stimulation is kept well below accepted safety guidelines. This device has been designed to allow 
safe at-home use.  

16 
 
  
EEG 
 
EEG is a passive recording technology and has been utilized with simultaneous tES devices without 
any reported major side effects or complications (23, 56). Participants will be assessed for discomfort of 
the EEG cap prior to its use.  
 
 
XVII.      MANAGEMENT OF RISKS 
 
There are no major risks associated with this study. Regarding the mild tACS side effects listed 
above, we will minimize these by use of a device with automatic limits of current intensity, voltage, 
and impedance. Additionally, we will review of tACS session logs, verification of tACS delivery by EEG 
recording, and patient report inquiry for any side effects.  
  
 
XVIII.    POTENTIAL BENEFITS 
 
Subjects are not expected to benefit from this study.  However the risks to participants are minimal 
given the following: 1) tACS is well tolerated and not associated with any serious adverse side effects 2) 
The data is not sensitive. 
 
With regard to societal benefits, this study will provide data that may benefit patient populations that 
suffer from primary sleep disorders, as well as poor sleep due to neurologic and psychiatric illness. 
This study may indicate that home application of tACS during sleep is a practical and affordable 
treatment for patients. tACS is an inexpensive, noninvasive, and safe intervention, so providing data 
that supports its efficacy may substantiate its utility in reducing healthcare costs. 
 
XIX.       PROVISIONS TO MONITOR THE DATA FOR THE SAFETY OF PARTICIPANTS 
 
Identification and documentation of adverse events will be the responsibility of the PIs and co-
investigators, who will also be performing data collection. Reporting of adverse events will be the 
responsibility of the principal investigator, Dr. Brice McConnell. A review of summarized safety 
information will be performed by Dr. McConnell and will occur after 1 subject has participated in the 
study as well as midway through data collection. The study will be stopped if any serious adverse event 
occurs. A statistical interim analysis will not be performed given that this study is minimal risk. 
 
XX.         PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS 
 
All efforts will be made to protect the privacy of research subjects. However, since this study does not 
involve sensitive data, no privacy measures will be taken other than the data management steps 
outlined in section XIV. 
 
XXI.       MEDICAL CARE AND COMPENSATION FOR INJURY 
 
Medical care and compensation for injury are not applicable given that this is a minimal risk study. 
 
XXII.      COST TO PARTICIPANTS 
 
There are no costs to subjects. 
 
XXIII.    DRUG ADMINISTRATION 
 
Not applicable. 
 
XXIV.     INVESTIGATIONAL DEVICES 
The StarStim (http://www.neuroelectrics.com) stimulator qualifies as an investigational device. It will 
deliver the tACS to the patient. The device is battery powered and controlled by a microprocessor for 

17 
 
safety monitoring and to ensure precise current delivery. The device consists of a stimulator, a 
programmer, and EEG recorder and a set of electrodes. The device is programed with safety features to 
limit current intensity, voltage, and impedance to assure stimulation is kept well below accepted safety 
guidelines, and has been designed to allow safe at-home use. There are no anticipated changes to the 
device during the course of this study. Starstim is considered a non-significant risk device, as defined 
under 21 C.F.R. § 812.3(m). 
XXV.      MULTI-SITE STUDIES 
 
Not applicable. 
 
XXVI.     SHARING OF RESULTS WITH PARTICIPANTS 
 
Participants interested in the results of the study will receive a summary of findings via mail following 
completion of data analysis and dissemination of results. 
 
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