Effectiveness of a Non-Invasive, Low-Intensity Brain Stimulation Approach in Addressing Emotional Regulation
Phase: NA
Conditions: Mild Cognitive Impairment, Neuropsychiatric Syndrome
Sponsor: University of Rochester

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Effectiveness of a Non-Invasive, Low-Intensity Brain Stimulation Approach in Addressing Emotional 
Regulation & Memory
(CogT BEEM Study)
Principal Investigator – Feng Vankee Lin, PhD, RN
Co-Investigator: Kathi Heffner, PhD
1.
PURPOSE OF STUDY
Neuropsychiatric symptoms (NPS) are a distinctive set of behavioral disturbances that are prevalent in 
mild cognitive impairment (MCI) and Alzheimer’s disease (AD), worsening of which, particularly, can 
accelerate patients’ cognitive and functional decline and cause significant distress to caregivers.1,2 NPS 
often co-exist, rendering the need to understand the shared biological mechanisms underlying multiple 
NPS, which is crucial for the development of effective interventions to address them simultaneously. 
Notably, we recently discovered a neural circuit shared by MCI and AD patients with multiple NPS; the 
circuit is composed of 10 frontal-temporal-striatal regions3 and is highly related to both study partner- 
rated Neuropsychiatric Inventory Questionnaire (NPI-Q) and AD pathology (indexed by cerebrospinal fluid 
A/ptau ratio).3 The goal of this proof-of-concept mechanistic intervention study is to confirm the causal 
relationship between this neural circuit and various NPS, by modifying a key region within the neural 
circuit [i.e. left precentral gyrus (LPG), critical for regulating visual attention4] with anodal transcranial 
direct current stimulation (tDCS).
Why focus on the LPG via tDCS to understand the contribution of this shared neural circuit to NPS? Our 
previous work on NPS-shared neural circuit shows that while different NPS are associated with the same
10 frontal-temporal-striatal regions, the strength of functional connectivity (FC), as well as its 
directionality, varies for different NPS. For example, the strength of most FCs in MCI/AD patients with a 
depressive symptom is lower than that in patients without this symptom, while the strength of most FCs 
are higher in patients with an anxiety symptom. Across NPS, however, LPG is the only region that has 
lower FCs with frontal and striatal regions within the circuit whenever a NPS is present.3 LPG, parallel to 
C3 in the 10/20 EEG system,5 is one of the most frequently examined and effective tDCS targets modifying 
affective, psychiatric, and psychosomatic symptoms, in addition to motor function.6-8 Administering 
anodal tDCS also enhances the strength of FCs linking LPG to frontal and limbic regions that are part of 
the NPS-shared neural circuit.9-12 Notably, our feasibility study demonstrated our readiness and safety of 
administrating anodal tDCS to C3 in older adults. Synthesizing these separate lines of evidence, we 
hypothesize that administering anodal tDCS to C3 in patients with NPS will result in enhanced activation 
of LPG and reorganization of NPS-shared neural circuit, both of which will improve NPS.
Aim 1. Determine the effect of tDCS on NPS-shared neural circuit. H: After intervention, the active group, 
relative to the sham group, will have a greater increase in LPG activity, indexed by greater activation in 
LPG in response to a visual attention task (H1a) and greater increase in resting FC strength between LPG 
and other regions within the NPS-shared neural circuit (H1b).
Aim 2. Determine the relationship between NPS-shared neural circuit and study partner-report NPS. H: 
After intervention, the active group, relative to the sham group, will have greater improvement in study 
partner-rated NPS in terms of lower severity and fewer co-existing symptoms (H2a). Changes in LPG task- 
induced activity combined with an LPG-seeded NPS-shared neural circuit will contribute to the

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improvement in study partner-rated NPS across groups (H2b).
Exploratory aim. Examine the relationship between NPS and the coherence between structural and 
functional aspects of the NPS-shared neural circuit. Cumulative literature suggests that white matter 
(WM) tracts play a critical role in supporting and shaping brain function.13 It is often assumed that FC is 
dependent on underlying anatomical connections,13-15 with decreases in WM integrity in dementia related 
to reduced functional efficiency.16 The magnitude of correlation between the structural and functional 
aspects of NPS-shared neural circuit may implicate the severity of NPS. Here, we will collect diffusion 
tensor imaging (DTI) at baseline, as part of MRI data acquisition, and examine whether the effects of tDCS 
on NPS-shared neural circuit and study partner-rated NPS depend on WM integrity. Exploring this question 
will provide broaden our mechanistic understanding of NPS.
We propose that probing the LPG via tDCS provides a way to experimentally test the causal relationship 
between our previously discovered NPS-shared neural circuit and study partner-rated NPS. The proposed 
research is highly innovative, while scientifically grounded, for targeting one brain region that may affect 
multiple NPS. Validating the hypotheses has the potential to support a future R01 study that directly 
conducts a Stage 2 trial addressing NPS in MCI or AD, thus ultimately improving patients’ quality of life 
and reducing the caregiver burden.
Exploratory aim 2: Examine blood biomarkers at baseline for predicting cognitive and brain MRI 
biomarker responses to intervention. Blood neuropathological (amyloid beta [Aβ] 42, total tau [t-tau], 
and neurofilament light [NfL]) and neurotrophic biomarkers (brain-derived neurotrophic factor [BDNF], 
insulin growth factor-1 [IGF-1], and short-chain acylcarnitines [SCACs]) relate to cerebral amyloidosis, 
neurodegeneration17-19 and neurogenesis.20,21 Blood Aβ42 may indicate cerebral amyloidosis,19  and 
blood t-tau, and NfL levels have been shown to reflect neurodegeneration across populations (older 
adults with AD, MCI, or normal cognition).17,18 Their blood levels also correlate with their cerebrospinal 
fluid (CSF) levels, as well as several neuroimaging biomarkers (amyloid plaques, AD-related brain 
atrophy, and brain hypometabolism).17-19 Decreased blood Aβ42 and increased t-tau and NfL levels were 
also found in individuals with MCI or AD and were associated with cognitive decline and incident AD 
over time.17-19 Preliminary data from colleagues at the University of Minnesota demonstrated that 
increased baseline plasma t-tau levels correlated with greater cognitive decline in older adults with MCI 
over time.22 Moreover, plasma phosphorylated tau (p-tau) is a promising biomarker of neuronal injury. A 
recent study showed that plasma p-tau levels were better biomarkers for both acute and chronic 
traumatic brain injury than plasma t-tau levels alone - further providing evidence in support of blood 
biomarkers as surrogate endpoints for treatment responses in neurological conditions such as aMCI and 
AD.23
Blood neurotrophic factors have been shown to cross the blood-brain barrier to increase hippocampal 
volume and memory.20,25-32 Higher plasma BDNF levels were linked to better memory, larger 
hippocampal volume, and reduced risk for AD.25,28,29 Whereas higher plasma IGF-1 levels were
cross-sectionally associated with better cognition33 and lower odds of AD,34 longitudinal data have been 
inconsistent. However, a recent study showed that higher plasma levels of IGF binding protein-3 
(IGFBP-3), which are essential for IGF-1 physiological action,35 were associated with decreased risk for 
dementia.30
2.
BACKGROUND AND RATIONALE
Co-existing NPS in MCI, especially those worsening over time, are associated with more rapid cognitive 
and functional decline and a greater risk of AD.1 The majority of the existing literature has focused on the 
neural mechanism and management of individual NPS in MCI/AD.36,37 Optimal NPS management,

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meaning effective management of multiple NPS simultaneously, is a major challenge in MCI/AD care.2
Feasibility of administrating tDCS in older adults: Previously, 14 cognitively normal older adults (65-85 
years) were randomly assigned to active vs. sham tDCS group. TDCS was applied for 20 minutes (as 
described in the protocol below) while subjects performed, in random order, two computer-based visual 
attention tasks that also recruit working memory (1-back) and inhibition (color test in Stroop). Participants 
were asked to make responses as accurately and quickly as possible (10 minutes per task, Figure 1A). 
Active tDCS was anodal stimulation of C3 with cathode on Fp2 (Figure 1B). There were no adverse effects. 
The two groups were similar in baseline global cognition, age, education, and sex. The 20-minute tasks 
were segmented into four 5-minute blocks with intra-individual variability in reaction time (IIVRT) 
computed within each block, ensuring the comparability of cognitive performance between the two types 
of tasks. IIVRT was calculated using standard deviation divided by averaged reaction time of all the trials 
with correct responses. The active condition induced significantly better cognitive performance (indexed 
by lower IIVRT) for the last three blocks, compared to the sham condition (Figure 1C).
A
…
4s
3s
4s
1.5s
3s
0.5s
4s
…
1.5s
Figure 1. tDCS pilot study. A. Visual attention tasks (upper: 1-back; lower: Color test in Stroop); B. location of the 
tDCS electrodes; C. cognitive performance across four 5-minute blocks between sham and active groups. * p < .05.
We propose to examine the influence of LPG, a region within the NPS-shared neural circuit and a region 
known to regulate visual attention, on the NPS-shared neural circuit and study partner-rated NPS. In the 
proposed study, we capitalize on a non-invasive brain stimulation process to manipulate the activation 
and FC strength seeded in LPG. This design will provide an understanding beyond the correlational 
relationship between the neural circuit and NPS in patients with MCI. TDCS non-invasively induces a low 
direct current in the cortical region of interest (ROI), with a potential neural mechanism of inducing 
synaptic changes that affect neural network activity, reflected in changes in both activation and strength 
of FC, as well as changes in visual attention-dominant tasks.38 LPG is one of the primary tDCS targets for 
obtaining effects on psychosomatic and affective symptoms6-8; furthermore, tDCS can easily target (i.e., 
on the cortical surface) and modulate (i.e., produces large effects) the region. Applying an average of 20 
minutes of continuous tDCS can yield acute effects for up to 90 minutes, while 2-4 weeks of sessions can 
yield effects for up to 6 months.39-42 Most importantly, tDCS is safe and non-invasive, thus, these 
characteristics together make tDCS an ideal manipulation technique to modify LPG.
Scientific premise and hypothesis: This proposal aims to determine the causal relationship between our 
recently discovered NPS-shared neural circuit and study partner-rated NPS by stimulating a region within 
this circuit (LPG). We integrate the evidence from existing literature and our preliminary work that are 
potentially relevant to what is proposed here: (1) a worsening pattern of NPS in MCI is most
Cathode C
Sham
G
G
(feedbac
red
(feedback

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disturbing for cognitive and functional decline1; (2) a neural circuit (i.e., NPS-shared neural circuit) 
supports multiple NPS and links to study partner-rated NPS and AD pathophysiology3; (3) the strength of 
FCs within the NPS-shared neural circuit varies across individual NPS, with LPG exhibiting greater FC 
strengths with frontal and striatal regions within the circuit but weaker FC strengths with other regions, 
the latter of which is linked to higher chances of presenting NPS3; (4) LPG is a hub region that regulates 
visual attention and processing speed4,43,44; (5) anodal tDCS targeting LPG enhances brain synchronization 
and whole-brain resting-state functional connectivity between LPG and its neighboring regions 
(particularly frontoparietal regions) or between LPG and caudate9-12; (6) anodal tDCS targeting LPG also 
modifies affective, psychiatric, and psychosomatic symptoms (e.g., humor, appreciation, anxiety, pain)6-8.
We hypothesize that anodal tDCS stimulating LPG can affect LPG activation (indexed by enhanced neural 
efficiency during the visual attention task) and its connectivity with other regions within the NPS-shared 
neural circuit, which, in turn, will reorganize the NPS-shared neural circuit and improve study partner- 
rated NPS (Figure 2). Validating these hypotheses will extend separate bodies of literature on the 
symptomatic understanding of multiple NPS, neural mechanisms underlying NPS, and the impact of tDCS 
on neural and behavioral effects, as well as facilitate an explicit elaboration of a shared neural mechanism 
underlying multiple NPS in MCI. This elaboration has strong potential to inform treatment development 
for managing multiple NPS simultaneously by addressing the shared neural circuit as the primary 
therapeutic target. This proposal’s significance is further underscored by the implications of our model for 
potentially preventing AD pathology: our pilot work suggests the NPS-shared neural circuit predicts the 
trajectory of AD pathology progression, indexed by a change in cerebrospinal fluid A/ptau ratio. If the 
neural circuit is modifiable via tDCS applied to the key region within the circuit, this approach may be 
applicable to
delaying 
AD 
pathology 
from 
developing and benefit other clinical 
domains, such as cognitive
deficits and impaired functional Figure 2. Conceptual framework
independence, thereby potentially slowing overall AD progression.
3.
ADMINISTRATIVE ORGANIZATION
Study-related appointments will be conducted on-site at University of Rochester Medical Center
locations. Subjects will be given the option to do the tDCS interventions at the subject’s home or at our 
lab. During home visits, study team members will assess the environment (ex. dog barking, TV on, etc.) 
and adjust accordingly depending on the specific situation. Regardless of intervention location, a trained 
study team member will be administering all tDCS interventions. All in-person assessments for this 
research study will be conducted in Dr. Lin’s CogT Lab (located at the Annex Building). All MRI 
appointments will be conducted at the Rochester Center for Brain Imaging/Center for Advanced Brain 
Imaging and Neurophysiology (RCBI/CABIN). Baseline blood collection will be conducted at URMC’s 
Clinical Research Center (CRC).
4.
STUDY DESIGN
This is a Stage 0 study for mechanistic understanding. We will recruit older adults with study partner- 
rated NPS that has worsened in the past 2 years. Our previous study shows that this will capture
rated NPS
tDCS
LPG activation
NPS-shared 
neural circuit

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the most detrimental type of NPS.1 We will focus on the MCI group, since understanding and modifying 
NPS among this group may assist in slowing the progression of dementia. See Table 1 for the overview of 
assessment and intervention timeline.

Double-blind randomized controlled trial of 40 participants and their study partner subjects; all 
eligible and interested intervention subjects will be enrolled and undergo a baseline assessment, 
MRI scan, and blood draw; PI, staff conducting follow-up assessments and intervention subjects 
and their study partner subjects will be blinded. Interventionists and data managers will know 
randomization.

After baseline, all intervention subjects will be randomly assigned to one of two groups - active 
anodal or sham C3 tDCS. A MATLAB block-based randomization code will be used to randomly 
assign study ID to group. Each study ID-group pairing will be printed and placed inside a sealed 
envelope labeled with only the study ID to ensure blinding. After an intervention subject and their 
partner subject finish baseline assessments, the interventionist or data manager will open the 
randomization envelope to assign the respective study ID.

All intervention subjects will undergo a total of fourteen (14) 20-minute tDCS sessions over the 
course of four weeks: ideally, five times a week for two weeks, followed by twice a week for an 
additional two weeks. However, we will extend the intervention for additional two weeks for 
make-up sessions.

Assessments will occur at baseline, within 2-week after finishing intervention (post-intervention 
assessment), and 4 to 6 weeks after post-intervention assessment (follow-up assessment).

Unblinding will occur upon the completion of the follow-up assessment. We will not provide those 
in the sham group with the active tDCS procedure.
Primary endpoints:

Resting-state and visual attention task-related fMRI; 45
fMRI data will be collected using a gradient echo-planar imaging sequence. Participants will undergo 
a 5-minute resting-state scan at first, being instructed to relax with their eyes open, followed by a 5- 
minute event-design ‘target among distractors’ visual search task. For the task, participants fixate on 
a black screen for a constant inter-stimulus interval of 1000ms, follow by 5500ms presentation of the 
search pattern. Participants’ task is to search for target symbol “ 申 ” (which was present for 50% of 
trials), shown among 6 distractors (e.g., “由”, “甲”, etc.). Participants are instructed to press one of 
two response buttons to indicate whether the target was present or absent.
Secondary endpoints:

Study partner-rated NPS (frequency and severity scores from NPI and NPI-Q46).
Other measures:

Cognitive functions will be measured using tests from three different versions of the computer- 
based battery Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and 
Research (EXAMINER);

Paper-based measures of cognitive functioning will be measured using two versions of the Rey 
Auditory Verbal Learning Test (RAVLT, Lists A&B and C&D) and the Brief Visuospatial Memory

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Test-Revised (BVMT-R, Forms 1-3);

Functioning in daily life will be measured with the self-report version of the Activities of Daily 
Living-Prevention Instrument (ADL-PI-self).

Fatigue across 5 domains (general, physical, mental, and reduced motivation & reduced activity) 
will be measured using the Multidimensional Fatigue Inventory (MFI);

Sleep habits and quality of sleep will be measured using the total score from the Pittsburgh 
Sleep Quality Index (PSQI);

Depression will be measured using both the 15- and 30-item versions of the Geriatric Depression 
Scale (GDS);

Risk of suicide (current & past) and current suicidal ideation will be measured using Columbia 
Suicide Severity Rating Scale (C-SSRS);

Anxiety will be measured using both the state and trait anxiety scales from the State-Trait 
Anxiety Inventory (STAI);

Perception of stress will be measured using Perceived Stress Scale (PSS);

Apathy will be measured using the 18-item self-report and informant-rated Apathy Evaluation 
Scales (AES);

Quality of life (QoL) across multiple life domains (including physical health, mood, relationships, 
activities, ability to perform tasks) will be measured using the 13-item self-report and informant- 
rated Quality of Life in Alzheimer’s Disease scales (QOLAD);

Cognitive reserve will be measured using Cognitive Reserve Assessment Scale in Health (CRASH);

Decision making and risk-taking behavior will be measured with the 30-item Domain-Specific Risk- 
Taking scale (DOSPERT)

Blood biomarkers collected at baseline will be analyzed and compared to changes of cognitive and 
MRI brain scan cortical thickness outcomes. Diet history will also be measured by asking three 
questions assessing the intervention subject’s consumption of fish oil prior to the blood draw.

Medication changes will be assessed by asking the intervention subject for an updated list of their 
prescribed medications. Of note, although we will ensure the stability of the medication (e.g., anti-
depressants, antipsychotics, and/or anxiolytics, memory medication) as part of the eligibility 
criteria (see section 5.a), we cannot ensure the changes of medications throughout the study 
procedure, which may interfere with the understanding of the proposed mechanism between 
brain regions and NPS, therefore, we will consider them confounding factors in later analyses.
Alternate forms of cognitive measures (EXAMINER, RAVLT, BVMTR) will be used across time points (see
Table 1 for details) to avoid practice-effects.
4.1.
SUBJECT POPULATION
a)
Number of Subjects: The total sample will include 40 intervention subjects with MCI

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(NIA-AA diagnostic criteria47) and their study partner subjects (who live with or regularly visit the 
intervention subjects, one partner subject per intervention subject). We expect to consent and 
screen approximately 200 intervention subjects with MCI, resulting in a likely screen failure rate 
of 160 intervention subjects.
b)
Gender and Age of Subjects: Intervention subjects with MCI must be 60-89 years, with 
approximately an equal number of men and women enrolled. Study partner subjects must be 18 
years or older. Racial and Ethnic Origin: We will proactively recruit minority subjects – focusing 
primarily on African American and/or Hispanic/Latino groups, as both are major minority groups 
affected by dementia & make up most of the minority population in the Rochester area. We plan 
to enroll approximately 15% African American intervention subjects (about 6 intervention 
subjects) and about 5% of intervention subjects who are ethnically Hispanic/Latino (about 2 
intervention subjects). Resulting in a total minority make-up of approximately 20% (8 intervention 
subjects) in our research sample. General demographics (DOB, sex, education) of the partner 
subjects will function as control variables considered for NPI.
Study partner-rated NPI-Q will be used to identify intervention subjects with NPS that has worsened in 
the past 2 years: (1) in the past month, presence of > 2 symptoms; and (2) compared to 2 years ago, having
> 1 pre-exist symptom of which severity rating gets worsened, or having >1 new symptom. We are 
interested in MCI patients with worsened NPI-Q since they are the groups with highest risk for cognitive 
and functional decline.1
4.2 STUDY INTERVENTIONS
Our study is registered at ClinicalTrials.gov (registration # NCT04099524).
We follow tDCS device related information according to this panel review: 48
tDCS will be administered using a 1x1 Low-Intensity Transcranial Electrical Stimulator (tES) device 
(Model 2001) manufactured by Soterix Medical.

This device is limited, by federal law, to investigational usage and does not meet any of the 7 
exemption categories listed in 21 CFR §812.2. No notification from the FDA to the study sponsor 
requiring application approval was sent. Therefore, this device is considered to have an 
approved application as an IDE but will require our Institutional Review Board to make a 
determination regarding whether the IDE is a significant risk or not. We believe the following
information may be relevant in the IRB’s risk determination:
o
Meets criteria for investigation of device without significant risk: device is not intended 
as an implant, does not support or sustain human life, is not used for diagnostic 
purposes, and does not present any potential for serious risk to the health, welfare, or 
safety of subjects. Please see Section 9 for further information regarding the reported 
risks of tDCS usage (all of which are minimal).
o
Device will be labelled in accordance with 21 CFR §812.5 – including manufacturer 
details, quantity of contents, a cautionary statement on device contents regarding its 
limitations to investigational use (as required by federal law), and bears no misleading 
statements
o
Records will be maintained in accordance with 21 CFR §812.140 regarding maintenance

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of records, including correspondences, device receipts and usage records, records of 
each intervention subject’s case history (including informed consent, exposure to
device), reports of adverse device effects, approved protocol with documented protocol 
deviations.
o
Reports will be made in accordance with 21 CFR §812.150 – including documenting 
unanticipated adverse device effects and reporting to IRB & sponsor within 10 business 
days; reporting of withdrawal of IRB approval within 5 business days; progress reports 
will be submitted at least annually, reports of any deviations from investigational plans, 
informed consent, final study report, as well as any other information requested by 
either the IRB or sponsor.
o
Study sponsor, investigator, and all other study team members comply with the 
prohibitions outlined in 21 CFR §812.7 prohibiting promotion and other practices.
4.2.1 Device Storage & Control & Accounting: The 1x1 tES device will be stored in a locked cabinet, with 
all of its original contents and appropriate labelling (as in accordance with 21 CFR §812.5). Only the 
investigator and project coordinator will have access to this locked device. Along with the device and its 
components, records for when the device was received by the manufacturer, when and on whom the 
device was used, who administered the device to the intervention subject, as well as up-to-date staff 
training and procedural logs will all be maintained by the investigator and project coordinator.
Furthermore, all safety precautions regarding storage and usage of device outlined in the 
manufacturer’s manual will be followed and records for compliance with storage, handling, and 
maintenance will be documented.
We will provide training of the stimulation to our experienced project coordinators prior to their 
administration of the device on intervention subjects. The training will be provided by co-I Dr. Tadin who 
is an expert in tDCS and Mia Anthony (an experienced tDCS coordinator working on our feasibility study). 
Evaluation will be conducted by investigator team before a project coordinator can independently work 
on it.
4.2.2 Intervention Procedures:
For all 40 intervention subjects, tDCS (LPG/C3-anode, orbitofrontal cortex/Fp2-cathode) or a sham 
intervention will be administered for 4 weeks (1 session per weekday for 2 weeks, and then 2 sessions 
per week for 2 weeks, for a total of 14 sessions).
If any sessions are missed, make-up sessions will be provided, and the length of intervention period will 
be extended to ensure everyone receives a total of 14 sessions. Intervention subjects can choose to 
have the tDCS sessions where they feel comfortable (e.g., CogT Lab or their home). The maximum 
window for make-up sessions is two weeks.
All intervention subjects will receive anodal tDCS stimulation or a sham intervention for 20 minutes per 
session, on C3 and the cathode electrode on Fp2 using 10/20 EEG system (Figure C3B). tDCS will be 
applied with a pair of 35 cm2 single-use sponges soaked in approximately 4mL of saline solution on each 
side (~8mL per sponge) connected to the stimulator. During the 20-minute tDCS session, we will use 
online tDCS design (i.e., an intervention subject will simultaneously work on the visual
attention-oriented task.

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Active tDCS Condition: We will apply the stimulation for 20 minutes using current at 1.5mA with a ramp 
up and ramp down period of 30 seconds at the start and end of the session (Of note, the two 30 seconds 
are counted in the 20-minute session).
Sham tDCS Condition: tDCS will ramp up for 30 seconds with 1 mA current and then ramp off within 10 
seconds. As 30 seconds is too short for tDCS to have any effects, this will be the sham condition. tDCS is 
on for 30-40 seconds because that is usually the only time individuals would experience tingling and 
itching – a factor we aim to equate between experimental and control conditions.
5.
INCLUSION AND EXCLUSION CRITERIA
a)
Inclusion Criteria:
1.Forty intervention subjects with MCI and comorbid NPS, which have worsened inthe 
past 2 years (as rated by their study-partner subject’s responses to the NPI-Q):
(1) In the past month, presence of > 2 symptoms; and
(2) Compared to two years ago, having > 1 pre-exist symptom whose severity rating has 
worsened, or having > 1 new symptom;
2.Consensus diagnosis of “mild cognitive impairment due to Alzheimer’s disease” basedon 
2011 NIA-AA diagnostic criteria by the investigators based on screening information:
i. Memory deficits at screening: 1 standard deviation (SD) below age- and/or 
education- corrected population norms for the Rey Auditory Verbal Learning Test 
(RAVLT, Lists C&D);
ii. Global memory deficits at screening: Montreal Cognitive Assessment (MoCA, Version
2) total score within the range 18 ≤ x ≤ 26, after educational adjustment;
iii. Preserved activity of daily living: ADL-PI-self total score ≤ 30;
iv. Absence of dementia.
3.Stable (same dosage, frequency, type) on memory medications for ≥ 3 months before 
screening;
4.Stable (same dosage, frequency, type) on any anti-depressants, antipsychotics,and/or 
anxiolytics for ≥ 7 days;
5.Community-dwelling: Intervention subjects live in homes or independent- and assisted- 
living facilities (i.e. – not nursing home residents, due to the large cognitive variabilityin 
nursing home residents);
6.Aged 60-89 years at screening;
7.English-speaking;
8. Adequate visual and hearing acuity for testing;
9. Verified tDCS and MRI safety: Intervention subject should not have any contraindications to 
either and pass safety screening questions for both (see exclusion section for more 
information);
10. Capacity to consent, based on responses and ratings to the UCSD Brief Assessment of 
Capacity to Consent (UBACC) form for this study;

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11. Availability of a study partner subject who spends at least several hours per week with the 
intervention subject, supervises his/her care, and who is willing to accompany the 
intervention subject to some study visits and participate in the study;
12. Informed consent for study participation obtained by both the intervention subject and 
his/her study partner subject;
13. Agree to donate 20mL of blood at baseline, after fasting for at least 8 hours (only water and 
prescribed medicines).
Study partner subject inclusion criteria:
1. Age 18 years or older;
2. English speaking;
3. Has regular contact with MCI intervention subject (at minimum weekly) and be able to 
answer questions about MCI intervention subjects’ current or past well-being ormood.
b)
Exclusion Criteria:
Intervention subjects may be excluded from enrollment, or have their enrollment deferred until 
they are eligible, for the reasons listed below. Final decisions regarding enrollment will be 
determined by the PI on a case-by-case basis.
1. Presence of any neurological or vascular disorders (e.g. – Multiple Sclerosis [MS], 
Traumatic Brain Injury [TBI], chronic heart failure [CHF], Parkinson’s disease[PD]);
2. Clinical diagnosis of dementia as defined by the most recent version of the DSM;
3. Current enrollment in another study aimed at improving cognitive abilities and/or 
emotional well-being;
4. MRI contraindications (e.g. – pacemaker, implantable cardioverter defibrillator[ICD], 
aneurysm clips, severe claustrophobia);
5. tDCS contraindications (e.g. – scalp or skin condition, history of migraines, seizures or 
epilepsy, and/or strokes, TBI), metallic implants, history of adverse effects to 
previous tDCS or other brain stimulation techniques).
6. RECRUITMENT METHODS
We will recruit participants using three main recruitment strategies: 1) clinic referrals, 2) established 
community partners, 3) communities at large. If those strategies fail to reach our recruitment goals, we 
may initiate additional strategies after IRB approval.

Clinic referrals: participants will be mainly recruited from local clinics, such as the Memory Care 
Program (MCP) and UR AD-Care, Research and Education Program (AD-CARE) where Dr. Anton 
Porsteinsson (Co-I) practices as a geriatric psychiatrist. Other local clinics include the internal 
medicine and geriatric medicine departments of the University of Rochester Medical Center.

Community partners: We will work with our established community partners e.g. Lifespan, 
Oasis and YMCA who have helped recruit participants in our preliminary studies. Our community 
partners will distribute flyers and help arrange talks. Communities at large: We will reach out to 
the broad metropolitan communities by distributing recruitment materials to various venues 
such as senior centers, churches, libraries, and stores. We will present materials at local

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conferences sponsored by organizations such as our local Alzheimer’s Association chapter, Area 
Agency on Aging, and Volunteers of America

Recruitment of minority groups: To emphasize the efforts for minority recruitment, we will 
reach out to Recruitment Consultation, a core service of Clinical and Translational Science 
Institute (CTSI) for consultation & recruitment strategy planning.

CTSI participant registry: This study will identify potential subjects for recruiting using the 
UR CTSI Research Participant Registry, STUDY00001978. Subjects will be sent an email 
including a flyer for the study, and be asked to respond if interested. If subjects respond 
with interest, that person will be added to our database and screened normally via phone 
screening. 

Emergency Department Research Associate Program (EDRA): Potential subjects for 
recruiting will also be identified using the EDRA program. This program utilizes 
undergraduate research enrollers to screen interested subjects coming through the Strong 
Memorial Emergency Department. Lab staff will train EDRA staff to administer initial 
screening materials to gain a list of eligible and interested participants. These participants 
will then be added to our database and contacted by lab staff for further screening 
measures. All newly hired EDRAs complete CITI module training on Human Subjects 
Protection, GCPs, and HIPAA in addition to study specific training. 
7. CONSENT PROCESS
Consent is an on-going process that starts when an intervention subject is first informed about the study 
and ends when the intervention subject’s study participation is completed.
Verbal Consent for Phone and In-Person screening: When potential participants contact us, the study 
staff will first explain the study and obtain their verbal consent to proceed with phone screening, using 
the phone screening script. A waiver of documentation of consent has been requested for this step 
because it is conducted over-the-phone so participants will not be able to sign this consent themselves. 
Staff will also obtain verbal consent from the participants’ study partner subjects before proceeding 
with their part of the phone screening. During phone screening, the opportunity to complete secondary 
screening and assessments over the phone will be offered. 
EDRA Recruiters: Participants who are recruited through the EDRA program will have their initial phone 
screening materials and verbal consents completed by the ED recruiters. ED recruiters will undergo 
training by lab staff in order to administer this measures. Participants recruited this way will also sign a 
permission to contact form to allow lab staff to contact for additional study measures and enrollment 
procedures. 
Consent and Re-consent: The initial signed paper consent will be obtained during the in-person 
interview by the intervention subject. (Screening Step 2). The partner subject will be consented either 
at an in-person appointment or via the mail if secondary screening appointment is completed over the 
phone. Secondary screening over the phone is included to ensure partner subject safety. The 
intervention subject and study partner subject may complete their secondary screening appointment 
and consented on separate dates. If the intervention subject completes their in-person screening 
appointment first and is deemed ineligible, the study partner subject will not proceed with their 
secondary screening and will not be consented to the study.
1)
Explanation of the study: During the second screening interview, the 

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staff will explain the study in detail to the participants and their study 
partner subject, including the study purpose, procedures, time 
commitment, randomization, data collection, risks, benefits, privacy, 
confidentiality, compensation, voluntary nature, and contact persons 
for questions and concerns. Emphasis will be placed on explaining the 
risks. Questions will be answered and any confusion about the study 
will be resolved.
2)
Assessment of capacity to consent: The staff will assess the potential intervention 
subject’s capacity to consent using the UCSD Brief Assessment of Capacity to 
Consent form (UBACC) for the study. A score of 2 on items 1, 2, 4, 6, 7, and 9 is 
needed for inclusion in the study. If a participant scores less than 2 on any item, 
the staff will re-explain the study and reevaluate the capacity of the subject. Given 
the potential fluctuation of their cognitive capacity, if a subject still fails to score 2 
on required items, we will ask the person to return on another day to re-take the 
UBACC. If the subject still scores below 2 on any required item during the 2nd visit, 
he/she cannot be enrolled in the study. Of note, other items than the required 6 
items are provided for education purpose. If they do not answer 2 on those items, 
the staff will re-explain the study, but such failures will not interfere with their 
eligibility in the study.
3)
The study partner subject signs the study partner subject consent for participating 
in the study after staff have reviewed the following study details with each study 
partner subject: 1) the objective of the project; (2) description of timeline, the 
assessment procedure and components; (3) description of the environment where 
the assessments are conducted; (4) description of how the confidentiality regarding 
participant data will be protected; (5) description of the potential risk, relevant 
protections, and benefits of participating in the study. Note: If the intervention 
subject’s in-person screening appointment is scheduled to occur before the study 
partner subject’s secondary screening appointment, and the intervention subject is 
deemed ineligible, the study partner subject will not be consented to the study.
8. STUDY PROCEDURES
COVID-19 Safety Regulations:
To ensure appropriate safety precautions when conducting in-person study procedures, the process 
for conducting in-person visits outlined in the Guidance for Human Subject Research webpage 
(https://www.urmc.rochester.edu/coronavirus/coronavirus-research/guidance-for-researchers/ 
human-subjects-research.aspx) will be followed. We will remain vigilant about any further changes 
to the research reboot guidance.
This study will screen participants and their study partner subjects in two steps (phone-screening and 
secondary interview, including capacity to consent and informed consent). Eligible participants and their 
study partner subjects will be enrolled, and participants will be asked to complete a baseline cognitive 
assessment, MRI scan, and blood draw. The participant will then be randomized and start their 
intervention program within two weeks. Each program will consist of 14 tDCS sessions over 4 weeks. 
Follow-up cognitive assessments and MRI scans will occur at 4- and 8- weeks after baseline.
Screening: Potential participants who respond to our recruitment strategies and initiate contact with us 
will be carefully screened for eligibility and safety through a 2-step screening process:
(1) Phone screening (approximately 20 minutes for intervention subject and partner subject 

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respectively): Upon over-the-phone contact, staff conducting the screening will explain the study 
using the phone screening script, answer any questions. If the participant is interested, the staff 
member will obtain their verbal consent to be administered the phone screening questions by 
signing and dating the verbal consent for screening form. Staff will collect basic self-reported 
health history to check for obvious contraindications for MRI or tDCS and to ensure a homogenous 
sample. Responses to these basic health history related items may need to be confirmed by their 
physician to ensure safety of MRI procedure are met. Identification of a “study partner subject” 
willing to participate in the study with the participant. Administration of the Neuropsychiatric 
Inventory Questionnaire (NPI-Q, a short form version of the NPI) with the study partner subject 
(after obtaining verbal consent from the study partner subject to be asked these questions) will 
also be conducted as part of this brief initial screening step,
Secondary cognitive screening: During the secondary screening interview (approximately 1.5 
hours for intervention subject and 0.5 hour for partner subject), capacity to consent and informed 
consent will be obtained from the participant and their study partner subject. Study staff will 
verify the accuracy of phone screen data and note any changes, administer demographic and 
comprehensive health history questionnaires, administer measures to assesspresence of a 
clinical diagnosis of MCI (see Table 1 for more information regarding measures used). Staff will 
also administer the full version of the Neuropsychiatric Inventory (NPI) with the study partner 
subject. Secondary screening should be completed within 3 months of phone screening. Note: For 
partner subjects, secondary screening may be completed over the phone, in which case informed 
consent and capacity to consent will be completed along with NPI. Once a study partner has 
passed the capacity to consent, blank versions of the consent form will be sent to the partner with 
a self-addressed, stamped return envelope, and be sent back signed. Coordinators will then verify 
partner signature, then sign and date each copy. A fully-executed copy of the consent form will 
then be sent back to the study partner. The intervention subject and study partner subject may 
complete their secondary screening appointments on separate dates if preferred.
We expect to invite 180-200 individuals for the secondary screening visit to enroll 40 fully eligible 
intervention subjects. 100-120 subjects are estimated to have signed consent forms but end up 
as screen failures or lose interest in the study. 
Assessments: Fully eligible participants and their study partner subjects will be notified of their eligibility 
for the study. Baseline assessments need to be scheduled within one month of in-person cognitive 
screening. Participants will then be asked to complete baseline measures (assessment, MRI scan, and 
blood draw), after which they will be randomized to either the active or sham tDCS intervention condition. 
The blood draw may occur within 2 weeks (before or after) the baseline assessment and MRI scan. The 
beginning of the intervention phase will start within two weeks after the baseline assessment and blood 
draw. Follow-up cognitive assessments and MRI scans for each participant will occur within 2 weeks after 
completion of intervention (i.e., post-intervention assessment) and then 4 weeks after post-intervention 
assessment (i.e., follow-up assessment). We will allow 2 weeks to make up the follow-up assessment. At 
the same time points, study partner subjects will be administered the NPI, AES, and QOLAD. Follow-up 
assessments for study partners can also be conducted over the phone, at the partners discretion.
A detailed overview of data collection measures for screening and assessments can be found below in 
Table 1. To reduce the burden on participants, study partner subjects, and staff, as well as to avoid 
practice effects of cognitive measures, for individuals who are eligible for the study, their screening data 
will be used as baseline data; for those who are not eligible for the study, their screening data will only 
be used for summarizing the reasons for ineligibility.

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Group assignment/randomization will be determined with a block-based matlab randomization.
Table 1: Study Measures
I = intervention subject; P = partner subject
Screening
Baseline
Interventions
Makeup 
Interventions
(if needed)
Post-Intervention 
Assessments
Study Activities
Phone
In-Person
BL Visit
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
Immediate 
Post-Interve
ntion
Final 
Post-Interve
ntion
Verbal Consent for 
Screening
I, P
Inclusion/Exclusion 
(verified at In-Person)
I, P
I, P
MRI Screening Form
I
Informed Consent
I, P
UBACC
I
Demographics & 
background
I,P
MoCA (V2)
I
RAVLT
I (Lists C&D)
I (Lists A&B)
I (Lists C&D)
ADL-PI-self
I
I
I
PSS
I
I
I
PSQI
I
I
I
MFI
I
I
I
GDS-15
I
I
I
I
I
I
I
AES
I, P
I, P
I, P
QoL-AD
I, P
I, P
I, P
Medications
I
Medication changes
I
I
NPI-Q
P
P
P
P
P
NPI (Full)
P
P
P
Examiner
I (Form A)
I (Form B)
I (Form C)
GDS-30
I
I
I
C-SSRS
I
I
I
STAI
I
I
I
BVMT-R
I (Form 1)
I (Form 2)
I (Form 3)
DOSPERT
I
I
I
CRASH
I
Blood Draw with 
questionnaire
I
MRI scan (& confirm MRI 
screen form)
I
I
I
Intervention (sham or 
active)
I
I - One session 
per each 
weekday
I - Two sessions 
per week
I – Makeup 
sessions
(if needed)
MATLAB computer task
I - During each intervention session
SAM
I - Before and after each intervention session
Fatigue scale
I - Before and after each intervention session

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Note: For further details regarding measures, please see Section 4: Study Design.
Blood collection and processing:
We will collect a single blood sample from each participant within 2 weeks of the baseline assessment 
(before or after), and prior to beginning tDCS intervention sessions. This blood collection visit will require 
a separate appointment from the baseline assessment and MRI scan. Study staff will schedule the blood 
collection with CRC staff and confirm the appointment with the participant. Participants will be reminded 
to fast for 8 hours prior to their blood draw but may drink water and should take all medications as 
prescribed. On the day of the blood collection appointment, study staff will meet the participant at CRC 
and CRC staff will collect blood following a venous-blood collection protocol. Study staff will also ask each 
intervention subject 3-questions related to their diet and health in the past week. A total of 20mL of blood 
will be collected – 12mL into two 6mL plasma (EDTA-treated) tubes, and 8mL into two 4mL BD red serum 
tubes. Blood will be processed and frozen in cryo-vials at CRC -80° F freezer. Once cryo boxes are full (due 
to lack of space for storage of multiple cry-boxes in CRC) then cryo boxes will be transferred to 4W-156, 
bio-safety level lab 2 in School of Nursing for storage in -80° F freezer until analysis.
No individual research results will be provided to intervention subjects or study partner subjects in this 
study. However, aggregate group results will be disseminated to all subjects after study completion.
9. RISKS TO INTERVENTION SUBJECTS
The overall risks to participants for this study are expected to be minimal. In our feasibility study, no 
adverse effects were reported. The risks associated in the participant characteristics or study procedures 
include: (1) concern about suicide; (2) MRI; (3) tDCS; (4) blood draw.
Concern and protection about suicide and harm to others:
The assessment of suicidality or need for hospitalization will be based on following assessments 
throughout the study period: (1) responses to the C-SSRS at baseline and follow-up assessments. The C- 
SSRS assesses past and current risk of suicide and suicidal ideation. All coordinators in this study have 
been certified to administer this measure and obtain a risk score based on intervention subject responses.
(2) GDS combined with P4 is assessed weekly during an in-person tDCS session, and follow-up assessment 
visits. GDS, specifically, responding ‘No’ to GDS item 11 – “It is wonderful to be alive now” will be followed 
immediately by the P4 suicidality screener, and by mental status examination of the participant. (3) the 
partner subject’s response to the Depression/Dysphoria item #7 on the NPI. In the event that a suicidality 
risk is detected by the NPI, we will ask the partner subject about the risk of the intervention subject for 
hurting himself/herself, and administer to the P4 suicidality screener to the intervention subject within 24 
hours. Across all three scenarios, the research staff will assess for severe hopelessness, passive death wish, 
suicidal statements, suicidal plan, or behavioral indicators of risk for self-harm. Need for hospitalization 
will be similarly assessed by a study physician. Hospitalization is typically indicated if there is imminent risk 
of harm due to agitation, such as refusal to eat, weight loss, violent behavior toward the caregiver, or 
suicidality. We have established a standard protocol for addressing concern on suicide patients at risk or 
with dementia, by working with certified geriatric psychiatrist or neurologist from our Memory Clinics 
(including Dr. Porsteinsson, co-I of the study and a geriatric psychiatrist working at the clinic). The clinician 
will provide immediate care to any participants at risk of suicide or clinically unstable. If a participant is 

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judged to be at immediate high risk and leaves study venue against the advice, we will contact security or 
other appropriate emergency personnel (e.g., ambulance, mobile crisis team).
For the partner subject’s response to the Agitation/agression item #7 on the NPI, we have procedure in 
place for training staff’s home visit to address the potential harm. If the staff detects an imminent risk of 
harm to the subject or others, the staff will call 911. Otherwise, the study team’s geriatric psychiatrist and 
the PI will be contacted.
Risk and Protection against Risk Related to MRI Imaging Assessments:
There is no immediate risk from exposure to magnetic fields of 3 Tesla. Possible anxiety may result from 
claustrophobia or dizziness experienced by the intervention subjects when placed in the magnet. During 
the imaging portion of the experiment, intervention subjects must remain in the bore of the magnet, 
which is approximately 3 feet in diameter. Also, the scanning coil closely encloses the intervention 
subject's anatomy being imaged. These two factors may increase the likelihood of claustrophobia.
Should the intervention subject feel discomfort, the experiment will be terminated upon their request.
In rare cases, contact with the MRI transmitting and receiving coil or conductive materials such as wires, 
or skin-to-skin contact that forms conductive loops, may result in excessive heating and burns during the 
experiment. The operators of the MRI scanner will take steps, such as using foam pads when necessary, 
to minimize these risks. The intervention subjects will be informed of the risk and instructed to 
immediately report any heating sensations. In the rare event that this would occur the experiment will 
be terminated and, if necessary, we will have the intervention subject seek medical treatment.
Intervention subjects will be screened for magnetic material before each study. Intervention subjects with 
pacemakers, aneurysm clips (metal clips on the wall of large artery), metallic prostheses (including heart 
valves and cochlear implants) or shrapnel fragments are at risk in an MR environment. Welders and metal 
workers are also at risk for injury because of possible small metal fragments in their eyes. Those at risk 
will be excluded from the study.
The effect of exposure to MRI scanning on an unborn child is unknown. Exposure to MRI scanning might 
be harmful to a pregnant female or an unborn child. There are no established risks at this time, but the 
intervention subjects will be informed that there is a possibility of a yet undiscovered pregnancy related 
risk.
MRI scanning produces a loud tone that can cause damage to the inner ear if appropriate protection is 
not used. Adequate protections in the form of earplugs or close-fitting silicon-padded headphones will 
be provided.
We cannot guarantee direct benefits from participating in the MRI assessment. fMRI are unique 
techniques in their ability to non-invasively study human brain function.
Discovery of Previously Unknown Conditions (conditions that can be diagnosed from having access to 
research-quality MRI):
Our scans are not read by a neuroradiologist, and the intervention subjects are explicitly told that the 
experiment will not provide information regarding their health status. However, if the certified MRI 
technician suspects something abnormal, he/she will seek advice from a qualified neuroradiologist, and 
the subject will be notified that his/her MRI indicated a potentially abnormal finding. With the subject’s 
permission we will send information to their physician.
If a participant withdraws from the study, all attempts will be made to collect data to allow for inclusion 
in the analysis. Reasons for withdrawal will be recorded.

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Risk and Protection against Risk related to tDCS Conditions:
The protocol described here uses stimulation levels that fall well within established safety limits. More 
than 500 research studies involving thousands of subjects have been published using tDCS (source: 
PubMed). A number of researchers have addressed the safety of tDCS. They have all concluded that tDCS 
is a painless technique for safely modulating cortical excitability. No serious or long-lasting effects have 
been reported. A recent meta-analysis of 209 studies found no serious adverse effects. The same meta- 
analysis found frequent mild adverse effects, such as itching and tingling49. All of these effects were 
transient and were localized to the skin at the stimulation site. A more focused study with 131 subjects 
undergoing 277 tDCS sessions reported similar findings: no serious adverse effects, but frequent mild 
effects, including itching and tingling50. The most common mild, localized, and transient adverse effects 
are, in order of decreasing frequency: itching, tingling, mild headache and burning sensation. Most people 
do not find these sensations to be painful. Skin redness in the area of stimulation is often reported. 
Itching, tingling and burning usually occur at the beginning of stimulation while the current is ramped up. 
These sensations are reduced by gradual current ramping (as it will be done in this study). Finally, some 
subjects report that these sensations are uncomfortable as some individual characteristics such as type of 
skin and hair might result in a higher stimulation of the skin nerve receptors. tDCS has only short lived, mild 
effects on brain activity. To ensure safe use of the tDCS device, the device will be carefully inspected before 
each use. The batteries will be removed after each use to prevent corrosion that could occur after long 
periods of non-use. The device will be stored in a dry location. Of note, in our pilot study of older subjects 
(reported in the “preliminary studies” section), there have been no adverse events.
We will provide training of the stimulation to our experienced project coordinators. The training will be 
provided by co-I Dr. Tadin, who is an expert in tDCS, and Mia Anthony (an experienced tDCS coordinator 
working on our feasibility study). Evaluation will be conducted by investigator team before a project 
coordinator can independently work on it.
The interventionists will ask every intervention subject’s study partner subject to complete the NPI-Q 
weekly during the intervention period to monitor changes in NPS among the intervention subjects during 
the 4-week tDCS sessions. If any symptoms worsen over the intervention period and a worsening is 
confirmed by the study partner subject, it will be reported as an adverse event (in accordance with 
reporting procedures described in Section 16). The intervention will then be discontinued. Our co-I, Dr. 
Anton Porsteinsson, who is a geriatric psychiatrist, will be notified and provide medical assessment and 
further advice for medical assistance.
Device-Specific Risk Minimization:
Soterix Medical outlines the same risks and risk control features for both devices, tES Model 2001 and 
tDCS Model 1300A, as follows:
Irritation

The applied current may cause minor irritation, discomfort, and/or and redness at the 
electrode sites.

Soterix Medical EASYpad™ electrodes should not be placed over previously irritated, burnt, 
or damaged skin.
Methods of Risk Minimization:

SMARTscan™: a visual 20 bar LED display (1 to 20 from left to right) that indicates to the 

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operator the contact conditions of the electrodes before, during, and after stimulation. LED 
1 denotes short condition and LED 2 denotes open-circuit condition. Stimulation should not 
begin if either LED 1 or LED 2 is lit.

PRE-STIM TICKLE: a pre-stimulation feature that conditions the skin prior to full stimulation,

RELAX: a feature that allows the operator to decrease the set level of current from the 
maximum (FULL CURRENT) value to accommodate subject feedback at any point without 
aborting the stimulation session.

TRUE CURRENT™ display is active whenever the device is on and indicates the actual value 
of current (in mA) being supplied from the device to the electrodes, regardless of device 
settings. This feature functions as a fully independent and redundant safety feature when 
monitored by the operator.

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
Stimulation ABORT: this feature allows the operator to terminate the stimulation at any 
point by pressing the ABORT button, which will ramp down the current to zero in 30 seconds 
and terminate the entire stimulation run. Of note, too rapid ramp down (< 10 seconds) are 
not recommended. Aborting the stimulation run is recommended if the TRUE CURRENT™ 
display deviates from expected output current, the TIME REMAINING display deviates from 
expected duration setting, intervention subject complaints any unusual adverse effects (i.e., 
beyond itching, tingling, mild headache, and mild burning sensation), and/or request to 
stop. In the event that the stimulation is terminated, the device will not be re-started and 
the session will be considered complete.
Risk and Protection against Risk Related to Blood Collection:
We will explain to intervention subjects the potential risks from venous blood collection, which include 
pain, a bruise at the point where the blood is taken, redness and swelling of the vein, infection, and a rare 
risk of fainting. We will utilize trained CRC staff to implement the following strategies to reduce the 
potential risks associated with venous blood collection and to protect research intervention subjects. To 
reduce pain, the CRC staff will use a needle of smaller gauge than the selected vein. To prevent bruising, 
CRC staff will insert the needle into the selected vein at an angle of 30 degrees or less. In addition, the use 
of a needle of smaller gauge helps prevent bruising. For the rare risk of fainting, intervention subjects will 
be asked to lie down if they express concern. Snacks will be provided to intervention subjects after each 
blood collection.
Other Procedure-related Considerations for Protection Against Risks
Informed Consent: At the screening stage, we ask the intervention subject for verbal consent for phone 
screening. If eligible to continue with step 2 of screening, decision-making capacity will be assessed 
using San Diego Brief Assessment of Capacity to Consent (UBACC) to ensure older adults who attend the 
proposed study have adequate capacity for giving consent and making decisions prior to enrollment (see 
section 7 for informed consent details).
Additionally, intervention subjects who lack capacity to consent may become emotionally distressed by 
that determination. However, intervention subjects will be reminded that this determination is merely 
meant to ensure their continued safety and understanding of the research study only, and does not 
indicate any impairment in their daily lives (see additional protections against risks for more details).
Psychological Distress: Although the questions asked of the intervention subjects and study partner 
subjects involved in the study have been regularly used in RCTs, the challenges from answering questions 
about another person, or knowing a study partner subject will be asked to answer questions about the 
intervention subject themselves, may produce frustration or anxiety. The PI will work closely with the 
research staff and intervention subjects/study partner subjects to help alleviate anyconcerns.
Confidentiality and Privacy:
Intervention subject data will be collected with the verbal and/or written consent of the intervention 
subject and study partner subject. Information pertaining to individual participants will be released with 
the participant’s permission only. All participant data will be identified by a uniquely coded screening ID 
assigned to each respondent and study ID for participants eligible for enrollment. Access to the master

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links between name and screening ID, as well as between screening ID and study ID, will be restricted to 
the study team.
All hard-copy based materials and data will be kept in a locked research office in a locked file cabinet. No 
one other than the study team will have access to the data. Once data have been entered into a REDCap 
Consortium (Research Electronic Data Capture), only code numbers (not names) will be associated with
individuals’ research data records. REDCap is a free, secure, HIPAA-compliant, web-based application 
used for electronic management of research study data, which can then be downloaded into SPSS for 
data analysis. REDCap servers are housed at the University of Rochester and all web-based information 
transmission is encrypted. Data from the REDCap database will be directly downloaded to a
password-protected UR-SON server for access by the PI and study team. A list of names, home 
addresses, email (optional), telephone numbers of study participants will be used only for study purpose, 
and study management software (Filemaker Pro) will be used by the study team only, in a secure
manner on UR-SON servers. All School of Nursing servers are routinely audited for vulnerabilities or 
improper configurations by the University of Rochester's Information Security team using the Nessus 
scanner, which is an industry leader in security assessment.
10. POTENTIAL BENEFITS TO INTERVENTION SUBJECTS
Non-invasive brain stimulation has the potential modify cognitive and affective status for older adults at 
risk for dementia but this has not yet been proven. The relatively modest risks associated with the 
activity are reasonable in light of its potential benefits. Participants will have the opportunity to receive 
a 4-week guided and supervised tDCS sessions (including visual attention task for each tDCS session) and 
interact with the study staff.
11. COSTS FOR PARTICIPATION
No
12. PAYMENT FOR PARTICIPATION
Participants will be compensated for up to $170 for the entire study, including $50 for each assessment, 
and $20 for the blood draw. Study partner subjects will be compensated for up to $60 for the entire study, 
including $10 for each NPI completed at each of the 4 weeks of the intervention and post-intervention 
and follow-up assessments. We believe this is a reasonable amount for the time and effort a participant 
and their study partner subject will contribute to the study. In addition, participants will be providing 
reimbursements if they incur parking or transportation costs when attending study-related activities.
13. SUBJECT WITHDRAWALS
Participants may be excluded from the study without their consent or withdraw from the study at 
their own discretion.
Withdrawal Circumstances: Anticipated circumstances under which participants may be excluded from 
the research without their consent include:

Medical conditions which make ongoing participation in the study unsafe for a participant (e.g., 
change in MRI eligibility, seizures, severe depression, and/or suicidal ideations)

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
If the intervention subject withdraws then the study partner subject is automatically withdrawn
14. PRIVACY AND CONFIDENTIALITY OF SUBJECTS AND RESEARCH DATA
Data Security: Participant data will be collected with the verbal and/or written consent of the 
participant. Information pertaining to individual participants will be released with the participant's 
permission only. All participant data will be identified by a uniquely coded screening ID assigned to each 
respondent and study ID for participants eligible for enrollment. Access to the master links between 
name and screening ID as well as between screening ID and study ID will be restricted to the study 
coordinator, interventionist, and staff involved in screening.
Only trained study personnel will have access to participants’ research materials, which will be kept in 
locked facilities and password protected computer system. Manuals for training staff on different parts of 
the data collection have already been developed for different studies, which will be assembled for the 
proposed study.
All participant data (including those collected at the screening) will be collected with the verbal or written 
consent of the participant and study partner subject. Information pertaining to individual participants will 
be released with the participant's informed and written consent only. Participant data will be identified 
by a uniquely assigned study number. Access to the master list of study numbers will be restricted to the 
PI and study staff and maintained and stored in a lab database (Filemaker, Filemaker Inc.) on Filemaker 
server at the URMC. The primary source of study data (computer- and questionnaire-based data) will be 
stored at the lab database (SPSS and Excel). All of these databases are located at a secured site, 
coordinated through the Medical Center at the University of Rochester. Access to these databases is 
restricted to the investigators and trained study personnel. Publications or presentations will report only 
cumulative data or descriptions certain to maintain participants' anonymity. We understand that these 
data are subject to the Privacy Act, Freedom of Information Act, and other Federal government rules and 
regulations, and we will comply with those rules and regulations.
None of the information collected in the study will be automatically recorded to EHR since they are all 
collected in research settings.
For intervention subjects with suspected brain changes identified by CABIN appointed 
radiologist/neurologist (informed by CABIN technician), we will communicate this information with the 
subjects, and send them a picture from T1 upon signing the MRI release form. It is the subject’s 
responsibility to share the form with their healthcare providers.
15. DATA AND SAMPLE STORAGE
Blood Specimen: Blood samples will be collected & processed at CRC. Full cryo boxes will then be 
transferred to 4W-156, -80 freezer in the SON until analysis is completed. Blood Sample Data: We will 
collect information on the following 8 biomarkers: Aβ42, t-tau, p-tau, NfL, BDNF, IGF-1, APOE 4, and 2 
SCACs [C0 and C5]. In addition, we will measure other blood-based biomarkers such as phospholipids. All 
data will be stored on an encrypted, password-protected database on the URMC server that is only 
available to study staff. Individual databases used to house identifying subject information (telephone 
number, address, date of birth) will also be stored on the URMC server, on a password-protected file 
management system, accessible only to study staff. Both databases will be managed by the UR 
information analyst on site. All datasets will be stored pursuant to IRB protocols.
16. DATA AND SAFETY MONITORING PLAN

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We propose a Stage 0 pilot intervention study. The study risk is minimal. The safety monitoring of which 
will be conducted by the research team. All investigators will compose an administrative core to oversee 
the project, holding regular monthly meeting with the research team. For each monthly meeting, the PI 
will present an overall progress statement. The issues/concerns related to the safety of participants will 
include:
(1) The evidence of safety issues that should be addressed;
(2) All serious adverse events determine whether individual patients should be removed from the 
protocol. We acknowledge that there may be rare instances where some emergent situation 
occurs that was unanticipated regarding the welfare of the participant. In these situations, the 
UR IRB may be contacted to help resolve the situation.
In addition, the following steps will be taken to protect the confidentiality of data and computer records 
and participant safety:
(1) Confidentiality will be assured by the maintenance of the data forms in locked offices, and by 
restricted access to computerized data. Only core research team members will have access to the 
name, address, telephone number, and other information corresponding to each identification 
number. Participants will be fully informed of the study requirements throughout the conduct of the 
study and will be allowed the opportunity to withdraw from participation if they cannot, or do not 
comply with the rigors of the research protocol. Handling of data will be limited to the numerical 
values and statistical summaries.
(2) Identifiers linking identification codes with individual names will only be available to the PI and study 
staff who contacts participants.
(3) The PI has obtained the policies of the UR IRB specifically regarding adverse events associated with 
the study. The PI will adhere to those policies and maintain a copy of the policies in the study file.
(4) The investigators will protect the health and safety of participants, inform them of information 
relevant to their continued participation (e.g., newsletters) and pursue the research objective with 
scientific diligence.
(5) The following policies required by our IRB and NIH will be adhered to: (1) any adverse events that 
are serious and unexpected and are related (possibly or probably) to the study will be reported to 
the IRB and NIH within 15 calendar days; (2) adverse events that are both unexpected and related
that are either life threatening or result in death will be reported to IRB and NIH immediately; and (3) 
for adverse events that do not meet the criteria above will be documented in the summary report 
submitted to the IRB and NIH annually at the time of the study’s continuing review. Because the 
proposed study is minimal risk, we do not anticipate any serious adverse effects as described in the 
first two categories from a result of participating in this study.
Expected Adverse Events:

Temporary tingling or itching sensation from tDCS.

Dizziness, mild nausea, headache, a metallic taste in their mouth, sensations of flashing lights, 
heating, and risk of metal projectiles during MRI.

Rating criteria for the severity of adverse events: 
1 = Mild event, no treatment required;
2 = Moderate event, resolved with treatment;
3 = Severe event, resulted in inability to carry on normal activities, ongoing medical 
treatment required;
4 = Life threatening or fatal.

Attribution of the adverse event to the study:
Non-study related = Event clearly not related to doubtfully related to the study; 

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Study-related = Event possibly, likely, or clearly related to the study.
(6) The PI will ensure that the NIH (funding Institute and Center) is informed of the actions, if any, taken 
by the IRB as a result of its continuing review, and recommendations that emanate from the 
monitoring activities.
17. DATA ANALYSIS PLAN
This is a pilot study for mechanistic understanding of the relationship between our previously discovered NPS- 
shared neural circuit and study partner-rated NPS. Results from the study will provide information for accurately 
calculating effect size for future clinical trial. Regardless, in addition to follow the rule of 12-20 subjects per group 
for a pilot clinical trial, we will calculate the sample size. The sample size calculation is based on the effect size of 
LPG related tDCS on visual attention performance (f = 0.45, n = 36). Additionally, the effect size of correlation 
between NPS-shared neural circuit and patient-report NPI-Q was r2 = 0.70 in our previous study3 – here we use a 
much more conservative estimation at r2 = 0.20, the sample size will be n = 37. All of these calculations are based 
on power at 0.80 and alpha at 0.05. For an 8-week follow up, we estimate 10% attrition rate. Therefore, we 
propose a total of 40 intervention subjects for the study.
Aim 1. Determine the effect of tDCS on NPS-shared neural circuit. H: After intervention, the active, 
relative to sham group will have greater increase in LPG activity, indexed by greater activation in LPG in 
response to visual attention task (H1a) and greater increase in resting FC strength between LPG and 
other regions within the NPS-shared neural circuit (H1b). To assess the activation pattern in LPG, we will 
conduct GLM analysis with the SPM software. The coefficients of GLM corresponding to LPG will be 
analyzed through hypothesis testing. We will first conduct a simple t-test to evaluate whether the 
intervention increases LPG activation for each group (at 4 or 8 weeks), and then a more powerful two 
sample kernel test will be used to test activations distribution difference between groups.51 Similarly, we 
will take the FCs between LPG and other regions as a multivariate covariate and apply the two-sample 
kernel test to evaluate group difference in the change of LPG FC pattern after intervention (at 4 or 8 
weeks). In addition, simple multiple testing for each connection will be used as a screening procedure to 
identify a subset of connections included in the kernel test.
Aim 2. Determine the relationship between NPS-shared neural circuit and study partner-report NPS.
H2a. After intervention, the active, relative to sham group will have greater improvement in study 
partner-rated NPS in terms of lower severity and fewer co-existing symptoms: We will fit linear mixed-
effect models for changes in NPS:
where
represents the
NPI measures across time,
is a
 
 
design matrix for the fixed effects and
is a
matrix for
the random effects. The models will include fixed effects such as data collection visit (categorical variable), 
group, visit and group interaction, and covariates identified as being imbalanced among groups. Stepwise 
variable selection based on Akaike Information Criteria will be used to select the fixed effects for inclusion. 
A random participant-specific effect will be included to account for correlation between visits for the same 
participant. The model-based average within-group change will be computed for each outcome at 4 and 
8 weeks. This will allow us to rank the groups in terms of average within-person gains in each outcome. 
We will conduct a composite hypothesis test to assess if the changes at 4 or 8 weeks differ by groups 
(similar to a one-factor ANOVA but accounting for repeated measures). H2b. FC change in NPS-shared 
neural circuit will contribute to the improvement in study partner-rated NPS across groups: We will 
perform epsilon-intensive support vector regression (SVR) with RBF kernel using LIBSVM library.52 The 
Leave-One-Out-Cross-Validation scheme will be applied: each intervention subject will be designated as 

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the test sample once, while the remaining intervention subjects will be used as training sample. All training 
sample’s features (change of voxel activation from the task or change of FCs from the NPS-shared neural 
circuit after intervention) will be trained to predict the test sample’s outcome (change of NPI severity or 
frequency score). We will then perform model fitting of the raw and predicted NPI using linear function 
(f(x)=ax+b). Adjusted R2 will be used to estimate goodness of fit for the model.
Exploratory aim. Examine the relationship between (a) NPS and (b) the coherence between structural 
and functional aspects of the NPS-shared neural circuit. We will conduct a connectome-based analysis to 
find structural connections that are unique to severity of NPI. The TN-PCA method53 will be used to 
correlate with severity of NPI. We can replace the high dimensional tensor network summarizing an 
individual's brain connectome with a K-dimensional vector of brain PC scores; these scores can be used 
for visualizing variation among individuals in their brain connectomes and in statistical analyses studying 
relationships between structural and functional aspects of NPS-shared circuit and covariates. We will 
compare similarities of involved brain regions of NPS circuit for FC and WM across the entire sample at 
baseline. Quantitatively, we will use the Dice similarity coefficient to evaluate the percentage of 
overlapped regions. To examine whether tDCS’ effects on NPS-shared neural circuit and study partner- 
rated NPS depend on baseline WM integrity, first we will compare the correlations between FC (at 
different time points) and baseline WM integrity on the overlapped regions between active vs. sham tDCS 
groups. We expect to see a higher correlation between FC and WM in active group in later time points. 
Next, using SVR described earlier52 we will examine the relationship between the sample’s features 
(baseline WM tracts) and outcome (change of NPI severity or frequency scores).
Blood analysis plan: We will compare AD pathology markers from blood with changes of NPS, cognitive 
measures, and MRI data using correlational analyses. We will also examine if individuals with positive AD 
pathology respond differently to tDCS compared to those with negative AD pathology using ANOVA.

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