Promoting Adaptive Neuroplasticity in Mild Cognitive Impairment
Phase: NA
Conditions: Mild Cognitive Impairment, Alzheimer's Disease
Sponsor: VA Office of Research and Development

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Promoting Adaptive Neuroplasticity in Mild Cognitive Impairment 
NCT02155946 
July 1, 2022 
 
Note: this protocol has been edited to focus on study methods and to update terminology since the last IRB 
modification 11/14/2019. Some site-specific information has been removed to enhance clarity; the 
methods/procedures remain unchanged. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Objectives: 
Alzheimer’s disease (AD) threatens to overwhelm our national healthcare resources in the coming 
decades [1]. The VA Healthcare System will be disproportionately affected since virtually all of the 7.6 million 
Vietnam Veterans will turn 65 years old in the next decade [2] and the incidence rate of dementia doubles every 
5 years after age 65 [3, 4]. To mitigate the impact of AD, efforts have focused on identifying at-risk participants 
as well as interventions that prolong functioning and delay conversion to AD. The diagnosis of mild cognitive 
impairment (MCI) identifies cognitively symptomatic individuals who are likely to convert to AD [5]. Unfortunately, 
there has been far less progress from an intervention standpoint as existing pharmacological agents have 
questionable impact on cognition and conversion rates and can carry troubling side-effects [6-8]. 
Non-pharmacologic interventions, such as cognitive rehabilitation, offer viable treatment options that are 
comparatively inexpensive and carry virtually no risk. Across a series of studies funded partially through the PI’s 
VA Career Development Awards 1 and 2, we have demonstrated that mnemonic strategies, which are cognitive 
techniques that utilize semantic processing to increase the organization and structure of information, can improve 
MCI participants’ learning and memory for ecologically relevant information, such as face-name [9] and object- 
location associations [10]. These behavioral improvements are accompanied by increased activation within the 
left anterior ventrolateral prefrontal cortex (avlPFC) [11]; a region that is critical for successful memory encoding 
[12, 13] and that is known to play a role in working memory [14] and semantic processing [15]. The primary 
limitations of our work to date are that (1) MCI participants have difficulty generalizing the mnemonic strategies 
to novel contexts, which is critical for improving everyday functioning, and (2) that not all participants show 
improvement. Data from our three independent data sets, two of which are randomized controlled trials, indicate 
that the ability to engage the left avlPFC is critical for mnemonic strategy generalization. Thus, the central 
premise of the proposed study is that non-invasive brain stimulation can enhance functioning in the left avlPFC, 
thereby inducing adaptive neuroplastic changes and increasing the efficacy of mnemonic strategy training in 
participants with MCI. We intend to use transcranial direct current stimulation (tDCS) for this purpose since it 
uses a weak electrical current to modulate neuronal excitability, is safe, and very well tolerated [16, 17]. Critically, 
tDCS has not been used in participants with MCI or paired with mnemonic strategy training, facts that 
make the proposed study truly groundbreaking. 
In the proposed randomized, double-blind study, participants will complete 5 consecutive treatment 
sessions in which they receive either active or sham tDCS targeting the left avlPFC in combination with 
mnemonic strategy training or a conversational control condition (autobiographical memory recall). Participants 
will complete both laboratory-based and real-world memory testing and complete a self-report questionnaire to 
examine strategy generalization. They will also undergo fMRI scanning before and after intervention, which will 
provide critical information about the underlying neural mechanisms, especially whether the targeted brain region 
(left avlPFC) does, in fact, mediate behavioral improvement. Persistence of memory improvement and fMRI 
changes will be examined at a 3-month follow-up. 
 
Specific Aims/Hypotheses: 
Specific Aim 1: Examine the cognitive benefits of tDCS on mnemonic strategy generalization. 
Hypothesis 1: Participants receiving active tDCS will more successfully generalize mnemonic strategies, which 
will be reflected by significantly greater improvement on the outcome measures, when compared to those in 
the sham tDCS group. Active tDCS should also result in more persistent gains when measured at follow-up. 
Specific Aim 2: Examine neuroplastic changes associated with tDCS and mnemonic strategy training. 
Hypothesis 2: The behavioral improvement is mediated by increased use of the left avlPFC, as measured by 
fMRI. We predict that the active tDCS group will show greater training-related increases in left avlPFC activation 
than the sham group (post-training vs. pre-training), and that the magnitude of activation increase in this region 
will correlate with the magnitude of behavioral improvement on our ecologically relevant memory tests. Finally, 
we will use Granger causality analysis to examine effective connectivity changes between the left avlPFC and 
the remainder of the brain. The extent to which active tDCS results in long-term behavioral benefits will be 
reflected by stable activation and effective connectivity patterns at follow-up, versus a regression toward baseline 
in the sham group. 
Specific Aim 3: Examine the relationship between working memory, semantic processing, and mnemonic 
strategy generalization. Hypothesis 3: By increasing left avlPFC activation, active tDCS will also enhance 
working memory and semantic processing whereas sham will not. Subsequent analyses will determine whether 
one or both of these cognitive processes is vital for mnemonic strategy generalization. 

Methodology 
Participants: We will recruit, enroll, and randomize up to 125 participants, age 50 and older, over a 4-
year timeframe from the VA Ann Arbor Healthcare System, the University of Michigan Alzheimer’s Disease 
Center, and the surrounding community (eg.TrialMatch through Alzheimer’s Association). The study team may 
need to consent and screen as many as 225 participants to account for high screen failures. We are also utilizing 
internet resources, such as social media through local businesses and organizations (eg. Barnes and Noble 
Facebook page) for study recruitment purposes. The internet resources will only be used to propagate 
awareness of the study and to supply study member contact information for those that may be interested in 
study participation; these sites will not collect any data. Both veterans and non-veterans will be enrolled for the 
following reasons: 
1) The 2010 Census data show that over 93% of all Veterans are male. However, aging is a universal process 
and females outlive males. There is no empirical or ethical justification for limiting enrollment to just males; in 
fact, the scientific integrity and ecological validity of the study would be compromised by the exclusion of females. 
2) Non-Veteran enrollment must include both males and females in order to avoid confounding sex and military 
service. Enrollment is open to participants regardless of race, gender, or social status. These are the recruitment 
parameters outlined in the Merit Review application, which was approved by VACO. 
Inclusion criteria: Participants will receive a diagnosis of MCI based on the Albert et al. criteria [5], which 
are considered the “gold standard” in the field. Specifically, participants will 1) report a subjective decline in 
memory (report can also be provided by an informant), 2) demonstrate objective impairment in memory (based 
on Neuropsychological testing), and 3) remain independent in activities of daily living. All participants will be 
stable on nootropic medications for at least 1-2 months prior to study initiation. 
Exclusion criteria: A history of 1) contributory other neurological (e.g., epilepsy, moderate - severe 
traumatic brain injury) or medical conditions that are known to affect cognitive functioning; 2) significant 
psychiatric conditions (e.g., moderate - severe depression, bipolar disorder, schizophrenia); 3) sensory 
impairments that limit the ability to take part in the study; 4) a significant history or current use of alcohol or drug 
abuse/dependence. Participants will also be screened to ensure MRI compatibility (assessed using the 
guidelines set forth by the American College of Radiology [78]); some of the criteria for which are also reasons 
for excluding someone from tDCS (e.g., metallic or electronic implants). Eligible participants who cannot undergo 
MRI will be enrolled in the study and will complete only the stimulation and behavioral portions of the study. We 
have successfully used this same approach in our previous RCTs. 
Recruitment: As noted, participants will be recruited from both the VA Ann Arbor Healthcare system and the 
University of Michigan Alzheimer’s Disease Center. The primary recruitment source for the VA will be the   
Neuropsychology Clinic (see letter of support from Dr. Buchtel). Two methods will be used to identify potential 
participants. First, we will review CPRS records for this clinic from the last 6 months in order to identify those 
diagnosed with MCI. Once identified, we will mail an “opt in” letter to such individuals that provides information 
about the study and the study team’s contact information. Second, we will engage in prospective recruitment for 
newly diagnosed participants (or more remotely diagnosed participants who are re-evaluated). This will rely on 
provider referral in which the provider will 1) hand the patient an approved flyer or 2) ask the patient if the provider 
may inform our staff of their interest via in person contact, telephone, or VA-encrypted email. Flyers will also be 
posted within the clinic. 
The primary recruitment site for non-Veterans will be the University of Michigan Alzheimer’s Disease 
Center (MADC). The MADC recruits participants from several sources including its memory disorders clinic, 
community screening events, and external referrals. Participants interested in research are maintained in an 
IRB-approved database (IRB# HUM00000382), which is available to the PI and his study team (see letter of 
support from MADC Director Dr. Paulson). 
While the study team will have a designated member for recruitment efforts, all members are likely to 
contribute to recruitment efforts. Dr. Hampstead personally reviews all relevant information and is the final 
authority on whether or not participants are brought in for screening/cognitive assessment. 
Screening & Cognitive Assessment: After providing informed, written consent, participants will undergo 
a brief neuropsychological protocol to ensure they continue meeting MCI criteria as outlined above. This protocol 
includes standardized measures that are shown in the Table below. Other standardized measures may be added 
to the protocol to characterize the nature of the patient’s cognitive functioning as necessary. The PI has used 
this same protocol in his previous RCTs, which will facilitate direct comparisons between current and previous 
studies. Total time is approximately 85-120 minutes. 
Measures that will be used for both primary and secondary outcome assessment will be collected during 
this session. These include: the Object-location touchscreen test (OLTT), the face-name generalization test, 
ecologically relevant memory tests that require participants to recall the location of objects within our 
laboratory/suite and the names of novel staff members, and the multifactorial memory questionnaire [81]. The 
former tests are all developed by Dr. Hampstead and are critical for assessing the generalization of the trained 
technique(s) to novel information. We have integrated non-invasive eye-tracking technology, via the TOBII 

demonstrating and quantifying training-related changes in cognitive processing following intervention. We may 
also include other ecologically relevant tasks (e.g., Ecological Memory Simulations; spatial navigation task) in 
order to fully evaluate generalization effects. Total time for these tasks is about 30-40 minutes. Thus, total testing 
time is approximately 2 hours – far shorter than standard clinical neuropsychological evaluations. The PI’s 
extensive clinical and research experience indicates that participants tolerate this protocol well. However, they 
will be given breaks as necessary to ensure their comfort and allowed to discontinue at any point. 
 
 
The entire study team(or as many members as are 
present) reviews the neuropsychological 
results to ensure participants meet inclusion criteria 
(Dr. Hampstead has the final decision on whether to 
include a patient). This occurs via weekly laboratory 
meetings (or more often as necessary) that are led 
by Dr. Hampstead. Eligible participants move 
forward into the study, details of which are 
provided below. 
 
Study Procedures: Participants who are 
deemed eligible will undergo a total of 7 sessions 
within a 2-week period of time. An additional 
assessment will be performed at 3-months in order 
to examine the persistence of the training effects. 
Some degree of flexibility is necessary with these 
time frames in order to accommodate both patient 
and MRI availability. If needed, through the 
University of Michigan Fleet Services, participants 
may be also offered transportation in a University-
registered vehicle to and from research related 
activities only. 
 
Session 1: 
fMRI Scanning: Activation will be assessed 
using both memory encoding, working memory, and 
semantic processing paradigms. As noted in the 
above figure, participants will complete scanning 
during Sessions 1, 7, and 8. 
Memory encoding: Participants will complete 
functional runs during which they will encode novel 
stimuli from each of our experimental paradigms 
(face-name and object-location associations). Two 
repeated stimuli within each paradigm will be 
presented multiple times and will serve as the control 
condition. Novel stimuli will be used during each 
scanning session (i.e., Sessions 1, 7, 8). Run order 
will be randomized for each patient while stimulus list. 
The interaction contrast of list and time 

is of primary interest (Novel (post-training > pre-training) > Repeated (post-training > pre-training) or similar 
contrast). We refer to this as the encoding contrast hereafter. Participants will complete a memory test consisting 
of these stimuli outside of the scanner. 
Working memory: Participants will complete a standard n-back working memory paradigm, which requires 
participants to determine whether a given stimulus (e.g., a picture) was seen 2 stimuli ago (i.e., 2-back). In the 0-
back control condition, participants simply push a button as each stimulus appears. The n-back paradigm is 
especially appropriate since a number of populations have shown improvement after prefrontal tDCS. The 
primary contrast of interest will examine the interaction between condition and time: (Post-training (2-back > 0- 
back) > Pre-training (2-back > 0-back). We refer to this as the contrast for item working memory hereafter. 
Semantic processing: Participants will complete an additional semantic decision making task using the 
same 2-back format. The 2-back condition will require them to determine if a given picture is of the same semantic 
category (e.g., an animal) as the one presented 2 stimuli ago. Similar paradigms have effectively engaged the 
left avlPFC [80]. Using the same n-back design holds all task demands constant except for the addition of 
semantic processing. Thus, the primary contrast of interest will subtract out BOLD signal associated with working 
memory from the semantic task via the interaction contrast of task and time: (semantic (2-back post 
> 2-back pre) > item (2-back post > 2-back pre)). We refer to this as the contrast for semantic processing 
hereafter. 
These paradigms allow us to directly examine the cognitive processes underlying mnemonic strategy use 
(Aim 2) as well as any tDCS-related improvements in these other cognitive abilities (Specific Aim 3). 
 
MRI Image Acquisition: All imaging will be performed at either the 
VA Research fMRI facilities or the fMRI laboratory located on North Campus 
at the University of Michigan. Total scan time will be approximately 60-75 
minutes per session. Participants will also have the option to utilize the 
mock scanner at the University of Michigan. The mock scanner has been 
developed by the fMRI laboratory at the University of Michigan, and is used 
to get participants accustomed to a scanner environment. There are no 
magnetic fields associated with the scanner and no data will be collected 
from the mock session. Use of the mock scanner may require an additional 
20 minute session, although we will try to add this on to the evaluation 
session. High-resolution anatomic images will be acquired using a 3D 
MPRAGE sequence with repetition time (TR) 2300 ms, echo time (TE) 3.9 
ms, inversion time (TI): 1100ms, flip angle (FA) 8°, 176 sagittal slices of 1 
mm thickness, in-plane resolution (IPR) 1x1 mm, in-plane matrix (IPM) 
256x256, field of view (FOV) 256 mm. A FLAIR sequence may also be 
utilized to assess white matter hyperintensities. All fMRI data will be 
collected using T2*-weighted functional images acquired with a multi-band slice accelerated gradient-recalled 
echoplanar imaging (EPI) sequence with BOLD contrast and the following parameters: TR: 1000 ms, TE: 25 ms, 
FOV: 220 mm, FA: 50°, 56 axial slices of 2 mm thickness, IPR: 2.0×2.0 mm, IPM: 110×110, 32 channel head 
coil, 2mm isotrophic functional voxels. Resting state data have proven to be beneficial in understanding network-
level changes in those with MCI. Time permitting, such data will be acquired using standard parameters (e.g., 
FOV = 220 mm; TR/TE 2000/25ms, flip angle = 60˚; 74 x 74; matrix size; bandwidth = 2164 Hz/pixel; 64 2.5mm 
interleaved axial slices covering the whole brain, 240 scan volumes). We will modify the above MRI-related 
parameters as necessary in order to optimize data quality and achieve study goals; such changes will occur after 
initial pilot testing and will be held constant throughout the trial thereafter. 
 
Randomization: Participants will be randomized on a 1:1:1:1 ratio to either the combined active tDCS + 
mnemonic strategy training, sham tDCS + mnemonic strategy training, sham tDCS + autobiographical memory 
recall, or active tDCS + autobiographical memory recall groups using a blocked randomization schedule. 
Randomization will use the sealed envelope method in which a group assignment (i.e., a numeric code for the 
tDCS stimulation unit) is placed within a sealed envelope at the beginning of the study. Envelopes are then 
randomly shuffled and numbered with enrolled participants being assigned the next available number. In order to 
keep both participants and our staff blinded to study procedures, the PI had Soterix Medical Inc. program 
stimulation codes into the tDCS unit, such that half provide active and half provide sham stimulation. Study staff 
(i.e., research assistants/coordinators) will remain blinded until the data are analyzed. 
 
 
 

Sessions 2 – 6: 
All groups will undergo 5 training sessions on consecutive days. In order to facilitate participation, we will 
allow for weekend visits if necessary. Each session will last approximately 80 minutes. The first 10 minutes will 
be used to measure and place the tDCS electrodes. The cognitive intervention (i.e., mnemonic strategy training 
or autobiographical memory recall) will occur during the next 60 minutes (the first 20* minutes are concurrent 
with tDCS) and the final 10 minutes will be used to answer any questions. *note – an error in selecting codes 
such that the first 24 participants received 30 minutes of active or sham tDCS while the remaining participants 
received 20 minutes.   
tDCS: Stimulation will be performed using a Soterix Medical Inc. tDCS unit (Clinical Trial system and HD 
stimulation unit) within a quiet room. Each unit automatically discontinues stimulation after the specified time has 
elapsed (here 20 or 30 minutes). The participant will complete a brief questionnaire about the nature and severity 
of any side effects (see tDCS Safety below) as well as whether they believe they received active or sham 
stimulation. The FDA considers these units investigational devices. Based on the safety information provided 
above, review of the scientific literature, and consultation with colleagues, we believe these devices are of non-
significant risk (NSR).  
 
The active tDCS protocol will provide a 30 second ramp-up period in which the electrical current is 
gradually increased, followed by 19 minutes of stimulation at 2mA, and finally a 30 second ramp down period 
during which the electrical current is gradually removed. This “dose” of tDCS is a reasonable starting place and 
has been used in two of the previous tDCS studies in participants with AD [71, 72]. 
The sham tDCS protocol will receive a 30 second ramp-up period to the full 2mA, followed immediately 
by a 30 second ramp down. This is an effective sham condition since it provides the sensation of stimulation but 
without measurable physiologic effects [16]. We will repeat this process during the 19th minute of “stimulation” in 
order to provide participants with a “recency” effect of stimulation. 
 
Mnemonic strategy training condition: This phase of the training will begin at the same time as the tDCS 
stimulation and will persist for approximately 30 minutes after stimulation has ended. This approach capitalizes 
on the neuroplastic changes induced by tDCS and adaptively shapes them to reinforce the interactions 
necessary for successful strategy use. Participants will use the same 3-step FRI process described above. They 
will be required to independently develop the feature, reason, and image cues for each stimulus. A member of 
our research team will monitor and record each step of the process to ensure participant compliance. We will 
provide assistance and model appropriate cues as needed in order to promote successful strategy use. 
Participants will practice developing these cues with faces and names as well as objects and locations within 
each session. 
 
Autobiographical Recall (control): This condition also begins at the same time as tDCS and persists for 
approximately 30 minutes after stimulation has ended. This approach acts as a control condition for the 
mnemonic strategy training by engaging participants in general conversation with our research team, thereby 
matching non-specific factors like engagement and total session time. Conversational prompts will be used to 
facilitate continuous dialogue if participants are unable to spontaneously generate conversation. For example, 
participants may be asked to discuss recent events in the news, daily life (their plans for the day/weekend, etc.), 
and/or historical events in their life (e.g., favorite childhood memory, their wedding day). A member of our research 
staff may also transcribe and subsequently analyze the dialogue for linguistic qualities by Linguistic Inquiry and 
Word Count or other related methods. This approach may be especially informative given that tDCS is being 
performed over the left inferior frontal gyrus (i.e., “Brocca’s area”), which is known to be vital for speech 
production. Thus, it is possible that active tDCS vs. sham tDCS could facilitate speech output over the course of 
the 5 sessions (this possibility will be evaluated in exploratory analyses). It should be noted that we have 
established a method of preserving anonymity during this process; we will screen for potential identifiers listed 
by the Data Privacy and Security stipulations and remove all such identifiers during the transcription phase. We 
will then review the transcription immediately following the session to ensure there are no identifiers. In order to 
protect subjects’ privacy, absolutely no identifiers will be recorded. 
 
Conversations during the above sessions will be recorded using a VA approved and compliant audio 
digital recorder. Digital audio files will also be stored in patient files located in an encrypted virtual server on the 
Virtual Machine NetApp information system hard drive using Fips 40-2 validated software. This system is outlined 
in the approved Data Use Agreement for the study. 
 
 

 
 
Session 7: 
Approximately two or three days after the final training session (depending on scheduling limitations), 
participants will complete fMRI scanning using different versions of each type of stimuli. Participants will complete 
both primary and secondary outcome measures at this point as well. 
 
Session 8: 
Three months after Session 7, participants will return and will perform the ecological memory tests. They 
will then be escorted to the fMRI scanner, where they will perform alternate versions of our scanning paradigms. 
Participants will complete both primary and secondary outcome measures at this point as well. 
 
Statistical Design: 
The primary analytic technique will be regression using the SAS mixed procedure (PROC MIXED – or 
equivalent method), which allows the interdependence of observations to be modeled directly and can include 
subjects with missing data at one of the follow-up periods. PROC MIXED has the capacity to handle unbalanced 
data when the data are missing at random (skipped visits, patient dropout, etc). Each equation will model the 
change from baseline (Session 1) for one of the outcome measures of interest as a function of intervention group, 
post-training session (i.e., Session 7 or 8), and group*post-training session interaction. In addition, all models 
may include potential confounders that differ at baseline between the groups (at p=0.05*) even despite 
randomization (there should be few, if any, given the sample size). We will adjust p-values for significance level 
using the false discovery rate (FDR*). *Note – since the study began, the American Statistical Association released 
a position statement and associated special issue calling for the use of effect sizes and confidence intervals rather 
than strict p-value cut-offs. We will integrate this updated statistical conceptualization in our interpretation.  
 
fMRI data analysis will be performed with standard neuroimaging programs (e.g., AFNI [72], FSL [73], 
BrainVoyager QX, SPM) and in-house programs written in Matlab (Natick, MA). Preprocessing: fMRI 
preprocessing will be performed according to standard methods. For group-level analyses, we will calculate 
voxelwise area-under-curve (AUC) in which the hemodynamic response is averaged across all voxels and time 
points for the contrasts described above (see fMRI scanning section). This has the benefit of providing a single 
value for each group in each session, thereby substantially reducing the number of contrasts and increasing 
power. We will examine the data in the two ways described below, using an FDR-corrected alpha. 
1. The immediate post-training differences in activation change within this ROI will be examined using 
a 4 group X 2 time (Session 1 vs. 7) analysis of variance (ANOVA). The resulting interaction term will 
directly test our hypothesis that active tDCS will result in greater activation than will sham tDCS. A 
second such ANOVA will be performed to examine the long-term effects (i.e., Session 1 vs. 8), where 
the resulting interaction term will test our hypothesis that active tDCS results in a more persistent 
increase in activation relative to sham tDCS. 
2. We will then correlate the change in activation for both the immediate and long-term effects with the 
corresponding average change in behavioral performance on our primary outcome measures of the 
OLTT and FNGT. Separate FDR corrected correlations will be performed for each group. These 
behavioral measures are completely independent of the fMRI data and, therefore, will provide an 
unbiased measure of the relationship between these variables. We predict that the active tDCS group 
will demonstrate more robust relationships between these variables than will the sham group. 
3. To determine whether the activation changes for encoding are associated with item working memory 
and/or semantic processing, we will perform two separate conjunction analyses: (1) the item working 
memory contrast + encoding contrast; (2) semantic processing contrast + encoding contrast. These 
analyses will be performed within both groups using whole-brain activation. 
Because we expect functional reorganization throughout the brain within both groups as a result of 
intervention, we intend to use Granger causality analysis (GCA) to examine changes in the effective connectivity 
between the left avlPFC ROI and the remainder of the brain. 
 
 
 
 
 

 
Additional analyses will be completed using automated modeling software (currently in beta-version) that 
determines, at the individual participant level, how much electrical current reached the targeted brain region(s). This 
will allow us to correlate electrical current at the targeted brain region with both behavior and BOLD signal (i.e., 
“activation” via fMRI) and furthers our a priori intent to examine individual predictors of intervention response. 
Additional analyses will be completed using NeuroQuant (or comparable software) to obtain volumes of brain 
structures. 
Additional analyses will be performed as necessary in order to fully characterize the nature of 
intervention-related changes. 
 
 
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