Understanding How Alzheimer's Disease Impacts the Therapeutic Response to Transcranial Direct Current Stimulation
Phase: NA
Conditions: Alzheimer Disease
Sponsor: Baycrest

 
 
Date: August 9th, 2022 
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Research Study Title: Understanding how Alzheimer's Disease impacts the therapeutic response to 
transcranial direct current stimulation 
Primary Investigator: Carlos Roncero, Rotman Research Institute, Baycrest Health Sciences, 
troncero@research.baycrest.org 
Co-Investigators: Howard Chertkow, Rotman Research Institute, Baycrest Health Sciences,  
hchertkow@research.baycrest.org 
Clinicaltrials.gov ID: NCT05508841 
INTRODUCTION: 
 
750,000 Canadians have dementia from Alzheimer Disease or other causes, this number will 
double within the next generation, and no new therapies have emerged in the past 20 years. However, a 
new promising therapy is transcranial direct current stimulation (tDCS), a near painless treatment where 
mild electrical current is applied through the scalp to the brain. This has been found to improve 
symptoms in people with dementia. Unfortunately, some studies have also reported that tDCS failed to 
improve symptoms in their participants, so it’s important to understand why tDCS seems to work in 
some cases, but fails to produce an improvement in other cases.  One possible reason is the intensity 
level of tDCS, which is normally 2 mA in studies. Some researchers believe a higher intensity level, 4 mA, 
would produce a bigger improvement.   
LITERATURE REVIEW: 
 
Symptomatic therapy in neurodegenerative diseases (NDD) is very limited. Since 
introduction of the cholinesterase inhibitors in 1995 and Memantine in 2002, there have been no 
new available pharmaceutical therapies. As a result, researchers are looking beyond chemicals for a 
means to ameliorate cognitive impairment. Neuromodulation, particularly tDCS has garnered 
increasing attention as a potential ancillary symptomatic brain therapy for neurological and 
psychiatric conditions, reaching the level of being made clinically available for pain and depression 
[1, 2].  

 
 
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In tDCS, two electrodes (anode and cathode) are secured to the scalp and continuous 
current flows through the brain from anode to cathode, which modulates corresponding neural 
activity. It has been theorized that if these neuronal pathways are activated to a certain level, a 
long-lasting change will occur in the network which allows information to be more easily retrieved 
or remembered. Consistent with this hypothesis, recent studies at a few centers have shown 
clinically meaningful improvement in individuals with neurodegenerative diseases treated with 
transcranial direct current stimulation (tDCS). For instance, we have previously shown a robust 
effect of improved picture naming [3-4] in individuals with Primary Progressive Aphasia (PPA) and 
people living with dementia who also suffered from anomia [5]. We have also published case 
reports where tDCS improved the quality of life in an individual with advanced dementia [6] and 
walking speed in a person with Progressive Supranuclear Palsy [7]. Others have found similar results 
[8-10].  
 
Despite these encouraging results, studies examining tDCS for people with dementia have 
produced variable results. For example, Khedr et al. [11] reported positive tDCS effects, whereas 
Cottelli et al.[12] and Suemoto et al.[13] reported no improvement or equivalence to a placebo 
condition. Neuromodulation, however, is both diverse and relatively recent, with differences 
between approaches, techniques, and electrode montages across studies, making it difficult to 
compare results. As reported by Prehn and Flöel [14] in their review of tDCS for people with 
dementia: “The most effective stimulation parameters for enhancing cognitive function in older 
subjects and patients with AD and MCI are still unclear.” 
 
Our research has increasingly focused on identifying the parameters that increase efficacy. 
For example, in our previous study [5], we found a montage focused on the parietal lobe was 
superior to one focused on the dorsolateral prefrontal cortex (DLPFC) for improving naming ability. 

 
 
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Finding such parameter optimizations is critical for advancing tDCS as a therapy for people with 
dementia as we learn to tailor its administration. In the current project, our central goal is to 
examine a critical additional stimulation parameter: intensity. 
RATIONALE: 
 
tDCS studies typically report significant group effects despite the variability demonstrated 
among participants, with some showing clear, meaningful improvement, while others only show 
statistical improvement or none at all. These variable results may be related to the conventional 
stimulation intensity level of 2mA. Recent evidence suggests an electric field of at least one v/m is 
needed to affect local networks in the brain [15] reliably. However, tDCS at 2mA produces an 
electric field around only 0.6 v/m because a large amount of shunting (a dilution of the incoming 
current) occurs as the current travels from the electrode on the scalp, through the skin, skull, and 
cerebral spinal fluid (CSF), before reaching the brain. The most direct way to increase the electric 
field produced in the brain is to increase the intensity delivered. Current tDCS machines can have an 
intensity level of 4mA, resulting in more substantial electric fields than one v/m. We predict that if 
we were to administer tDCS at 4.0 mA, a more significant number of participants would show a 
meaningful response, and those who improve at 2mA may improve even more from 4.0mA due to 
having a larger electric field produced. 
 
We aim to test this hypothesis in people with Alzheimer’s Disease because they have unique 
attributes that may impact tDCS differently from other populations. More specifically, the amount 
of shunting is predicted to be larger due to increasing CSF from brain atrophy [16]. Thus, 2mA may 
be too weak to be very effective in some people with Alzheimer’s Disease due to the higher level of 
shunting. More significant improvements would be observed from a higher intensity level that can 

 
 
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better interact with the remaining cortex. Alzheimer’s Disease is also predominately female, and 
past studies have suggested men and women respond differently to tDCS [17-24]. For example, 
women have smaller skulls than men in general, which are predicted to receive more of the 
incoming stimulation. Finally, as Alzheimer’s Disease is progressive, the degree of impairment may 
be relevant [25]. We will check if individuals who are more impaired benefit more when the 
stimulation intensity is set higher. The level of impairment will be measured in two ways: (1) the 
baseline score on the task training in the study (baseline severity); and (2) scores collected from 
cognitive testing (cognitive severity). 
Purpose of the Research 
Demonstrating results are possible with 4 mA, which may be superior or unachievable with 2 mA, would 
persuade other researchers to also explore if the improvement (or the lack thereof) in their own tDCS 
studies would be present or larger using 4 mA tDCS. Over time, just as tDCS researchers began favouring 
2 mA over lower intensity levels, 4 mA rather than 2 mA could become the new convention. Also, by 
exploring how individual differences impact the response observed, we can target those individuals who 
are expected to most benefit from tDCS. In this manner, tDCS studies can become more efficient. 
Hypotheses Addressed  
 
The degree of improvement observed in people with Alzheimer’s disease will be significantly 
 
greater when training is carried out at higher stimulation intensity (4mA vs. 2mA, SHAM).  
 
There will be significantly more significant improvement observed when:  
1. individuals have more atrophy (decreased brain volume, higher CSF volume).  
2. Individuals have a higher degree of impairment.  
                             3. The participant is female.  
 

 
 
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PRELIMINARY STUDIES  
 
The proposed study models after our original three-round study [5] where three different 
tDCS montages were compared for improving naming ability. We recently completed another 
three-round study [31] where a mixed group of people with dementia (AD and FTD) concluded 
three consecutive rounds of executive function training with either: 4mA tDCS targeted towards the 
left dorsolateral prefrontal cortex (DLPFC), 2mA tDCS via two anode electrodes to the left and right 
DLPC respectively, or SHAM stimulation, which is the accepted placebo condition in tDCS studies. In 
SHAM stimulation, tDCS is only briefly active at the beginning and end of the session, which mimics 
the real-life sensation of tDCS as feelings are felt mainly only at the beginning and end of the 
session when the current is ramping up or down. We measured how much participants improved 
on an N-Back task, defined as having faster response times. For evaluation, participants completed 
two versions of this N-Back task: one practiced during the tDCS sessions, and another never 
practiced and was only given during evaluations. For trained items, results were similar regardless 
of stimulation condition, but the most significant improvement was found for the 4mA condition for 
untrained items.  
Because the bilateral montage delivered 2mA to each anode electrode over the left and 
right DLPC, finding superior results for the unilateral 4mA condition could be related to the 
involvement of the right DLPFC being stimulated, or due to a stronger intensity level being 
administered. The study proposed here will investigate the latter hypothesis: results were due to a 
more vigorous tDCS intensity (i.e., 4mA). 

 
 
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METHODS: 
Sample 
 
Based on pilot data, we expect a pooled standard deviation for response time on the N-Back 
test of 3,000 ms and a correlation of 0.89 between adjacent time points (pre, post, follow up). For 
80% power to detect a difference across the three levels of intensity, while also accounting for the 
sex of a participant, a repeated-measures ANOVA test at an alpha level of 5% will require 54 
participants with AD (27 men and 27 women). To compensate for anticipated attrition over the 
study, we will recruit a sample of 30 men and 30 women, 60 total, randomized into the three 
treatment arms. These participants would have received the diagnosis of probable AD from 
Baycrest’s Memory Clinic expert staff [32, 33] according to standard clinical criteria. Only patients 
with no family history of epilepsy and who can give consent will be tested. We will seek people with 
mild to moderate AD (Reisberg stages 3, 4, or 5, [34]). Participants must show no history of stroke 
or traumatic brain injury, nor shunts or metal in the head that could interfere with the delivery of 
tDCS. Finally, people will have no evidence of significant heart disease, alcoholism, drug use. All 

 
 
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enrolled participants will be expected to complete an MRI; however, if they are unable to complete 
an MRI due to the presence of an exclusion criterion, they will still be allowed to complete all 
subsequent stages of the study. In the initial assessment, we will verify participants can complete 
the study task (N-Back). Only individuals able to complete this task will be allowed to complete the 
study. 
Recruitment and Pre-Assessment 
 
All participants are recruited following the same enrollment protocol: Initial contact, 
screening, and pre-assessment. For the initial contact, the research coordinator will receive names 
of potential participants from the Clinical Trials Unit at Baycrest. The files of these individuals will be 
acquired from Sam & Ida Ross’s Memory Clinic. Their contact information and diagnosis will be 
noted. They will then be contacted using a prepared telephone script. Those individuals who show 
interest in the study will then be scheduled a screening with Dr. Carlos Tyler Roncero.  
This screening can be done in person at Baycrest, or virtually over Zoom, and the 
participants can choose a particular modality if they have a preference. During the screening, Dr. 
Roncero will go over the consent form with the participant, including the mechanics, history, and 
side-effects of tDCS, and the planned study design (i.e., what participation would entail schedule-
wise). The screening also allows Dr. Roncero to evaluate subjectively if the person may be too 
impaired for the study (for example, if they are unable to communicate or answer questions during 
the screening). If this scenario were to arise, Dr. Roncero would explain to the participant, and 
presumed caregiver, that the person is too impaired for the study. The screening is also an 
opportunity for the potential participant to ask any questions they might have. Assuming the 
participant is agreeable to participating in the study, a pre-assessment will be scheduled.  

 
 
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In this pre-assessment, the participant will be asked to complete versions of the tasks that will be 
administered during the study. In this manner, we can further verify that the potential participant is 
a good candidate for completing the study. Assuming they are able to successfully complete the 
tasks during the pre-assessment, and continued to be interested in participation, he or she would 
then be formally enrolled and scheduled into the study. Otherwise, the participant would be 
explained that they are unable to be enrolled into the study because they are unable to successfully 
complete the tasks planned. Because tDCS is an interactive therapy (a targeted behaviour must 
occur while the stimulation is administered), it is crucial that participants be able to complete the 
planned tasks, and simply receiving tDCS passively (i.e., while doing nothing) would be largely, if not 
completely, ineffective. 
tDCS Parameters 
 
Stimulation will be delivered for 20 minutes concurrent with the beginning of the session,  
with the anode electrode placed over the left DLPC and the cathode over the right DLPC. 
Figure 1 (below). Dorsolateral Prefrontal Cortex Montage. Activation prediction based on modeling 
software from Soterix HD-Explore; color gradients reflect increasing levels of predicted intensity, 
where red reflects a peak intensity of 0.61 mA.   
 
 
 
 
 
 
Study Design 

 
 
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 Participants will be randomized into three treatment arms. Participants will complete three 
rounds of executive function training in each arm, with each round paired with different stimulation 
intensity (SHAM, 2mA, 4mA). The below flowchart displays the procedure that participants will 
follow:
 
Initial Assessment 
 
 In the first week, all participants will receive an initial assessment to gather demographic 
information (age, sex, years of education, racial background, and hand preference) and conduct a 
formal evaluation of participants. Evaluation includes the Montreal Cognitive Assessment (MoCA; 
[26]) and the Mini-Mental State Exam (MMSE; [27]) to assess the level of cognitive function, as well 
as a practice version of the study task (N-Back) where they must state via a button press on a 
computer if the presented image is the same or different from the previous image. This is to ensure the 
participants can complete it in the upcoming study rounds. From these tasks, participants’ 
impairment scores will be calculated. Cognitive severity will be measured as the combined total 
from the MoCA and MMSE (x/30 + x/30). In contrast, baseline severity will be measured as the 

 
 
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average response time on the practice version of the N-Back. Assuming inclusion criteria are met, 
participants in the first week will also complete a structural MRI [view MRI protocol – page 11]. We 
will use SPM 12 to quantify head and tissue layers, including CSF, which will be quantified relative to 
the participant’s skull size. For skull thickness and grey matter, we will quantity regions around the 
left DLPFC. 
Baseline Evaluation  
 
Neither the evaluators nor the participants will be told if the tDCS they received during the 
training sessions was 2mA, 4mA, or SHAM. Therefore, the study will be double-blind. The first 
evaluation will take place right before the first training session begins. Two versions of the N-Back 
task (described later) will be administered: one that will be trained in the upcoming round and one 
that will never be trained. Evaluating performance on trained and untrained lists allows us to 
examine the impact of tDCS on training and how well this improvement generalizes to an untrained 
version, indicating a more global improvement. To determine if the executive function training has 
any additional generalized effects, we will also administer the following tasks to participants during 
evaluation to check for improvement in the following domains: General Cognitive Status, as 
measured by the MoCA and MMSE, Verbal Fluency, as measured by letter fluency tests (letters FAS) 
from Dellis-Kaplan executive function system (D-KEFS, [37]); Mood, assessed by the Geriatric 
Depression Scale (GDS, [38]); Short-Term Memory, measured by a traditional Corsi Block task [39] 
and a digit span forward and backward from Wechsler adult intelligence scale [40]]. These tasks are 
exploratory to check for generalized improvement.  
Training Sessions 
 
 All training sessions will have the same format and involve the administration of tDCS 
combined with training. More specifically, during the first 20 minutes, a research participant will 

 
 
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give sham or tDCS set at 2mA or 4mA for 20 minutes and will remain during the session with the 
participant for safety precautions and troubleshoot any computer problems. Simultaneously with 
the stimulation, participants will use the computer to practice the given N-back task. This N-back 
task is modeled off of the 1-back version of the N-back Matching Task [41]. In that study, 
participants were asked whether a presented digit (e.g., a red 5) was the same as the previously 
shown digit (either a red five or some other number-color combination); they gave their response 
by pressing a key on a keyboard to indicate if the number is the same (i.e., a red 5), or different (i.e., 
something other than a red 5). Following Basak and O’Connell [42], we have created different 
versions of this task but use images (animals, fruits, vehicles, faces) rather than numbers to make 
the task slightly easier for people living with dementia. The only difference between these versions 
is the stimuli presented. We also have normed these versions with normal elderly controls and 
found that response times and errors were similar for all versions. In each round, participants will 
practice a different version of the N-Back. Evaluations specific to that round will also administer a 
round-specific untrained list. 
Subsequent Evaluations 
 
 For each round, in addition to the evaluation just before the first stimulation session, an 
additional evaluation will take place during the final training session, and two weeks later after the 
final session. In this manner, we can obtain a baseline measurement, check for post-stimulation 
changes, and if those changes have continued two-week’s post-stimulation.  
Structural MRI Protocol 
 
Participants will undergo a Structural MRI at Baycrest. The protocol has been informed to 
the MR Technicians (please see attached documents). The Project Coordinator will book the MR 
suite using the Baycrest MR Web Scheduler with a 72 hour notice at the least. 

 
 
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Participants will be asked to arrive 15 minutes before their scheduled scan to review and fill 
the consent and MR screening forms. The participant will then be escorted to the Interview room to 
be interviewed by a Level 11 MR Personnel with respect to their MR screening form and medical 
history prior to changing for the MR exam. After changing, the MR technologist will escort the 
research participant into the magnet room and the accompanying researcher (Assistant, 
Coordinator or PI) to the control area. Post scanning, the lab member accompanying the research 
participant will monitor the change process, and other processes outlined in the “MR Research 
Suite Process Bacycrest – RRI.”  
 
To be able to successfully perform the MRI, lab members will undergo the Virtual MR Safety 
Training & Orientation session and will also receive an in person suite tour.  
Planned Analyses 
 
The primary outcome measure will be improvement on an N-Back Task, both a trained 
version and an untrained version. Improvement will be measured in terms of the average response 
time (i.e., the amount of time needed to make a response). A repeated-measures ANOVA will be 
run to compare the three stimulation conditions (SHAM, 2mA, 4mA) with sex (male, female) as a 
between-subject variable. This analysis will be conducted separately for the trained and untrained 
items. Scheffé tests will compare the different conditions. We expect to find the greatest 
improvement in the 4mA condition.  
 
Next, we will calculate a tDCS time improvement score for each participant per condition: 
the difference between the final average response time on the N-Back task from the last 
stimulation session subtracted from the baseline response time in each condition. To produce tDCS 
effectiveness scores, the time improvement score in the SHAM round will be deducted from the 
number calculated in each real tDCS round. In other words:  

 
 
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• Time Improvement in the 4mA condition minus Time improvement in the SHAM condition;  
• Time Improvement in the 2mA condition minus Time improvement in the SHAM condition.  
 
Thus, a tDCS effectiveness score is calculated for each participant in the 4mA and 2mA 
conditions. These tDCS effectiveness scores will then be the dependent variables in a multivariate 
logistic regression; once for trained items, again for untrained items. The predictors will be the CSF 
level of a participant, grey matter volumes and skull thickness around the DLPFC, impairment scores 
(baseline and cognitive severity), and interactive terms representing the sex of the participant. In 
this manner, we can examine what individual differences predict the tDCS response in people with 
AD and if these predictors are the same for two and 4mA tDCS while checking for sex differences. 
We expect more significant levels of CSF, less DLPFC grey matter, thicker skulls, and greater 
impairment levels will be predictive of more substantial improvement in the 4mA condition. CSF 
and grey matter values may be less predictive for how well women respond to tDCS as their 
relatively smaller heads could compensate for increased shunting levels.  
Finally, a 2 (male AD, female AD) x3 (4mA, 2mA, SHAM) between-subject repeated measures 
ANOVA will be run for tasks administered in evaluation: MoCA scores, to check for changes in 
general cognition, as well as for verbal fluency, digit span, and Corsi to check for generalized 
executive function differences. These analyses are exploratory. 
Funding 
 
This study is supported by BrightFocus Foundation, which reviewed the submitted protocol, and  
awarded funds to Dr. Carlos Tyler Roncero towards completing the proposed study.  
Risks 
 
The tDCS protocol for this experiment was determined according to the best practices observed 
in previous research using tDCS stimulation [45]. Furthermore, tDCS is safe, has virtually no side effects, 

 
 
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is technically easy to carry out, and is not uncomfortable to undergo [46,47]. Multiple studies have also 
reported that the administration of 4 ma tDCS has no more adverse effects than 2 ma tDCS [48]. No 
incidence of seizure has been recorded, although side effects could include headache, drowsiness, 
itching sensation, nausea, and, in rare cases, disorientation.  In our experiences, the only observed and 
reported side-effect has been temporary redness post-stimulation where the sponge was placed, as well 
as the occasionally reported headache.   
 
If the event were to result in lasting pain and hospitalization, then it would be reported as a 
‘Serious Adverse Event” and full details would be noted to the research ethics board as well as Health 
Canada. These events would be recorded on the worksheets being used to collect the rest of the data. 
We must stress, however, that after administering 4 mA tDCS to around 60 participants, for hundreds of 
tDCS sessions, we have never encountered any such event. Although we have safety protocols in place 
for any encountered adverse or severe adverse events, we believe such events will fail to occur in the 
present study. 
Confidentiality 
 
A research study file as well as medical records identifying participants will be maintained within 
Dr. Howard Chertkow’s lab. Names and identifying information will be replaced with a code, and the 
information will be kept on file for 10 years after the end of the study. Data collected from participants’ 
who withdraw from the study will also be kept, unless participants withdraw consent for its use.  
Communication and Publication of Research Results 
 
The found results may be presented at research conferences and written up in a manuscript 
submitted for a publication in a respected science journal. The data will never be used for commercial 
goals and all participant information will remain confidential. Individual’s participant data will be 
presented using a code (e.g., Participant 1), which ensures no reader of the data could identify the 
participant. The results found can also be used to back-up further studies involving 4 mA tDCS because 

 
 
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we will be able to present formal data demonstrating its effectiveness compared to other intensities of 
stimulation (SHAM, 2mA) in people with Alzheimer‘s Disease.  
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