Prevention of Alzheimer's Dimentia With Cognitive Remediation Plus Transcranial Direct Current Stimulation in Mild Cognitive Impairment and Depression
Phase: NA
Conditions: Mild Cognitive Impairment, Major Depressive Disorder, Recurrent, In Remission, Major Depressive Disorder, Single Episode, in Full Remission
Sponsor: Centre for Addiction and Mental Health

 
 
Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial 
Direct Current Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) 
 
 
NCT02386670 
 
Document Approval Date: December 8, 2020 
 

 
 
PACt-MD Protocol V20 (December 1, 2020) Page 2 
 
 
 
 
Final Protocol 
 
TITLE: 
Prevention of Alzheimer’s Dementia with Cognitive 
Remediation plus Transcranial Direct Current Stimulation 
in Mild Cognitive Impairment and Depression (PACt-MD) 
 
LEAD SITE: 
Centre for Addiction and Mental Health 
 
LEAD INVESTIGATOR: 
Benoit H. Mulsant, MD, MS, FRCPC 
Clinician Scientist, CAMH 
Professor & Chair, Department of Psychiatry 
University of Toronto 
 
LEAD INVESTIGATOR CONTACT: 
Geriatric Mental Health Services. 
1001 Queen St. West Toronto, ON, M6J1H4  
Tel (416) 535-8501 Ext 34749, 
Fax- (416)-260-4189 
E-mail: benoit.mulsant@camh.ca 
 
Co-PIs: 
Bruce. Pollock, M.D, PhD, FRCPC  
Vice President, Research, CAMH 
Professor & Director, Campbell Family Mental Health 
Research Institute University of Toronto 
 
Tarek K Rajji, MD, FRCPC 
Deputy Physician-in-Chief of Research, Geriatric Psychiatry 
Division, CAMH  
Professor, Department of Psychiatry 
University of Toronto 
SOURCE OF SUPPORT: 
Brain Canada 
ORIGINAL PROTOCOL VERSION #1: 
           April 30, 2014 
REVISED PROTOCOL VERSION # 2: 
June 26, 2014 
REVISED PROTOCOL VERSION # 3: 
September 14, 2014 
REVISED PROTOCOL VERSION # 4: 
October 8, 2014 
REVISED PROTOCOL VERSION # 5: 
February 12, 2015 
REVISED PROTOCOL VERSION # 6: 
June 2, 2015 
REVISED PROTOCOL VERSION # 7: 
September 3, 2015 
REVISED PROTOCOL VERSION # 8: 
December 8, 2015  
REVISED PROTOCOL VERSION # 9: 
February 5, 2016 
REVISED PROTOCOL VERSION # 10: 
March 22, 2016 
REVISED PROTOCOL VERSION # 11: 
August 3, 2016 
REVISED PROTOCOL VERSION # 12: 
November 8, 2016 

 
 
PACt-MD Protocol V20 (December 1, 2020) Page 3 
 
 
 
 
REVISED PROTOCOL VERSION # 13: 
January 27, 2017 
REVISED PROTOCOL VERSION # 14: 
May 25, 2017 
REVISED PROTOCOL VERSION # 15: 
January 15, 2018 
REVISED PROTOCOL VERSION # 16: 
July 12, 2018 
REVISED PROTOCOL VERSION # 17: 
October 17, 2018 
REVISED PROTOCOL VERSION # 18: 
February 20, 2020 
REVISED PROTOCOL VERSION # 19: 
September 22, 2020 
REVISED PROTOCOL VERSION # 20: 
December 1, 2020 
 
 
 
TASHN Participating Sites: 
PARTICIPATING SITE: 
Baycrest Centre for Geriatric Care 
 
Co- I 
Linda Mah, MD 
Staff Physician, Baycrest Centre for Geriatric Care 
Assistant 
Professor, 
Department 
of 
Geriatric 
Psychiatry 
University of Toronto 
 
Co- I 
Nicolaas Paul Leonard Gerrit Verhoeff, MD, PhD, FRCPC  
Staff Psychiatrist, Baycrest Geriatric Psychiatry Community 
Service and Brain Health 
Assistant Professor, Department of Psychiatry,  
University of Toronto 
 
PARTICIPATING SITE: 
Centre for Addiction and Mental Health 
 
Co-I:                                                        Sanjeev Kumar, MD, FRCPC 
             Staff Psychiatrist and Clinician Scientist, Geriatric     
             Psychiatry Division, CAMH 
             Assistant Professor, Department of Psychiatry   
             University of Toronto 
 
Co-I:                                                       Dr. Angela Golas, MD, FRCPC    
  Staff Psychiatrist, Geriatric Psychiatry Division, CAMH  
  Geriatric Psychiatry, St. Michael’s Hospital 
                
 
 
 
 
  Assistant Professor, Department of Psychiatry   
  University of Toronto 
 
PARTICIPATING SITE: 
St. Michael’s Hospital 
 
Co- I 
Corinne Fischer, MD, FRCPC 
Director of Geriatric Psychiatry St. Michael's Hospital 

 
 
PACt-MD Protocol V20 (December 1, 2020) Page 4 
Assistant Professor, Department of Psychiatry, 
University of Toronto 
 
 
 
 
PARTICIPATING SITE: 
University Health Network 
 
Co- I 
Alastair Flint, MD, FRCPC, FRANZCP 
Director of Research, Department of 
Psychiatry University Health Network 
Professor, Department of Psychiatry 
University of Toronto 
 
 
 
PARTICIPATING SITE: 
Sunnybrook Health Sciences Centre 
 
 
Co- PI 
Nathan Herrmann, MD, FRCPC 
 
Head, Division of Geriatric Psychiatry Sunnybrook 
Health Sciences Center 
 
Professor, Department of Psychiatry 
 
University of Toronto 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
PACt-MD Protocol V20 (December 1, 2020) Page 5 
 
 
 
 
 
Signature Page for Lead Investigator 
 
Title: Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current 
Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved by the following: 
 
 
 
 
  
 
Dr. Benoit Mulsant 
Signature Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
PACt-MD Protocol V20 (December 1, 2020) Page 6 
 
 
 
 
Signature Page for Site Investigator 
 
Title: Prevention of Alzheimer’s Dementia with Cognitive Remediation plus Transcranial Direct Current 
Stimulation in Mild Cognitive Impairment and Depression (PACt-MD) 
 
 
I have read this protocol and agree to conduct this trial in accordance with all stipulations of the protocol 
and in accordance with the International Conference on Harmonization / Good Clinical Practice. 
 
 
Corinne Fischer, MD, FRCPC 
 
 
 
 
  
 
Signature                                                                    Signature Date 
 
 
Alastair Flint, MD, FRCPC, FRANZCP 
 
 
 
 
  
 
Signature 
Signature Date 
 
 
Nathan Hermann, MD, FRCPC 
 
 
 
 
  
 
Signature 
Signature Date 
 
 
Linda Mah, MD 
 
 
 
 
  
 
Signature 
Signature Date 
 
 
 
 
 

 
 
PACt-MD Protocol V20 (December 1, 2020) Page 7 
 
 
 
Nicolaas Paul Leonard Gerrit, MD 
 
 
 
 
  
 
Signature 
Signature Date 
 
 
Sanjeev Kumar, MD, FRCPC 
 
 
 
 
  
 
Signature 
Signature Date 
 
 
Angela Golas, MD, FRCPC 
 
 
 
 
  
 
Signature 
Signature Date 
 
 
Bruce Pollock, MD 
 
 
 
 
  
 
Signature 
Signature Date 
 
 
Tarek Rajji, MD 
 
 
 
 
  
 
Signature 
Signature Date 
 
 
 
 
 
 
 
 
 
 
 

 
 
PACt-MD Protocol V20 (December 1, 2020) Page 8 
 
 
 
1.1 Objective and Specific Aims 
 
1.2 Abstract: 
By the time Alzheimer’s Dementia (AD) and related disorders (ADRD) are diagnosed the brain has 
sustained substantial insult that limits the efficacy of current treatments. Preventive interventions are 
urgently needed but prevention studies require large numbers of participants and long follow-up periods 
unless they can target a high- risk population. 
 
We propose to study the efficacy of a preventive intervention for AD in three high risk groups: (1) older 
persons with Mild Cognitive Impairment (MCI); (2) older persons with a major depressive disorder (MDD), 
(as indicated by a past major depressive episode (MDE)), without MCI; and (3) older persons with a MDD 
and MCI. MCI is considered a prodromal condition for dementia with a progression rate of about 1% per 
month. Depression has independently been identified as one of the most promising targets for AD 
prevention studies, as, even after successful treatment of their depressive episode, older depressed 
participants develop MCI or dementia at a rate of 1-2% per month. Having a MDE at any time during adult life 
statistically significantly increases the risk for dementia in late life. Several studies have compared the risk of 
developing dementia and its association with a MDE occurring in mid- vs. late-life and observed mixed results. 
Of these studies, some found that the risk of dementia is higher in older adults with a MDE in mid-life; some 
found that the risk is higher in those with a MDE in late-life, and some found that the risk is similar regardless 
of when the MDE occurs. In addition, a large epidemiological study has shown that having been treated with 
an antidepressant at any time during one’s adult life and for any duration is associated with an increased risk 
for dementia. Paradoxically, brief remote exposure to an antidepressant appears to be associated with a higher 
risk for dementia than a prolonged recent exposure. 
 
Our proposed intervention is a combination of cognitive remediation (CR) and non-invasive brain 
stimulation – transcranial Direct Current Stimulation (tDCS). Participants with MCI or a  MDD (with or 
without MCI) will be randomized to tDCS + CR or sham tDCS + sham CR. Both CR and tDCS have been 
shown to induce neuroplasticity and improve cognition. We hypothesize that their combination will enhance 
cognitive reserve and protect against cognitive decline. 
 
Our design is informed by our experience conducting randomized controlled trials (RCTs) in older 
participants with dementia, MCI, or MDD over more than two decades. In our recent donepezil prevention 
trial, combining donepezil with standard antidepressant maintenance prevented cognitive decline and the 
incidence of dementia in participants who had both a MDE in late life and MCI. Building on this 
prevention trial, we conceptualize the proposed study as a high-risk, high-gain RCT aimed at enhancing 
cognitive reserve and preventing cognitive decline and dementia in a high risk population. If we are 
successful in this high risk population, then tDCS + CR can be tested in, and extended to, the general 
population (i.e., for universal prevention) or other groups at high risk for AD (i.e., for selective or indicated 
prevention). 
 
Five Toronto academic sites with a history of successful collaboration will consent up to a total of 500 
participants meeting criteria for MCI (age 60 and older) and MDD (age 65 and older) to reach a target of 375 
enrolled participants initiating the study intervention.  Where a MDD is defined as one or more MDE(s) that  
 
 

 
 
PACt-MD Protocol V20 (December 1, 2020) Page 9 
 
 
 
occurred during the participant’s adult life (i.e., they must have been 18 years of age or older at the time of the 
MDE). For a MDE(s) with an offset date that is more than five years from the time of the study screening visit, 
the participant must have received medical attention (see below) for at least one of their MDEs. For a MDE(s) 
with an offset date of two months to five years from the time of the study screening visit, medical attention for 
the MDE is not required. Participants will be randomized under double-blind conditions to either: i) tDCS + 
CR or ii) sham + sham. They will first receive tDCS + CR (or sham + sham) 5 days a week for 8 weeks, 
followed by home-based CR (or sham) and booster sessions of tDCS + CR (or sham + sham) for 5 days 
every 6 months and followed for 24-84 months, until they develop dementia (or MCI for those who are 
deemed cognitively intact at baseline) or complete the study. 
 
1.3 Objectives: 
By the time Alzheimer’s Dementia (AD) and related disorders (ADRD) are diagnosed the brain has 
sustained substantial insult that limits the efficacy of current treatments. Preventive interventions are 
urgently needed but prevention studies require large numbers of participants and long follow-up periods 
unless they can target a high- risk population. We propose to study the efficacy of a preventive intervention for 
AD in three high-risk groups: (1) older persons with MCI; (2) older persons with a MDD without MCI; and 
(3) older persons with a MDD and MCI. MCI is a significant risk factor for developing AD; while the annual 
incidence of AD in the community in people > 65 years of age is 1-2%/year, in individuals with MCI it is up 
to 15%. Currently there is no pharmacological or non-pharmacological intervention that has demonstrated 
efficacy at reducing or delaying the development of AD in those with MCI. Thus, this high risk, untreated 
population represents an excellent and urgent target for a novel preventative intervention. 
 
In a 2010 report from the National Institutes of Health (NIH), depression was identified as one of six 
potentially modifiable risks for cognitive decline, AD, or both (the five others were diabetes mellitus, 
present smoking, cognitive inactivity, physical inactivity, and diet with high saturated fat and low vegetable 
intake)1. A subsequent Lancet Neurology review2 calculated that successful interventions targeting 
depression could reduce the prevalence of AD by up to 15% in North America, making depression the 
second most promising target for prevention studies after physical inactivity. However, our and others’ data 
have shown that even after successful treatment of depression, older participants still show cognitive deficits3-
6 and develop MCI or dementia at a rate of 1-2% per month3, 7, 8. 
 
Our proposed intervention is a combination of cognitive remediation (CR) and non-invasive brain 
stimulation – transcranial Direct Current Stimulation (tDCS) – in participants with MDD (with or without 
MCI) or with pure MCI. All participants will be randomized to tDCS + CR or sham tDCS + sham CR 
(“sham + sham”). CR enhances frontal lobe activation and neuroplasticity9 and it has been shown to improve 
cognition in depression10-12; tDCS modulates neuronal activity and enhances neuroplasticity13 and it has been 
shown to improve cognition in mild AD14-16. We propose to combine CR and tDCS to optimize CR effects on 
neuroplasticity through tDCS neuromodulation. We hypothesize that through this synergistic effect, tDCS + 
CR will improve and maintain cognition in participants with MDD or MCI, thus preventing the incidence of 
dementia in those with MCI or of MCI in those who are cognitively normal. 
 
Our design is informed by over two decades of experience conducting randomized controlled trials (RCTs) in 
older participants with dementia or a MDD. In our recent donepezil prevention trial, combining donepezil 
with standard antidepressant maintenance prevented cognitive decline and the incidence of dementia in 
participants who experienced a MDE in late-life8. However, donepezil also caused severe mood symptoms 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 10 
in many of these participants supporting the need for a different preventive 
intervention. We conceptualize the proposed RCT as a high-risk, high-gain attempt 
to enhance neuroplasticity and cognitive reserve to prevent dementia in three 
high-risk groups. If we are successful in this population, tDCS + CR can then be  
tested in, and extended to, the general population (i.e., for universal prevention) or other populations at high 
risk for AD (i.e., for selective or indicated prevention). 
 
1.4 Specific Aim and Hypothesis: 
The two primary aims are to compare the efficacy of tDCS + CR vs. sham + sham in participants with a MDD 
(with or without MCI) or pure MCI in (1) preventing long-term cognitive decline (Aim 1) and (2) preventing 
the incidence of dementia (or MCI) (Aim 2). A secondary aim is to assess whether tDCS + CR improves 
cognition acutely. 
 
In addition, exploratory aims will assess the moderating effects of several biomarkers (e.g. peripheral 
biomarkers (e.g., BDNF), genotype, and neuroimaging measures) on tDCS + CR effects. 
 
Hypotheses: Compared to sham + sham, tDCS + CR will significantly slow down long-term cognitive decline 
(H1); reduce the progression of those with MCI to dementia (and of those who are cognitively normal to 
MCI or dementia) (H2); acutely improve cognition (H3). 
 
2.0 Background and Significance 
 
Focus on participants at high-risk for AD 
(1) Participants with MCI. We will enroll participants who meet DSM 5 criteria for Mild 
Neurocognitive Disorder. While all participants will undergo genotyping for ApoE allele carriage and other 
genes that have been identified as risk factors for cognitive impairment, dementia, and depression outcome, 
we chose enrolment based on clinical criteria rather than biomarker-based criteria because most MCI in 
Canada will be diagnosed by clinicians using clinical criteria - Biomarkers such as CSF, ApoE allele status, 
specialized EEG, or quantitative MRI measures are not necessarily recommended at the present. 
(2) Participants with MDD: Participants with  MDD are an ideal group to conduct an RCT of secondary 
prevention of ADRD for the following reasons: first, MDD is prevalent and many participants with MDD  
seek treatment, thus they can be recruited and retained in long-term RCTs (see Preliminary Studies) at a 
higher rate than in studies enrolling participants with pure MCI or mild AD17. Second, preventing recurrence 
of MDD is already well established and can be offered “in the background”, forming a structure for the 
retention of participants for an AD prevention RCT. Finally, even with successful treatment of MDD and 
prevention of its recurrence, older participants with MDD remain at high risk for dementia and about half 
already suffer from MCI, thus most are motivated to receive an intervention that may prevent ADRD (see 
Preliminary Studies below). 
 
MCI. As an intermediate state between normal cognition and incipient dementia, MCI represents the  
highest known clinically identifiable risk-indication of non-familial Alzheimer-type dementia; the incidence of 
AD in the community in people >65 years of age is 1-2%/year, whereas in individuals with MCI the risk is up 
to 15%. While clinically established, no therapies exist to treat MCI symptomatically or to slow its 
progression to dementia. Thus, individuals identified as having MCI constitute the most important at-risk  
 
population for developing AD, and represent a critical participant population for prevention of further 
progression of disease. 
 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 11 
MDD and Dementia. Depression has been identified as the second most promising 
modifiable risk factors for ADRD after physical inactivity2. In two meta-analyses, 
a life-time history of depression doubles the risk of AD18, 19. A recent depressive 
episode (i.e., within 10 years) increases the risk of dementia or AD 4-6 fold20, 21. Among non-demented older 
participants with MDD and cognitive impairment, progression rates to dementia are 30-45% over follow-up of 
up to 3 years3, 8 and > 50% over longer periods7, 21. 
 
MDD and MCI. The relationship between MDD and MCI is complex. In the CHS population-based study, 
20% of MCI participants exhibited depression22. Conversely, in our and others’ studies, 40-60% of non-
demented older participants with remitted MDD qualify for a diagnosis of MCI: 44% of older participants 
with MDD in our donepezil prevention RCT8 were diagnosed with MCI after having responded to 
antidepressant treatment and 33% of them progressed to dementia over the next 24 months. Of those who 
became demented, 83% were diagnosed with AD. The literature suggests that cognitive impairment in MDD 
is a form of MCI2, which is a major risk factor or precursor to AD23. 
 
MDD and Cognitive Impairment. Cognitive deficits in non-demented older participants with MDD are 
highly prevalent and they lead to dementia in a large proportion of participants7, 8, 21, 24. They are mainly 
observed in information processing speed, executive function, attention and inhibition, and both verbal and 
visuospatial memory4-6, 25-30. Deficits in executive function and memory both increase the risk of 
depression relapse during antidepressant maintenance25 and predict progression to dementia21, 24. 
 
Rationale for CR: Cognitive-behavioural therapy or problem-solving therapy improves depressive symptoms 
but they do not directly target cognitive deficits and there is no published evidence that they improve them in 
MDD33. By contrast, CR addresses cognitive inactivity- one of the six identified major modifiable risk factors 
for AD1  and it enhances executive function and memory, both highly relevant to cognitive decline and 
progression to ADRD in MDD (see above). CR has been shown to improve cognition in schizophrenia34, 
bipolar disorder35, 36, alcohol dependence37, and major depression10-12. 
Table 1: Controlled Trials of CR in Major Depression: Effect on Cognition10-12. 
Ref. N (mean 
age + SD) 
Frequency and 
duration of CR 
Results 
Media
n ES 
10 
24 (50.3 + 6.4) 
2/wk x 10 wks 
Verbal memory and attention 
0.54 
11 
16 (33.6 + 11.2) 
2/wk x 10 wks 
Verbal learning and recall 
0.45 
12 
33 (49.2 + 11.8) 
1/wk x 10 wks 
Verbal learning and memory 
Attention and processing speed 
1.07 
0.65 
 
The third trial in depression12 was led by Dr. Bowie, one of the team members. Its effect sizes (ES) were larger 
and it differed from the two previous trials by including not just computerized drill–based exercises but also 
strategic self-monitoring and bridging to real life. We propose to use this approach with the same computer 
exercises and therapist-based group sessions (see below). The rationale for using daily CR initially is two-
fold. First, we are proposing that CR and tDCS will have a synergistic effect and tDCS will be  
 
 
 
administered daily (see below).Second, the amount of CR completed and cognitive improvement are 
correlated12 suggesting that more frequent CR is likely to increase its effects. Thus, participants will also 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 12 
performed computerized drill-based cognitive exercises at home daily for 20 
minutes, between the therapist-led group sessions.  
 
Table 2: Trials of tDCS in Mild to Moderate AD: Effect on Cognition14-16 
Ref. N (mean age 
+ SD or range) 
Duration of tDCS 
and design 
Results 
14 
10 (75.2 + 7.3) 
15-min 
session 
Anodal tDCS vs. sham 
17% improvement in word 
recognition and discrimination 
15 
10 (70-92) 
30-min session 
Left DLPFC or left temporal 
cortex vs. sham 
Improvement 
in 
visual 
recognition memory: DLPFC: 
18%; temporal cortex: 14% 
16 
15 (78.9 + 8.2) 
30-min session 
1/day x 5 days to right & left 
temporal cortex vs. sham 
Improved 
visual 
recognition 
memory that persisted for length 
of study (four weeks) 
 
Rationale for booster: To date, all brain stimulation treatments that are used acutely (e.g., ECT, rTMS) 
require some form of long-term maintenance treatment, using either the same form of treatment (e.g., 
continuation/maintenance ECT or rTMS) or a different one (e.g., psychotropic medications or 
psychotherapy). Similarly, most preventive interventions typically require long-term courses regardless of 
whether a biological intervention is used (e.g., anticoagulants for the prevention of strokes41 or a behavioral 
ones (e.g., diet and physical activity for the prevention of diabetes42. Thus, we believe that maintenance 
(“booster”) sessions are necessary to maintain the expected effects of the initial 8-week intervention. 
Based on other maintenance and prevention models, we also believe that higher intensity and frequency 
would be more efficacious but also more burdensome. Thus, in the absence of data to guide the selection of 
the frequency or intensity of the maintenance intervention, we are proposing to study a 5-day “booster” every 
6 months because 5 days allow us to repeat all the CR exercises and we do not expect that it will burden the 
participants and their family. 
 
Rationale for tDCS: tDCS is a non-invasive brain stimulation method that can be safely administered to 
awake outpatients. It does not require general anesthesia or surgical implantation. It utilizes low 
intensity electrical current (e.g., 2 mA) either to increase cortical excitability with an anodal electrode or to 
suppress cortical excitability with a cathodal electrode13. Anodal tDCS improves memory in participants with 
mild to moderate AD when applied to the temporo-parietal cortex or left DLPFC14-16. These three studies 
suggest that even in AD, anodal tDCS improves cognition. Thus, we expect larger anodal tDCS effects 
among participants with MDD at high risk for AD but not yet demented. These and other studies also 
suggest that the priming effect of anodal tDCS could enhance the effects of CR administered shortly after  
tDCS. 
 
 
 
 
 
 
 
 
Optimal Electrode Placement and Stimulation parameters: 
Anodal tDCS has also been tested as a treatment for major depression43,44. In one recent RCT44, 120  

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 13 
participants (mean age: 42 + 12) with major depression were randomized to 
sertraline vs. placebo and active tDCS vs. sham using a 2x2 factorial design. 
During twelve daily 30-min. sessions, anodal tDCS (2 
mA) was delivered to the left DLPFC and cathodal tDCS to the right DLPFC. Depression improved with 
tDCS, sertraline, or their combination but the combination was most efficacious. Also, prior to 
randomization, one session of bilateral tDCS with the same parameters enhanced working memory45. We 
plan to use similar tDCS parameters in our RCT. In another study, one session of anodal tDCS to the left 
DLPFC of 22 antidepressant responders (mean age: 32 + 10) normalized deficits in cognitive control over 
emotional distractions during a working memory task46. These two studies suggest that tDCS improves 
cognition in participants with depression and targets the same function and structures as targeted by CR. 
 
We plan to deliver excitatory stimulation bilaterally to the frontal lobes and in particular the left and right 
DLPFC. Based on simulation models, we will place the anode at Fz and the cathode at Iz to acheive this 
bilateral frontal excitatory stimulation. This is different than the left anodal and right cathodal tDCS as in 
the two studies that included participants with depression described above43,44,46. Rubber electrodes will be 
inserted in 35-cm2 saline- soaked sponges and fixed with a headband. The direct current will be of 2 mA 
(current density = 0.57 A/m2) for 30 min per day, just before the start of each CR group session. 
 
The rationale of using bilateral frontal excitatory stimulation with a midline (Fz) anode is that anodal tDCS 
has been associated with enhanced cortical function while cathodal tDCS has been associated with reduction in 
cortical function14. In studies focused on acutely depressed participants, cathodal tDCS is delivered to the right 
and anodal tDCS to the left DLPFC as hyperactivity of the right DLPFC and hypoactivity of the left 
DLPFC are reported during acute depression47-50. In contrast, we will be administering tDCS to participants 
after they were successfully treated for an episode of MDD and are stable. These participants have been 
reported to have bilateral hypofrontality51,52. Hence, we chose to excite both the right and left DLPFC 
and consequently enhance DLPFC function and working memory. This approach is also relevant to the 
participants with pure MCI that we are now proposing to include: a course of daily bilateral anodal tDCS for 
5 days in participants with mild AD has been shown to improve visual memory with a persistent effect of up 
to 4 weeks53. 
 
Sham tDCS will use the same parameters except that the device will be turned off after 1 min of active 
stimulation. This approach has been shown in other studies to be effective in ensuring that the participants are 
blind to the type of stimulation (active vs. sham) since this sham condition is associated with the common 
side effects of mild scratching and discomfort that are experienced immediately after stimulation is 
initiated54,93. 
 
tDCS and sham tDCS will be administered by certified technicians under the supervision of research 
physicians. Although tDCS is straightforward to apply, these technicians will complete a tDCS practical course 
before administering tDCS; they will also participate in assessments and courses at regular intervals to 
ensure that the administration of the intervention remains standardized throughout the study. These technicians 
will not be blind to the interventions but they will not be involved in any research assessment. 
 
tDCS and Neuroplasticity 
Animal studies support that tDCS has lasting effects on neuroplasticity55 and that BDNF is a key mediator of 
this effect56. In healthy humans, anodal tDCS delivered to the DLPFC improves executive function and 
working memory 57-59. When combined with working memory training, it enhances performance beyond 
working memory training alone58. This supports our rationale for combining tDCS with CR. Enhanced 
executive function to anodal tDCS to the DLPFC persisted for 12 months after stimulation59, supporting long-

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 14 
lasting neuroplasticity effects. The persistent effects of tDCS on neuroplasticity are 
also supported by neurophysiological studies60, including a recent study using 
transcranial magnetic stimulation (TMS)-evoked EEG potentials61. Finally, this 
increase in neuroplasticity is proportional to the number of tDCS sessions62. Thus, we propose to use multiple 
sessions. In summary, animal and human studies support that tDCS increases neuroplasticity. Thus, we propose 
to combine tDCS with CR as we hypothesize that through its neuroplasticity effect, tDCS will prime the brain 
and optimize its response to CR. 
 
Safety Profile 
tDCS has previously been used in multiple studies involving older, frail participants with neuropsychiatric 
disorders such as AD, depression, Parkinson’s disease, or stroke, with no adverse sequelae noted 63-65,53,44. In 
our own experience, the procedure produces a mild tingling sensation initially which usually completely 
resolves within 30 seconds. In a study that systematically elicited side effects in 77 healthy controls and 25 
participants who underwent 567 tDCS sessions66, participants reported a mild tingling sensation (71%), 
moderate fatigue (35%), a slight itching sensation under the stimulation electrodes (30%), a mild headache 
(12%), nausea (3%), or insomnia (1%); only 18% as mildly unpleasant. 
 
Compliance and User Experience 
The investigators in this study have been involved in several clinical trials using brain stimulation that has 
required daily treatment as in the proposed study: over the past 7 years, they have successfully treated 
older participants with daily rTMS or tDCS for up to 6 weeks followed by various long-term maintenance 
protocols. In these studies, compliance issues did not interfere with the study scientific objectives. In general, 
we observe higher compliance with daily treatment in older adults than in younger ones since the majority of 
these older adults are not working. In the proposed study, participants will come on site for daily treatment 
with tDCS + CR or sham + sham. Thus, we will be able to monitor and support compliance with the core  
components of the intervention. We will also be able to monitor and support compliance with home CR 
exercise. 
 
Why Targeting the DLPFC with tDCS? 
Several lines of evidence suggest that the DLPFC provides neural substrate for cognitive reserve in 
participants with AD: it is hyperactive in healthy individuals who are carriers of ApoE4 during learning and 
recall67. It is hyperactive in participants with MCI during a semantic task68. Finally, amyloid plaques and 
thinning of micro- columns in the DLPFC of participants with mild AD are associated with decreased 
cognitive reserve rather than with cognitive deficits thought to be more specific of AD69. This is consistent 
with the compensatory role attributed to the prefrontal cortex in normal cognitive aging70. Given its capacity 
to experience neuroplasticity in response to injury71, the DLPFC is thought to compensate for the cognitive 
effects of plaques and tangles in other regions of the brain (e.g., parahippocampus). In turn, accumulation of 
these plaques and tangles in the DLPFC compromises its capacity for neuroplasticity and results in 
cognitive decline and dementia 69. Thus, we propose that enhancing neuroplasticity in the DLPFC with 
tDCS and CR will increase cognitive reserve, improve cognition, and alter the trajectory of cognitive deficits in 
participants with MDD. 
 
Why tDCS rather Than Other Forms of Brain Stimulation? 
Our team has experience in other forms of brain stimulation (i.e., ECT, MST, DBS, rTMS), some of which 
have shown some beneficial effects on cognition (e.g., rTMS, DBS). However, for this study, we chose 
tDCS because of: (1) the published data in both AD and depression (see above); (2) its tolerability and safety 
even in frail elderly; (3) its ease of use and low cost, increasing the likelihood that its use can be generalized 
(e.g., in primary care practice) if our RCT is successful. 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 15 
 
Rationale for Biomarkers: We will collect biomarkers at T0 (including MRI at 
T0, T2, T9/Tx, and other*) to better characterize our participants and their risk for 
developing AD (or MCI). These analyses should be useful whether the RCT leads to positive or negative 
results: if results are positive, biomarkers analyses could identify mechanistic moderators. If results are 
negative (e.g., because of lack of power), we could still detect significant changes in biomarkers because of 
their lower variability and higher effect sizes than cognitive and diagnostic measures72. 
* Additional LP biomarkers will be collected prior to the LP procedure which can occur at any point in the 
study.  
Table 3: Proposed Biomarkers and Brief Rationale for their Inclusion 
Genotyping 
including ApoE 
status 
Strongest genetic predictor for AD; vulnerability to stress associated 
with reduced hippocampal volumes and glucose hypometabolism75 
T0 
CSF biomarkers: a- 
beta 42, phospho- 
tau, and tau levels 
Abnormalities in CSF may also identify participants who are in the 
pre-symptomatic phases of Alzheimer’s Dementia76,77 
T0 
BDNF and other 
peripheral markers 
BDNF lowered in depression and increased by antidepressant78 
lowered in AD79 
T0, T9/Tx, 
other 
Structural 
and 
volumetric MRI 
measures 
Support diagnosis of AD vs. vascular dementia. Entorhinal cortex 
thickness and hippocampal volume predict dementia80; MDD 
associated with small temporal lobes 81 and smaller hippocampal 
volume82,83 
T0, T2, 
T9/Tx 
DTI measures 
MDD with MCI associated with more frontal, parietal and 
temporal white matter atrophy84 
T0, T2, 
T9/Tx 
EEG 
EEG will be used to study theta-gamma coupling during the working 
memory task (“N-back”) as a probe of the DLPFC function. We will 
assess whether: (1) baseline theta-gamma coupling during N-back is a 
moderator of cognitive change in response to CR + tDCS; (2) change 
in theta-gamma coupling during N-back is a mediator of cognitive 
change in response to CR + tDCS. Working memory is a core 
cognitive function that we aim at improving with CR + tDCS. 
T0, 
T2, 
T3..,T9/Tx 
 
Rationale for Main Design Choices:  
(1) In MDD, we will administer tDCS + CR (or sham + sham) only to the participants who have a history 
of a resolved MDE because we want to establish a stable baseline of cognitive performance and assess 
for MCI and rule out dementia after MDD response, without the confounding effects of a current 
depressive episode. The frequency of CR and tDCS during the induction phase is based on published  
 
 
results in depressed adults44. Based on our experience with brain stimulation trials43, we are confident that 
participants with MDD can comply with 5 sessions/week for 8 weeks. The acute effect of this induction phase 
will be assessed at T2. The consolidation phase is based on the evidence of a dose/response relationship for 
both CR and tDCS (i.e.,  more sessions result in better effect) (see above). A 5-day “booster” every 6 
months allows the repeat of all the CR exercises and we do not expect that it will burden the participants and 
their family. 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 16 
2) Using progression from cognitively normal to MCI or MCI to dementia as 
endpoints is congruent with recent recommendations for AD prevention trials2. 
As in the donepezil prevention trial, rather than cut-off cognitive scores, we 
will use a consensus conference to determine whether participants meet diagnostic criteria for MCI or 
dementia at all assessment points (T0 and T2 to T9/TX). If participants meet criteria for any dementia at 
baseline or at T0, they will not be randomized since our aim is to study the prevention of dementia. 
Subsequently (i.e., after randomization), if a participant meets criteria for any dementia (or MCI for those 
who are cognitively normal at T2), this will be an informative endpoint. The consensus conference will take 
into account scores of the neuropsychological tests, CDR89, and E-COG, and whether cognitive  impairments 
represent a decline, are accompanied by functional decline, or are attributable to causes other than a 
dementia. This approach has high inter-rater reliability for dementia89,90 and a high sensitivity (98%)  
and specificity (88%) for the diagnosis of probable AD89,90. It will ensure that participants receive appropriate 
diagnoses of MCI and dementia, maximizing their safety and protection. 
 
Preliminary Studies: The proposed study is the continuation of a series of NIH-funded prevention studies of 
MDD, primarily in persons who experienced a MDE in late life. In 2 RCTs published in JAMA86 and the New 
England J. of Medicine85, antidepressant maintenance prevented the recurrence of MDD in young-olds86 and 
old-olds with either an early-onset depression recurring in late life or a first (“late-onset”) depression85. These 
RCTs also served as platforms to study cognition in MDEs which occurred in late life (see above). Failure 
both to normalize cognition and to halt its decline despite successful antidepressant maintenance led to a 
third RCT designed to test whether donepezil combined with long-term maintenance with citalopram (a SSRI) 
or venlafaxine (a Serotonin-Norepinephrine Reuptake Inhibitor – SNRI) would be superior to placebo 
combined with antidepressant maintenance to prevent cognitive decline and dementia in participants diagnosed 
with MDD in late-life8. To our knowledge, this trial remains the only published RCT to assess the 
prevention of cognitive decline and MCI or dementia in MDD, which presented in latelife: 130 (62%) of 
209 non-demented participants with MDD aged 70 and older responded to acute open treatment with 
citalopram or venlafaxine and consented to be randomized; 57 (44% of those randomized) had MCI [amnestic: 
35 (27%); non-amnestic: 22 (17%)] and 73 (56%) had “normal cognition.” Donepezil temporarily improved 
global cognition, but ES were small (Cohen d=0.27). Donepezil was more likely than placebo to be 
associated with recurrence of a MDE (35% vs. 19%; HR = 2.09 [95% CI: 1.00-4.41]). Of the 27 
participants with MCI on placebo, 9 (33%) progressed to dementia over 2 years vs. 3 (10%) of 30 on 
donepezil (p=0.05) [8: probable AD; 2: possible AD; 1: FTD; 1: other dementia]. In the MCI subgroup, 
depression recurrence rates were 12% with placebo vs. 44% with donepezil (LR=4.91; p=0.03). Of the 36 
participants without MCI (“normal cognition”) on placebo, 8 (22%) progressed to MCI7  or dementia1  over 2 
years vs. 6 of 37 on donepezil (16%)  [all progressing to MCI] (p=0.56). Among the 63 participants on 
placebo, 9 (13%) terminated the trial due to non- informative events (intercurrent physical illness, 
withdrawal of consent, etc). 
 
3.0 Research Design and Methods 
 
Summary: We will consent up to 500 participants meeting criteria for MCI (age 60 and older) and MDD (age 65 
and older) in order to reach a target of 375 randomized participants initiating the study intervention,  where a 
MDD is defined as one or more MDE(s) that occurred during the participant’s adult life (i.e. they must have been 
18 years of age or older at the time of the MDE). For a MDE(s) with an offset date within two months to five years 
from the time of the study screening visit, medical attention for the MDE is not required. For a MDE(s) with an 
offset date that is more than five years from the time of the study screening visit, the participant must have 
received medical attention for at least one of their MDEs. They will be randomized to: (1) tDCS + CR or (2) sham 
tDCS + sham CR (“sham + sham”). Participants will be followed for 24-84 months or until progression of 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 17 
those with MCI to dementia (and of those who are cognitively normal to MCI or 
dementia For the purpose of normalizing the neuropsychological measures, we will 
also recruit up to 200 controls  in order to complete assessments in 
up to 80 cognitively intact participants age 60 and over. 
 
4.0 Research Design and Methodology 
 
4.1 Methods: 
A) Screening, Clinical and Baseline Assessments –  
 
Participants will fall into one of three Groups: 
 
Group 1: “Pure Depression”: Group 1 is made up of individuals who have a MDD and do not have 
MCI, defined as meeting the criteria of either (a) or (b): 
(a) Meeting the DSM 5 criteria for one or more MDE(s), with an off-set of 2 months to 5 years from 
the screening visit date. It is not necessary for this (these) episode(s) to have received medical 
attention. 
(b) Meeting the DSM 5 criteria for one or more MDE(s), with an off-set of ≥5 years from the screening 
visit date. It is necessary that at least one MDE received medical attention (e.g., previously been on 
one or more antidepressant(s), saw a psychiatrist, primary care physician, or had a previous 
hospitalization) and the MDE must have occurred during the individual’s adult life (i.e., 18 years of 
age or older).   
 
Group 2: “Pure MCI”: Group 2 is made up of individuals who only have a diagnosis of MCI and no 
history of depression. In other words, they meet DSM 5 criteria for a MCI diagnosis and do not meet 
SCID/DSM 5 criteria for a MDE at any time in their adult life. 
 
Group 3: "MCI and Depression”: Group 3 is made up of individuals who have a current MCI diagnosis 
and a MDD. In other words, they meet both DSM 5 criteria for MCI and SCID/DSM 5 criteria both 
forone or more MDE(s) at any time during their adult life (18 years of age or older) and may or may 
not have involved the use of antidepressants. 
 
After the risks and benefits of participating in the study are explained to them by a physician, potential 
participants will be asked to sign an informed consent form. They will then complete the baseline research 
assessment. Participants will be screened with the Structured Clinical Interview for DSM-IV updated for 
DSM127 and with DSM 5 criteria for a mild neurocognitive disorder (MCI) and major neurocognitive disorder 
(“dementia”) to determine eligibility based on inclusion and exclusion criteria. 
 
At the time of enrolment, all participants will have a medical history to assess their physical health, 
determine whether they can safely participate in the study, and determine whether there might be a medical 
illness that may be causing some cognitive impairment or other symptoms. In addition, all participants will 
have had a physical examination and standard laboratory tests within the past 6 months. During screening, 
if a clinically significant and/or unexpected disease or condition is detected, the individual will be 
encouraged to follow-up with their primary care physician or report to an emergency room. 
 
Diagnoses of Mild Neurocognitive Disorder and dementia and their subtypes will be based on the updated 
DSM-5 criteria and will be made during consensus. We will use a comprehensive neuropsychological battery 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 18 
(see appendix A) that are standardized, reliable, and sensitive to neurological 
and psychiatric disorders, in particular LLD. 
 
B) Randomization and Intervention - To ensure similar populations in the two arms of the study, 
randomization will be stratified based on having: (1) “Pure MC I” vs. “MC I an d D ep r ess i o n” ,  
vs. “Pure Depres sion”.  Participants in each of these three groups will be randomized to receive either 
tDCS + CR or sham tDCS + sham CR (“sham + sham”). 
 
Cognitive Remediation (CR) - Sessions will be administered in a group setting under the supervision of 
trained interventionists. Each group will meet daily for 2 hours, 5 days/week, for 8 weeks initially (“induction 
phase”) and then for 5 days every 6 months (“consolidation phase”). In addition, participants will perform CR 
exercises online at home. Participants will be followed for 24-84 months or until progression of those with 
MCI to dementia (and of those who are cognitively normal to MCI or dementia). CR group sessions will 
utilize didactic and drill-based exercises. The computerized drill-based exercises focus on practice and 
repetition of neurocognitive ability areas that are affected in depression such as attention, processing speed, 
executive function, verbal memory, and working memory. Performance feedback is given to reinforce 
progress and the exercises are designed to be enjoyable to complete, with titrated difficulty levels over 
time. “Strategic monitoring” promotes transfer of cognitive gains to everyday. Participants are also encouraged 
to discuss how to generalize therapeutic gains in the laboratory to community environments (“bridging”). 
 
During home-based online CR, participants will practice drill-based exercises that complement those 
performed in group sessions and also target attentional control, executive function, working memory, and 
information processing speed with tasks that adapt within- and between-sessions. Participants will receive  
training on the use of the home-based exercises. A manual will be provided and a help 1-800 number will be 
given for assistance in logging into or using the program. Participants will be asked to complete exercises in 
two 20-minute intervals each day. Online participation will be monitored as participants will have their own 
accounts. E-mails or phone reminders can be used for participants who do not complete prescribed tasks 
regularly. Based on previous performance, task difficulty is modified to maintain an optimal level of 
performance by adjusting the speed, complexity and integrity of target stimuli and the presence and salience  
of distracter items. Thus, tasks remain challenging enough to produce plasticity but not counterproductively 
discouraging. 
 
Sham CR - A key feature distinguishing active CR from sham CR is dynamic titration of difficulty. In sham 
CR, participants are exposed to the same exercises but the difficulty is set at a relatively easy level without  
adjustment. Sham CR was designed this way because an optimal sham CR should control for cognitive 
activation without leading to incremental learning. 
 
Transcranial Direct Current Stimulation (tDCS) - tDCS will be administered for 30 min/day, just before 
the start of each group session. tDCS montage will be bifrontal91 with one large anode placed over Fz and the 
cathode over Iz. The direct current will be of 2 mA (current density = 0.57 A/m2). 
Sham tDCS - For sham tDCS, the device will be turned off after 1 min of active stimulation. In other 
studies92,93, this approach has ensured that the participants are blind to the type of stimulation (active vs. sham) 
since the mild scratching experienced immediately after initiation of stimulation continue to occur. tDCS and 
sham tDCS will be administered by trained interventionists to ensure that its administration remains 
standardized  throughout the study. 
 
C) Frequency of Assessments 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 19 
All participants will be thoroughly assessed (pre-screened) as part of good clinical 
care by their clinician outside of the study and before starting the study. 
 
Baseline (T0): Confirmation of eligibility and baseline assessment (including mood, cognition, function, and 
biomarkers). This assessment will be split over several days to reduce participant burden. Following consent, 
the participant will be randomized to either tDCS + CR or sham tDCS + sham CR in the database. After the 
baseline assessments and randomization are completed participants will start an 8-week course of tDCS + 
CR or sham + sham and every 6 months one-week consolidation sessions and also complete on-site 
assessments every 12 months (for up to 84 months) or until progression of those with MCI to dementia (and of 
those who are cognitively normal to MCI or dementia). 
 
Follow-Up Assessments: Measures relevant to cognitive function and mood will be collected at the following 
time points: 
T2: Following completion of the 8-week induction phase (to assess the short-term effects of tDCS + 
CR); T3-T9/Tx: every 12 months from T1 or at time of termination (Tx). 
In-person booster sessions during the COVID-19 pandemic will occur in accordance to Infection, 
Prevention, and Control Department’s recommendations where the following steps will be followed 
for every group session: 
- 
Participants will be seated 6ft or more apart from one another. To mitigate risks, everyone will 
have to undergo CAMH/ Sunnybrook screening procedures at each visit and participants will be 
required to perform hand hygiene prior to entering the room where the sessions are held.  
- 
The RA will be required to wear a mask and a face shield or goggles when applying the tDCS 
cap placement where the 6ft physical distancing will not be feasible. Participants will also be 
wearing masks throughout the booster sessions. Disposable nitrile gloves will also be available 
for use.  
- 
The tDCS equipment will be wiped down with disinfectant  wipes prior to and after each use  
- 
Hand hygiene will be performed before/after each tDCS session and before/after handling tDCS 
equipment 
 
Induction phase (after randomization/T1) tDCS + CR vs. sham tDCS + sham CR 
– 
tDCS (30 min/day) + CR (2 hours daily) 
– 
5 days/week, for 8 weeks 
 
 
Consolidation phase (every six months ± 3 weeks from T1) 
tDCS + CR vs. sham tDCS + sham-CR 
– 
tDCS (30 min/day) + CR (2 hours daily) 
– 
5 days/week, for 1 week 
 
Remote Booster Sessions 
 
The method of administration for boosters will be determined by the participant’s preference or by other 
extraneous factors (e.g., pandemic restrictions). 
 
For those group of participants that are cannot attend the in-person booster sessions (every 6 months), there will 
be an option to complete the sessions via WebEx at CAMH and via Zoom at Sunnybrook. The video sessions 
may be recorded for fidelity purposes, the same way it is done during the in-person group sessions. The tDCS 
administration cannot be done remotely and hence the booster sessions will only consist of the CR exercises. The 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 20 
WebEx and Zoom sessions will be securely transferred from the researchers’ CAMH 
WebEx and Sunnybrook Zoom accounts to the study-specific folder on the secure 
CAMH and Sunnybrook servers within 30 calendar days, at which point the 
recordings will be deleted from the WebEx and Zoom servers. The WebEx recordings will be maintained and 
stored as per policy AR1.6 (Research Record Management and Retention) at CAMH and will similarly follow 
the appropriate policy at Sunnybrook. 
 
Participants will be invited to WebEx/Zoom group meetings led by a trained interventionist who will facilitate 
the sessions and will provide support and guidance through the exercises.  Each group will meet daily for ~ 1.5 
hour, 5 days/week, every 6 months (“consolidation phase”). Performance feedback is given to reinforce progress 
and the exercises are designed to be enjoyable to complete, with titrated difficulty levels over time. “Strategic 
monitoring” promotes transfer of cognitive gains to everyday.  
 
When recording testing sessions, only digital recording devices and methods approved by CAMH IT security 
will be used (i.e., it is encrypted, password protected and meets all CAMH related requirements).  Personal 
recording devices will not be used.  The recording device will be securely stored under the control of study 
research personnel while it contains the recordings.  Recordings will be transferred to and stored on secure 
CAMH servers, and will be deleted from the recording device after review.  
 
D) Monitoring - The PI of the study or one of the other study physicians will be available: (1) to assist 
the screening clinician with further evaluation of detected diseases/conditions and assuring that appropriate 
referrals for safe follow-up care are provided to the individual if needed; (2) during the study to assist with the 
management of a person deemed to be suicidal. 
 
Antidepressant Clinic Visits and Open Antidepressant Protocol 
Participants with MDD will be recruited if they are currently in remission. Participants receiving antidepressant 
maintenance will be seen regularly by their treating physicians or a psychiatrist associated with the study.  
Consistent with an intent-to-treat (ITT) approach, relapse or recurrence will be treated following a 
stepped–care protocol (e.g., maximization of c u r r e n t  a n t i d e p r e s s a n t  dose or initiation of sertraline, 
followed by a switch from sertraline to venlafaxine or from venlafaxine to bupropion). Consistent with an 
intent-to- treat (ITT) approach, once randomized, participants will be kept in the study even if they suffer a 
relapse or recurrence. 
 
E) Early Termination from Protocol Treatment- Participants who progress from MCI to dementia or 
from cognitively normal to MCI or dementia will be terminated from the protocol and will be referred for 
standard clinical management of MCI or dementia. 
 
F) Location of Procedures - Recruitment, screening, and clinical assessments will take place at each of the 5 
sites (Centre for Addiction and Mental Health [CAMH] and University Health Network [UHN] located in 
downtown Toronto; Baycrest Health Centre; St. Michael’s Hospital [SMH], and Sunnybrook Health Sciences 
Centre [SHSC] located uptown. Cognitive assessments, CR and tDCS sessions will take place at two sites: 
CAMH (located downtown) and SHSC (located uptown). Biomarkers will take place at CAMH. (If 
participants refuse to complete MRI, LP, and EEG and only agree to biomarker blood draws and genetics, 
these samples will be collected at CAMH or SBHSC). 
 
G)  
4.2 Schedule of assessments: 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 21 
Instruments and 
batteries 
Baseline 
Randomization/ Treatment 
 
T0 
T1 
(Week 0) 
T2 
T3 
T4 
T5 
T6 
T7 
T8 
T9/TX 
Other 
Week 
 
Weeks 
1-8 
Weeks 
9-12 
Month 
12 
Month 
24 
Month 
36 
Month 
48 
~Month 
60 
~Month 
72 
~Month 
84 
 
Structured Clinical 
Interview for DSM 
Disorders (SCID) 
(for depression and 
alcohol eligibility) 
• 
 
 
 
 
 
 
 
 
 
 
Socio-Demographic 
Information 
• 
 
 
 
 
 
 
 
 
 
 
Montgomery-Asberg  
Depression Rating 
Scale (MADRS) 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
NPI-Q 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Beck Scale for 
Suicidal Ideation 
(SSI) 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
Modified Hachinski 
Ischemic Scale 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
 
Handedness 
Inventory Scale 
• 
 
 
 
 
 
 
 
 
 
 
Driving 
Questionnaire 
• 
 
 
 
 
 
 
 
 
• 
 
Medical History 
• 
 
 
 
 
 
 
 
 
 
 
Vital signs – height, 
weight, blood 
pressure, pulse rate 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
EKG (within past 6 
months; obtained 
from health records) 
a 
• 
 
 
 
 
 
 
 
 
 
 
CIRS-G 
• 
 
 
 
 
 
 
 
 
 
 
PTT, PT INRb 
 
 
 
 
 
 
 
 
 
 
• 
Smoking Status 
• 
 
 
 
 
 
 
 
 
 
 
E-COG 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
 
Clinical Dementia 
Rating (CDR) 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
 
Neuropsych. Battery 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
 
EVLTc 
• 
 
• 
 
 
 
 
 
 
 
 
2-item version of 
PASS 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 22 
Instruments and 
batteries 
Baseline 
Randomization/ Treatment 
 
T0 
T1 
(Week 0) 
T2 
T3 
T4 
T5 
T6 
T7 
T8 
T9/TX 
Other 
Week 
 
Weeks 
1-8 
Weeks 
9-12 
Month 
12 
Month 
24 
Month 
36 
Month 
48 
~Month 
60 
~Month 
72 
~Month 
84 
 
Lab test results – 
(within past 6 months; 
obtained from health 
records) Electrolytes, 
BUN, creatinine, liver 
function tests, TSH, 
CBC, folates, B12, 
HDL-c, TC and 
others as clinically 
indicated) 
• 
 
 
 
 
 
 
 
 
 
 
LPd 
 
 
 
 
 
 
 
 
 
 
• 
EEGe 
• 
 
• 
• 
• 
• 
• 
• 
• 
• 
 
Genotypingf 
• 
 
 
 
 
 
 
 
 
 
• 
Peripheral biomarkers 
(BDNF) g 
• 
 
 
 
 
 
 
 
 
• 
• 
MRIh 
• 
 
• 
 
 
 
 
 
 
• 
 
UDSi 
• 
 
• 
 
 
 
 
 
 
• 
 
tDCS + CR or sham 
tDCS+ sham CRj 
 
• 
 
• 
• 
• 
• 
• 
• 
• 
 
AE/SAE assessmentk 
 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
a) If no EKG record is available through participant’s health records, the test will be completed at the 
recruiting site. 
b) Participants who consent to the LP will complete the PTT and PT/INR blood tests sometime before 
their procedure. 
c) The EVLT will be administered at both T0 and T2 for participants who consented after March 22, 
2016. For participants who consented before March 22, 2016, the EVLT will be completed at their 
next scheduled NP visit. The EVLT is to be administered at the end of Day 1 of NP testing (this is 
the preferable option); or, at the end of Day 2 of NP testing. 
d) LPs are optional and should only be performed among those patients who provide consent. LPs 
should be completed prior to the start of T1 visit and after the imaging scans, however, if 
extenuating circumstances prevent LPs from being completed prior to T1, the LP can be 
scheduled and completed anytime in the study.  
e) EEG is an optional assessment performed only once a study participant provides informed 
consent to have EEGs performed. EEGs will take place at the time of each cognitive 
assessment, specifically, during the working memory task, “N-back”. 
f) Genotyping should be completed prior to the start of T1 visit, however, if extenuating 
circumstances prevent them from being completed prior to T1, the sample collection can be 
scheduled and completed anytime in the study.  
g) "Other" timepoint for peripheral biomarkers refers to those that for the LP procedures; these 
are additional biomarkers that will be collected for those who consent to the LP.  

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 23 
h) MRI is an optional assessment performed only once a 
study participant provides informed consent to have an 
MRI Performed. The T0 MRI should be completed at 
T0, prior to T1 (first intervention visit); however if extenuating circumstances prevent it 
from being completed prior to T1, MRI can be completed during the 8-week intervention. 
For Healthy Controls, there will only be one MRI at one of their regularly scheduled T-
visits (i.e. T0, T2, T3, etc) 
i) Urine Drug Screen (UDS) will be obtained only in participants who consent to MRI 
j) tDCS + CR or sham tDCS + sham CR every 6 months between visits T2 and T9.  
k) AE/SAE collection from the time of consent. 
 
5.1 Assessments and laboratory measures 
 
The following measures will be used to characterize the participants, ensure they meet the inclusion criteria, 
and assess the outcomes and treatment response during the RCT. 
 
5.2 Screening Assessment: 
Structured Clinical Interview for the DSM-V (SCID)- Participants will be screened with the Structured 
Clinical Interview for the DSM-IV updated for DSM 5 and DSM 5 for MCI, MDE, and Major 
Neurocognitive Disorder (dementia) to determine eligibility. The SCID assesses current and lifetime 
depression and other psychiatric disorders. It will be used to clarify psychiatric inclusion and exclusion 
criteria. 
 
5.3 Assessment of depressive symptoms: 
The Montgomery-Asberg Depression Rating Scale (MADRS)122 will be our main outcome measure. A 
MADRS score ≤10 at baseline will establish study eligibility. The MADRS was designed to be used by both 
psychiatrists and non-psychiatrist raters. It is a 10-item checklist. Items are rated on a scale of 0-6 with 
anchors at 2-point intervals. The MADRS takes approximately 15 minutes to administer. 
 
5.4 Dementia scales: 
E-COG- This questionnaire is used as a screening tool to evaluate dementia. Higher scores on this scale 
indicate greater cognitive impairment. Administration time is approximately 10 to 15 minutes. 
 
Clinical Dementia Rating Scale (CDR)- This scale is useful in quantifying the severity of dementia based on 
six domains of cognitive and functional ability: memory, orientation, judgement and problem solving, 
community affairs, homes and hobbies, and personal care. Each item is rated on a 5-point scale through a 
semi-structured interview with the participant or reliable informant. Administration time is approximately 
40 minutes. 
 
5.5 Assessment of functional status: 
Performance Assessment of Self-Care Skills (PASS): The 2-items version of PASS (ReCALL), shopping 
capacity and financial capacity (bill payment and chequebook balancing) are assessed. It takes approximately 
20 minutes to administer. 
 
5.6 Suicidal ideation: 
Suicidal ideation is a key dimension of MDD because of the high suicide rates in depressed elders and because 
it independently predicts treatment outcomes. A systematic evaluation of suicidal ideation is needed in any 
depression treatment study for safety reasons and because clinicians need to know the effects of treatment 
on suicidality to understand risks vs. benefits. 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 24 
 
 
Scale for Suicide Ideation (SSI) - We will use the 21-item Scale for Suicide 
Ideation (SSI). It has been  
shown to predict completed suicide123, 124 and has moderately high internal consistency with Cronbach’s 
alphas ranging from 0.84 to 0.89 and good interrater reliability125, 126. To reduce participant burden,  five 
screening items are administered; if any is endorsed, the participant completes items 6-19. Items 20 and 21 
assess previous suicide attempts. The full SSI takes 10 minutes to administer. 
 
5.7 Neuropsychiatric Inventory Questionnaire (NPI-Q): The NPI-Q is used to measure 12 categories of 
behavioral 
disturbance, 
in 
particular: 
Delusions, 
Hallucinations, 
Anxiety, 
Depression/Dysphoria, 
Agitation/Aggression, Elation/Euphoria, Disinhibition, Irritability/Lability, Apathy/Indifference, 
Motor 
Disturbance, Nighttime Behavior Problems, and Problems with Appetite/Eating. The presence of the 
symptom as well as its severity and frequency over the last month is based on caregiver report. The NPI-Q 
is widely used in clinical AD trials as a behavioural outcome measure and is included in longitudinal studies 
such as the Alzheimer’s Disease Neuroimaging Initiative (ADNI)128,129. The administrator ranks the severity of  
each behavior exhibited on a scale of 1 to 3, with 3 being the most severe. The total severity score is the sum 
of the severity scores obtained for each behavioral category. Additionally, the administrator ranks the patient’s 
level of distress from each behavior, on a scale of 1 to 5, with 5 indicating the most severe level of distress. 
The total distress score is the sum of the distress scores obtained for each behavioral category. The assessment 
takes approximately 10 minutes to administer. 
 
5.8 Driving Questionnaires: 
The driving questionnaires included are used to measure: i) how much the participant drives and in what 
circumstances they drive (Situational Driving Frequency); ii) in what situations the participant avoids driving 
(Situational Driving Avoidance); iii) the participant’s perception of their driving ability (Perceived Driving 
Ability); iv) their comfort driving in the day or at night (Driving Comfort); and v) the participant’s decision-
making processes regarding driving (Decision Balance-Plus).  The questionnaires are self-administered at 
study entry and study termination, and will take 10-20 minutes to complete. In cases where participant is 
unable to complete an in-person TX visit, the questionnaire will be administered over the phone with the 
participant and informant (if necessary).  
 
5.9. Clinical Assessments Administration 
All follow-up clinical assessments (MADRS, NPI-Q, SSI, Driving Questionnaire, Medical History, AE/SAE 
Assessment) can be conducted in person as well as remotely (i.e., via WebEx or telephone). The method of 
administration will be determined by the participant’s preference or by other extraneous factors (e.g., pandemic 
restrictions). During the COVID-19 pandemic, each participant scheduled for in-person appointments will 
undergo CAMH and other institutional (i.e., Baycrest, St. Michael’s Hospital, Sunnybrook Health Centre, 
University Health Network),  screening procedures prior to their visit and on the day of their visit and wear a 
surgical mask for the duration of the on-site visit. 
 
   5.9 Cognitive assessments: 
The proposed battery developed with Meryl Butters, Ph.D. (collaborator at the University of Pittsburgh) is 
well- established, standardized, reliable, and sensitive to neurological and psychiatric disorders. These 
instruments draw on many well-validated NP tests to assess cognitive domains of memory, visuo-
construction, language, information-processing speed, and executive functioning. 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 25 
 
The assessments will be performed by trained psychometrists blind to the 
interventions. The investigators have published on the importance of achieving 
high levels of inter-rater reliability in multisite trials and they have developed methods to train and certify 
psychometrists on various instruments. 
 
Similar to clinical assessments, cognitive assessments can be done in person or remotely (via telephone or using 
WebEx/Zoom). Telephone calls or assessments done via teleconferencing/videoconferencing using WebEx may 
be recorded. Some assessments are modified to accommodate the change in format of administration while 
maintaining the validity and integrity of the data. The assessments that cannot be done via phone or 
videoconference will not be done (Table 5.9). 
 
Remote Administration of Neuropsychological Assessments 
Participants will be mailed large envelopes with an instruction sheet, a sealed envelope, and a pre-paid return 
envelope inside. The Instruction sheet will ask participants not to open the sealed envelope until they are instructed 
to do so. The sealed envelope will be opened during the videoconference. It will contain the necessary testing 
forms. Tasks will be administered via phone or videoconferencing with Screen Sharing (refer to table 5.9 below). 
When testing is completed, participants will mail back all completed forms and test stimuli using the return 
envelope provided.  
 
When recording testing sessions, only digital recording devices and methods approved by CAMH IT security will 
be used (i.e., it is encrypted, password protected and meets all CAMH related requirements).  Personal recording 
devices will not be used.  The recording device will be securely stored under the control of study research 
personnel while it contains the recordings.  Recordings will be transferred to and stored on secure CAMH servers, 
and will be deleted from the recording device after review.  
 
Table 5.9. Neuropsychological Assessments 
Administration Methods Legend: 
1. In-person 
2. Via phone 
3. Via WebEx/Zoom 
3a. Assessments remaining the same as in-person 
3b. Assessments modified to allow for remote administration  
4.  No available remote methods; assessment will not be administered remotely 
 
Name of Assessment 
Administration Method 
California Verbal Learning Test (CVLT-II)  
1 or 2 or 3a.   
Brief Visuospatial Memory Test (BVMT-R)  
1 or 3a.   
Trail Making A & B 
1 or 2* or 3a*  
Coding 
1 or 2 or 3a.  . 
Stroop 
1 or 2 or 3a.  
Judgment of Line Orientation (JLO)  
1 or 2 or 3a.  
2-item version Performance Assessment of Self-
care Skills (PASS) 
1 or 3b.   

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 26 
Continuous Performance Task (CPT) 
1 or 4.  
Clock Drawing 
1 or 2 or 3a.   
Letter & Semantic Fluency 
1 or 2 or 3a.  
Boston Naming Test (BNT) 
1 or 2 or 3a.  
Paced Auditory Addition Test (PASAT) 
1 or 4.  
N-Back EEG 
1 or 4.  
N-Back 
1 or 3a 
Everyday Cognition (E-Cog): Self & Informant 
1 or 2 or 3a.  
*for participants that do not have access to a computer, only Oral Trail Making A+B will be administered over the 
phone. For Webex/Zoom sessions, both Oral Trail Making and regular Trail Making will be administered.  
 
 
5.10 Emotional Verbal Learning Test (EVLT): 
The EVLT is an emotional memory test developed as a screening tool   for preclinical AD. Participants are read 
three lists of words and asked to recall as many of these words as possible. Each list contains fifteen common  
words, five of which are positive, negative and neutral. The test will cause minimal participant fatigue. The 
EVLT will be administered at both T0 and T2 for participants who consented after March 22, 2016. For 
participants who consented before March 22, 2016, the EVLT will be completed at their next scheduled NP visit. 
The EVLT is to be administered at the end of Day 1 of NP testing (this is the preferable option); or, at the end of  
 
Day 2 of NP testing. The test takes approximately five minutes to administer. 
 
      5.11 Biomarkers: 
We will collect biomarkers to conduct exploratory analyses on the pro-cognitive neuroplasticity effects of 
tDCS + CR. 
 
MRI Scan- Acquisition: We will obtain MRI data on the 3 Tesla GE Echospeed (General Electric, 
Milwaukee, WI) research-dedicated scanner at CAMH. This scanner permits maximum gradient amplitudes of 
50 mT/m and is equipped with an eight-channel head coil that provides major improvement in signal to noise 
ratio (SNR) over the standard quadrature coil94. The T1-weighted scan will be acquired as a sagittal 3D  
FSPGR: (echo time (TE): 3 ms; repetition time (TR): 8.2 ms; time to inversion (TI): 650; flip angle 8, FOV=24 
cm; number of excitations (NEX) = 1, with 0.9 mm isotropic voxels, no gap). For DTI, we will use an echo 
planar imaging (EPI) sequence with dual spin echo option to reduce eddy-current related distortions95 and 
ASSET with a SENSE-factor of  2. We will acquire 60 gradient directions with b=1000, 5 baseline scans with 
b=0. Scan parameters are: TR 8800 ms; TE min; FOV 38 cm; 128x128 encoding steps; 2.0 mm isotropic 
voxels, no gap. Axial slices will be acquired parallel to the AC-PC line covering the  whole brain.  B0  field  
inhomogeneity maps will  also  be collected and calculated. An exploratory multi-shell diffusion acquisition 
will also be acquired. For resting state fMRI an oblique/axial will be acquired with TR=2000, TE=30.0, FOV 
= 20 cm, Flip angle 77, Slice thickness = 4 mm, 40 slices (7 minute run). The entire scan session will take 
approximately 30 minutes. The entire scan session (including functional neuroimaging described below) will 
take approximately one hour. 
 
Cortical Thickness Analysis: Following acquisition, all T1-weighted MRI data will be submitted to the 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 27 
CIVET pipeline (version 1.1.10). T1 images will be registered to the ICBM152 
nonlinear sixth generation template with a 9-parameter linear transformation, 
inhomogeneity corrected96 and tissue classified97,98. Deformable models will then 
be used to create white and gray matter surfaces for each hemisphere separately, resulting in 4 surfaces of 
40,962 vertices each99, 100. From these surfaces, the t-link metric will be derived for determining the 
distance between the white and gray surfaces101. Cortical thickness maps will be aligned across all scans 
using non-linear surface based registration102, 103. The thickness data will then be blurred using a 20-mm 
surface based diffusion blurring kernel104 in preparation for statistical analyses. 
 
DTI Analysis: All diffusion-weighted scans will be preprocessed using eddy current correction and nonlinear 
EPI distortion 
correction, 
filtering, 
and 
tensor estimation 
(3D 
slicer software, 
www.slicer.org). A deterministic whole brain tractography approach105 and an eigenvector tracking 
algorithm based on the fourth order Runge-Kutta method will then be used to track white matter fibers. The  
 
 
 
linear anisotropy measure (CL) will be used for seeding and stopping thresholds instead of FA, because it 
lessens the effect of planar partial-volume regions where a fibre may jump from one structure to another. By 
reducing partial-volume tractography errors, it improves the ability of the clustering to separate different 
structures106. For segmentation, our clustering method takes advantage of fibre shape and groups fibres of 
similar appearance. Once the whole brain cluster model is produced, a trained operator combines the 
clusters that correspond to a fiber tract107, 108 (e.g. genu of corpus callosum). We have shown excellent 
reliability of this method in Schizophrenia participants for our white matter tracts of interest108. On an 
exploratory basis we will also measure axial diffusivity (sensitive to axonal membranes), and radial 
diffusivity (sensitive to myelin)109 to understand more about the specific tissue compartments that may 
contribute to potential changes in mean diffusivity . 
 
Resting state fMRI Analysis: Scans will be pre-processed as described in detail in several recent 
publications110,111. Structural images will be spatially registered to a group average anatomical image 
intended to serve as an unbiased anatomical template. We have employed this template in previous 
studies111,112. Functional data will be slice-time corrected using AFNI (afni.nimh.nih.gov/afni) and head 
motion corrected using AIR (bishopw.loni.ucla.edu/air5/). For each run, mean functional volume will be 
registered with each participant’s structural volume using a rigid body transformation model. We will 
then apply the FSL/FNIRT registration algorithm to find a non-linear transform between our template 
and MNI 152_T1 provided with FSL software (www.fmrib.ox.ac.uk/fsl). Data will be smoothed using an 8 
mm Gaussian kernel. 
 
We will correct transformed functional volumes with Independent Component Analysis (ICA) within separate 
runs, as implemented in FSL/Melodic113. We will further adjust voxel time series by regressing out motion 
correction parameters, white matter, and cerebrospinal fluid time series. To help localize regions from our 
functional output, we will submit MNI coordinates to the Anatomy Toolbox in SPM8, which applies 
probabilistic algorithms to determine the cytoarchitectonic labeling of MNI coordinates114, 115. We will then 
use a published template to identify 20 classic independent components in the data, which will be compared 
between the environmental enrichment groups116. 
 
Cerebro-spinal fluid (CSF) a-beta 42, phospho-tau, and tau levels: Since we expect that some participants 
may be willing to have a lumbar puncture (LP), we will collect CSF from participants who consent to have a 
one-time LP. We will measure a-beta 42, phospho-tau, and tau levels in their CSF. In our own 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 28 
experience and in the literature, research participants have been able to tolerate 
LPs well after a discussion through informed consent and listening to any of their 
concerns117, 118. We estimate that about 40% of the participants will consent to have 
an LP at the time of randomization. Participants who consent to the LP will complete the PT/INR before their 
procedure. 
 
The LP procedure for this study does not differ from the routine diagnostic LP performed at a neurologist’s 
office: participants are first screened for risk of bleeding complication (they should not be on anti-
coagulants and certain anti- platelet agents may be held for the day prior to the procedure) or herniation. 
Participants will be informed of the potential minimal risks of bleeding and infection and of the risks of post-
spinal headache. It is hard to predict which participants will develop the headache.  As we have done in other 
studies, if participants develop a moderate or severe headache that persists beyond a day, we will refer them to 
a local anaesthesiologist for a blood patch procedure. We will collect up to 15 mL of CSF from each 
participant, and use 4mL for analysis of a-beta 42, phospho-tau, and tau levels. We will store the remainder  
 
 
 
for repeat or further testing, should other relevant CSF biomarkers be identified during the study period. 
 
We will use the CSF samples from this study to assess potential neurological markers associated with aging. 
The CSF may be shared with study collaborators in order to analyze and assess the samples. 
 
Genotyping: Genetics sampling will take place at CAMH or SHSC. CAMH or SHSC will collect either 
whole blood preserved in EDTA or saliva, store for the short term, and ship batched samples at regular 
intervals to Dr. Kennedy’s CAMH laboratory. We will request a second specimen from any subject from 
which DNA is not isolated from the initial collection. Upon receipt of the samples, Dr. Kennedy’s lab will 
extract DNA from the specimens. At this time, we are planning to genotype 32 SNVs from among common 
variants associated with AD As new SNVs are identified, other approaches to genotyping may be used.The 
dataset including DNA samples will be available as a resource to researchers for future studies. We will work 
with the coded sample and will store the sample securely. The lab personnel will be blind as to the status of 
each sample. That is, the researcher coding the genes will not know the diagnosis of the participant. 
 
Theta-gamma Coupling: We will offer an optional Electroencephalogram (EEG) to study theta-gamma 
coupling during the working memory task (“N-back”) as a probe of the DLPFC function. To measure theta-
gamma coupling, EEG will be acquired through a 64-channel Synamps 2 EEG system. An EEG cap will be 
used to record the cortical signals, and four electrodes will placed on the outer side of each eye, and above and 
below the left eye to correct for eye movement artefacts in the analysis. Electrodes will be referenced to an 
electrode posterior to Cz electrode. EEG signals will be recorded using direct current and a low pass filter of 
100 Hz at 20 kHz sampling rate100. The electrodes that will be used to measure coupling during N-back 
performance will be the right and left frontal electrodes: AF3/4, F7/8, F3/4, and F1/2. 
 
EEG Data Preprocessing: EEG recordings will be processed offline using MATLAB (The MathWorks 
Inc. Natick, MA, USA) and EEGLAB toolbox. EEG data will first be segmented with respect to stimulus 
such that each epoch included 1300 ms pre-stimulus baseline and 3052 ms post-stimulus activity. Epochs 
will be baseline corrected with respect to the pre-stimulus interval (1000 ms to 10 ms prior to the stimulus) and 
filtered by using a zero-phase shift 1–120 Hz band pass filter. The 60-Hz power line artifact will be removed 
from each trial across all channels by using the Thomson F-test based on multitaper spectral estimate 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 29 
techniques. We will then create an channels-by-trials matrix of 1 s, and alter the 
value to zero if an epoch has: (1) amplitudes larger than +/- 150  μV, (2) power 
spectrum that violates 1/f power law, (3) standard deviation that is 3 times larger 
than average of whole trials, (4) kurtosis that is 3 times larger than average of whole trials, or (4) skewness 
that is 3 times larger than average of whole trials. Then, we will first reject channel(s) if its corresponding row 
represents zeros in more than 55% of trials. Second, we will remove epoch(s) if a trial has zeros in more 
than 20% of channels. Then, an independent component analysis (EEGLAB toolbox; Infomax algorithm) 
will be performed to remove eye-blink traces, muscle artifacts and/or head movements from the EEG data. 
Finally, an average signal will be obtained from each electrode for each subject. For more details, please see 
our recently published paper using these methods (Rajji et al. 2013)130. 
 
Theta Phase-Gamma Amplitude Coupling: We will measure theta-gamma coupling as a relationship 
between the phase of theta (4-7 Hz) and the amplitude of gamma (30-50 Hz) as we have recently reported 
using another form of brain stimulation130. We will perform the analysis on the time averaged file of each 
subject using Matlab by adapting previously published methods131,132. We will first filter the signal into 
separate theta and gamma waveforms with a zero-phase shift filter and then applied the Hilbert transform. 
Using the phase information of the theta wave, we will sort the corresponding gamma amplitudes into 6 bins 
(i.e. -180° to -120°, -120° to -60°, -60° to 0°, 0° to 60°, 60° to 120°, 120° to 180°) and then average them. 
Since the angle values correspond to a cosine reference, zero degrees correspond to a peak of the waveform. 
In order to quantify coupling, we will use an entropy based modulation index (MI)132: MI = [(log(N) – H(P)] 
/ log(N). N is the number of phase bins, log(N) represents the entropy of a uniform 
distribution, P is the 
relative amplitude distribution sorted according to phase bins, and H(P) is the entropy of the P distribution, 
which is calculated as: 
 
 
 
We will calculate the relative amplitude distribution P for each subject by dividing the amplitude of each phase 
by the sum of all amplitudes across bins. This maximum entropy for such a relative amplitude distribution 
happens when the amplitude is 1/N, which occurs when the distribution is uniform. Since an increase in 
coupling represents an increase of order, higher coupling translates to lower entropy H(P), which in turn  
results in a high MI value. We will generate surrogate data for each subject by maintaining the amplitude 
spectrum while randomizing the phase131. A total of 200 iterations will be done in order to generate an 
empirical distribution under the null hypothesis of no coupling. 
 
Peripheral Biomarkers: At this time, we are planning to measure brain derived neurotrophic factor (BDNF) 
due to its noted relationship with plasticity and cognitive performance. However, other biomarkers relevant 
to brain plasticity and cognitive reserve may also be characterized. 
 
6.1 Data analysis and Management 
 
6.2 Power Analysis: 
The power analysis assume a two-tailed α value of 0.05, 125 participants in each group and are based on the 
donepezil prevention trial8 in which participants with LDD had a global cognition z-score (compared to healthy 
controls) of about -0.50 (SD=0.80) after they responded to an antidepressant and a yearly decline of -0.40 on 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 30 
placebo. For H1, we will have adequate power of 84% at α of 0.05 to detect a 
difference between the two groups if the yearly decline in z-score in the tDCS + 
CR group is reduced to -0.10. For H2, hypothesizing that tDCS + CR halves the 
monthly progression rates (from 1.37% to 0.68% overall), we will have adequate power of 80% at α of 0.05 to 
detect this hazard ratio (HR) of 0.50. For H3, we will have adequate power of 85% at α of 0.05 if z-scores 
acutely improve by 0.30 with CR+tDCS (corresponding to a Cohen effect size of 0.38). 
 
6.2 Data Management and Analysis: 
At the time of the study start, the Applied Health Research Centre (AHRC) in the Li Ka Shing Knowledge 
Institute of St. Michael’s Hospital oversaw the daily operations of the data coordination; wrote the data entry 
guidelines and the data management plan, maintained the central study files, and lead development of the 
electronic Case Record Form (eCRF) and the research database, configure user accesses within the database. 
The AHRC will write custom reports and will make periodic updates to the database as necessary. They  
were responsible for reviewing entered data; raising, reviewing and closing system and site queries; creating 
customized reports for both reporting (e.g., analyses and reports for DSMB) and data validation purposes. 
 
During the study, the data from this study was transitioned into secure databases maintained by the CAMH 
Neuroinformatics, including REDCap, XNAT and LabKey. The database structure and management principles 
will remain the same as the original database with AHRC. At point-of-entry, data values will undergo consistency 
edits (e.g. ID validation, range verification, duplicate detection) and personnel will be required to correct errors. 
Reports will be created via the REDCap program. Data management staff at CAMH will run logic error programs 
to check for accuracy and irregularities within and across data structures and within and across sites. Quality 
assurance checks will be conducted regularly by site personnel, as well as by CAMH data management staff. 
Weekly/ Monthly reports will be generated (as needed) to monitor site data timeliness, completeness, and accuracy 
as well as participant flow through the study. Although unlikely, instances may occur where the databases are not 
available. In the case that this happens, we will follow the CAMH downtime procedures. 
 
Following the ITT principle, all randomized participants and all available longitudinal data (T0-T9/TX) will 
be considered in the analyses. We will account for missing data with terminations as being due either to study 
design (e.g., progression to dementia) or to any other type of termination (for example, adverse events). We will  
compare the temporal patterns of termination status by treatment arm for each type of termination by examining  
cumulative incidence curves adjusted for the competing causes of termination119. We will account for the 
impact of non- ignorable missing data through appropriate statistical modeling120. 
For H1 (and H3), we will first use an ANCOVA to test changes in cognition scores with age, education, 
and depression measure as covariates.  We  will  also  use  a  repeated  measures  mixed-effects  ANCOVA,  
which is superior to standard ANCOVA in handling missing data. These mixed-models with longitudinal data 
controlling for age, years of education, and scores at randomization (T1) will be used to compare cognitive 
and functional performance in the two groups over time. Covariates such as ApoE allele or family history of 
dementia can be used as moderators. If the depression recurrence rates are different in the two groups, the 
analysis can use the Ham-D scores as time-varying covariates. ITT differences in slopes of change across 
time in cognitive and functional performances between the two groups will be tested and estimated using 
likelihood ratio testing. Finally, comparisons of the two groups with respect to time to pre-specified decreases 
in scores will be performed with discrete time survival models. For H2, we will use Kaplan-Meier curves to 
quantify the percentage of those who remain free of MCI or dementia over time. Cox proportional hazard 
models will be used to quantify hazard ratios comparing the two treatment groups. Tests of proportionality will 
be conducted following Grambsch and Therneau121, after checking that proportionality assumptions are valid. 
Formal tests of treatment x MCI interaction and treatment effectiveness for those with normal cognition or MCI 
at baseline will use Cox proportional hazard models. 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 31 
 
In addition, we will address questions related to the relationship of clinical 
variables and biomarkers. To perform these analyses, we will use appropriate 
analytical methods building on the strengths of the investigators. 
 
7.0 e-CRF Entry 
 
The eCRFs will be built with customized edit checks to detect non-conformant data, missing data, and 
inconsistent data (for example: blank fields, future dates, dates inconsistent with study time frame, data 
value outside of expected range) and immediately flag these to the attention of the user entering data. These 
checks assure that common data entry errors are not made. There is also an audit trail, indicating the user 
responsible for the entry and a time stamp to allow for feedback as required. 
 
Data will be entered into the eCRF either manually or electronically. Direct Entry of Data Into the eCRF (real 
time) many data elements (e.g., blood pressure, weight, resolution of a symptom or sign, clinical assessments, 
social – functional tasks ) will be obtained at a study visit and will  be entered directly ( real time) into the eCRF 
by an authorized data originator. This direct entry of data will eliminate errors by not using a paper transcription  
step before entry into the eCRF. The eCRF will include the capability to record who entered or generated the 
data and when it was entered or generated. Changes to the data will not obscure the original entry, and will 
record who made the change, when, and why and the date and time the data element was entered into the eCRF 
(the audit trail begins at the time the data are transmitted to the eCRF).Only delegated clinical study staff will 
perform modifications or corrections to eCRF data. Modified or corrected data elements will have data element 
identifiers that reflect the date, time, originator and reason for the change, and will not obscure previous entries. 
Prompts will be designed to alert the data originator to missing data, inconsistencies, inadmissible values (e.g., 
date out of range), and to request additional data where appropriate. 
 
Authorized personnel (e.g., REB auditors, other monitors) can view the data elements in the eCRF before and 
after the investigator has electronically signed the completed eCRF. A list of the individuals with authorized  
access to the eCRF will be maintained.  All authorized personnel will have documented training and be assigned  
their own identification (log-on) codes and passwords. Log on access will be disabled if an individual 
discontinues their involvement in the study. 
 
8.0 Human Participants 
 
We plan to recruit up to 500 participants in order to enroll 375 in the following groups: 
1)      Participants with a diagnosis of Mild Neurocognitive Disorder with no history of depression (pure ‘MCI’) 
2)      Participants with diagnosis of MDD, Single or Recurrent, in Remission  
 
In addition, we plan to recruit up to 200 healthy control participants in order to enroll up to 80 non-demented, non-
depressed healthy controls that also match the age groups of the cases (MCI, MDD) enrolled in the study.  
 
8.1 Inclusion/Exclusion Criteria: 
No exclusion criteria are based on race, ethnicity, gender, or HIV status. 
 
To be admitted to this study, participants must satisfy the following inclusion and exclusion criteria: 
 
 
 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 32 
 
MCI Group 
Inclusion: 
• 
Age > 60 (on day of randomization) 
• 
DSM 5 criteria for Mild Neurocognitive Disorder (“MCI”) 
• 
Willingness to provide informed consent 
• 
MADRS score of 10 or below 
• 
Availability of a study partner who has regular contact with the participant 
• 
Ability to read and communicate in English (with corrected vision and hearing, if   
               needed)  
 
 Exclusion: 
• 
Met DSM 5 criteria for Major Depressive Episode in past 10 years. 
• 
Lifetime DSM 5 diagnosis of schizophrenia, bipolar disorder, or OCD. 
• 
DSM 5 diagnosis of alcohol or other substances use disorder within the past 12 months. 
• 
High risk for suicide. 
• 
Significant neurological condition (e.g., stroke, seizure disorder, MS) 
 
• 
Unstable medical illness, (e.g., uncontrolled diabetes mellitus or hypertension) 
• 
Having taken a cognitive enhancer (acetylcholinesterase inhibitor or memantine) within the past 6 
weeks.  
• 
Participants taking anticonvulsants, and other psychotropic medication (see exceptions below) that 
cannot be safely tapered and discontinued. The following psychotropic medications are allowed: i) 
any antidepressant; ii) zopiclone, trazadone, or a benzodiazepine if they have been taken at a stable 
dose for at least 4 weeks prior to study entry and; iii) gabapentin and pregabalin if they have been  
• 
taken at a stable dose for at least 4 weeks prior to study entry AND if prescribed for chronic pain.  
• 
A pace-maker or other metal implants that would preclude safe use of tDCS.  
 
MDD Group 
Inclusion: 
• 
Age ≥ 65 (on day of randomization) 
• 
Meets DSM 5 criteria for one or more MDE(s)with: 
 
a) an offset of 2 months to 5 years from the screening visit date. It is not necessary for this (these)     
      episode(s) to have received medical attention OR 
      b) an offset of 5 years or more from the screening visit date. It is necessary that at least one MDE 
received medical attention (e.g., previously been on one or more antidepressant(s), saw a psychiatrist, 
primary care physician, or had a previous hospitalization). Also, the MDE must have occurred during the 
participant’s adult life (i.e., at 18 years of age or older). 
• 
MADRS score of 10 or below 
• 
Willingness to provide informed consent 
• 
Availability of a study partner who has regular contact with the participant 
• 
Ability to read and communicate in English (with corrected vision and hearing, if needed) 
 
Exclusion: 
• 
Meets DSM 5 criteria for Major Neurocognitive Disorder (“dementia”) 
• 
Lifetime DSM 5 diagnosis of schizophrenia, bipolar disorder, or OCD 
• 
DSM 5 diagnosis of alcohol or other substances use disorder within the past 12 months. 
• 
High risk for suicide. 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 33 
• 
Significant neurological condition (e.g., stroke, seizure disorder, MS) 
• 
Unstable medical illness (e.g., uncontrolled diabetes mellitus or 
hypertension) 
• 
Participants taking anticonvulsants, and other psychotropic medication (see exception below) that cannot 
be safely tapered and discontinued. In addition to any antidepressant, the following  
psychotropic medications are allowed if they have been taken at a stable dose for at least 4 weeks 
prior to study entry: zopiclone, trazodone, or a benzodiazepine;  and gabapentin or pregabalin if 
prescribed for chronic pain. 
• 
Having taken a cognitive enhancer (acetylcholinesterase inhibitor or memantine) within the past 6 weeks. 
• 
A pace-maker or other metal implants that would preclude safe use of tDCS. 
 
Received electroconvulsive therapy (ECT) within 6 months of baseline neuropsychological testing. 
 
Control group 
Inclusion: 
• 
Age >  60 
• 
MADRS score of 10 or below 
• 
Willingness to provide informed consent 
• 
Ability to read and communicate in English (with corrected vision and hearing, if 
needed)  
 
Exclusion: 
• 
Meets DSM 5 criteria for Minor or Major Neurocognitive Disorder 
• 
Any other lifetime DSM 5 diagnosis except for simple/specific phobias 
• 
Significant neurological condition (e.g., stroke, seizure disorder, MS) 
• 
Unstable medical illness, (e.g., uncontrolled diabetes mellitus or hypertension) 
• 
Participants taking anticonvulsants, and other psychotropic medication (see exception below) that 
cannot be safely tapered and discontinued. The following psychotropic medications are allowed if 
they have been taken at a stable dose for at least 4 weeks: zopiclone up to 15 mg/day; trazadone 
up to 150 mg/day; benzodiazepine at a dose of up to 3 mg/day lorazepam-equivalents; gabapentin and 
pregabalin (if prescribed for pain). 
• 
A pace-maker or other metal implants 
• 
Neuropsychological testing within the past 12 months 
 
We plan to work collaboratively with the participant’s personal physician. All participants will complete a 
thorough evaluation of their physical health. If the psychiatrist or PCP of a potential participant thinks in his or 
her professional judgment that the participant cannot or should not participate in the study the participant 
will not be enrolled. 
 
9.0 Recruitment Procedures 
 
The five sites (CAMH, St. Michael’s Hospital, and UHN located in downtown Toronto; Baycrest Health 
Centre and SHSC located uptown), have busy geriatric psychiatry clinics where, collectively, more than 3,535 
older new patients are assessed yearly, with 1,210 new referrals for assessment and treatment of depression in 
the absence of a dementia. 
 
Recruitment for this study will be conducted through a few different methods: 
1) 
The process can be initiated by the clinical team who is treating the potential study participant. The 
treating physician/clinical care team will not obtain consent. They may identify potential research 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 34 
participants and obtain verbal permission from these potential 
participants for a member of the research team to approach them. 
Potential participants who indicate a further interest in hearing more 
about the study and provide assent to be contacted by a member of the research team will then be 
contacted by a member of the research team who will engage them in a pre-screen process 
which can be completed over the phone. The potential participant will then be invited 
to attend an appointment to review the informed consent. 
 
The study can be advertised through various sources (e.g. the newspaper, magazines, radio, etc.) and/or study 
flyers can be posted in the community. The research registry at each of the five sites (CAMH, St. Michael’s 
Hospital, UHN, Baycrest Health Centre and SHSC) is an online source of advertising that we will also utilize to 
post our study. We will also utilize online social media advertising (e.g. facebook, twitter) in order to promote 
our study using the REB approved flyers. Potential participants (including healthy controls) who express interest 
in the study by responding to the advertised contact information/research registries will complete the pre-screen 
questions with the RA over the phone. All pre-screen results are discussed with the site investigator(s) in order to 
establish the best type of clinical assessment/appointments for determining their potential fit for our research 
study. Potential participants are then contacted by the RA to explain the next step in booking a clinical 
appointment which will be covered by OHIP and is not considered a part of the study visit. This initial clinical 
appointment is used to help determine whether the potential participant will be a good candidate for our study. 
Potential participants are reminded that they will not be compensated for this clinical appointment as it is just a 
clinical assessment. If the clinical team determines the patient to be a good candidate for the study, the RA will 
then invite the potential participant to attend an appointment to review the informed consent. 
 
2) 
Other recruitment strategies will involve referrals by word of mouth and referrals by clinicians 
and community presentations to lay groups of elderly and their families. We will also contact 
former research participants who previously consented to be contacted for future research 
studies from the Geriatric Mental Health Services at CAMH. To avoid cold calling, the 
participants will be contacted by someone the former participant knows such as the participant’s 
former research coordinator. The procedures outlined above (see #2) will be followed in order to 
determine the eligibility of each referral/potential participant who expresses interest in our study. 
 
 
Primary care screening will depend on the various partnerships with several primary care or other health 
networks. We will accept clinician referrals from these practices and will also use affiliations with community 
agencies. In case of referrals from other programs, the treating physician/clinical care team will first identify 
potential research participants. The physician/clinical care team will inform the participants discuss the 
research project with the participant. If he/she expresses interest in study participation, he/she will be asked 
to give verbal consent to the physician/clinical care team for a member of the research team to approach 
them with information regarding participation in the research protocol. Protected health information of 
potential participants from other programs will be accessed only after written consent has been obtained from 
the participant. 
 
The participant’s recorded contact information will be stored by the researchers in a secure manner (e.g., 
locked offices, password protected database) accessible only to the researcher who was provided this 
information and other members of the research team involved in the conduct of the research study for which 
this information was originally provided. The participant’s recorded contact information will be destroyed 
immediately after researchers have contacted the participant to discuss the research study for which this 
information was originally provided or after ascertaining that the participant is not eligible for or declines 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 35 
participation in the research study. 
 
Capacity to provide consent will be assessed on an individual basis. Potential 
participants will have their capacity assessed by one of the study investigators or another study psychiatrist on 
the research and a note documenting the results of this assessment will be entered into the participant’s medical 
and research records.  
 
Even after a patient has provided initial consent to participate, we will use subsequent visits, and the 
implementation of study procedures as opportunities to again explain what is being done and to assure continuing 
informed consent. 
 
Study staff will review the study procedures, risks, benefits, and all other pertinent information contained in 
the consent form. The purpose of the research study, the procedures involved in the conduct of the study, 
potential risks and benefits, and the rights of study participants will be discussed with the potential participant 
prior to the attainment of written informed consent. Questions will be asked of participants to ensure they 
understand the nature of the research, the risks and potential benefits of participation, and their rights as research 
participants. We believe that consent is an ongoing process in any study, and we will continue to educate 
participants about the nature of the research and address any questions that may arise throughout the course 
of the study. We are not planning proxy consent. 
 
10.0 Consent Procedures 
 
Voluntary informed consent is required for participation in this study. No study procedures will be undertaken 
until such consent is obtained from participants. Consent will be documented on a written Informed Consent Form 
(ICF) or on an Informed Consent Update Form.  Full explanation about the study and any applicable updates will 
be provided to the participants whenever there are any protocol changes. Consent will always be obtained by 
appropriately trained and qualified study research personnel who do not have an existing clinical relationship with 
the participant.  The study PIs will not obtain participant consent. Even after a participant provides initial consent 
to participate, baseline as well as subsequent visits/ phone calls, will be used as opportunities to again explain the 
study details to assure informed consent on the part of participants. The process of obtaining consent will be 
documented in every case. Documentation of the consent discussion will be entered into the participant’s research 
records (i.e, consent date, version #, and consent choices). Further, the signed consent form will be uploaded into 
participant’s medical records as this study is a treatment clinical trial. 
REDcap and Informed Consent Checklist will also be used to document the consent process, including the consent 
method, date, version, and the consent decisions and options applicable to each version. 
Research procedures will only begin once consent documentation has been completed in accordance with the 
outlined procedures. 
 
There are a few different ways informed consent can be obtained from participants in the study. The mode of 
collecting consent will be documented in each participant’s research record on the study’s database.  
 
1) Verbal Consent: 
 
Verbal consent definition: A consent process whereby the consent discussion is conducted remotely, the 
participant confirms their consent verbally, and the consent documentation is completed by the study team 
(i.e., the ICF is not signed by the participant). 
Participants will be verbally informed of changes/ updates to the study via telephone and informed consent 
will be obtained for ongoing participation. The informed consent document will be shared with the 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 36 
participants prior to the consent discussion so they can follow the document during 
the phone discussion. The RA will either email or mail the consent document as per 
the participant’s preference. 
Informed consent will be obtained using the REB-approved consent script and it will be printed out and 
signed by the RA obtaining the consent from the participant and a witness observing the consent 
discussion. The witness will not be the principal investigator/project lead, an individual with a clinical 
relationship to the participant, a research volunteer, or the person conducting the consent discussion. The 
witness will be an observer to the consent discussion (i.e., they are not part of/do not contribute to the 
actual discussion) and will be able to hear both the person conducting the consent discussion and the 
participant. Wet-ink signatures (from RA obtaining consent and witness) will be obtained according to 
each institution’s guidelines.  
A copy of the signed ICF will be provided to the participant via mail and/or email, in accordance with the 
participant’s wishes. The original copy of the signed ICF will be filed in the Informed Consent binder 
(separate from the participant’s research records).  The Informed consent process will be documented using 
the study’s database on REDcap by filling out a form that will indicate the consent version, date, consent 
options and choices, as well as the person obtaining consent. 
 
2) 2)  REDcap e-Consent: 
Participants can also provide consent using REDCap. RED-cap e-Consent will be used only at those 
institutions that approve of the process and as per each institution’s guidelines.  
Participants will be provided with a read-only copy of the ICF via REDCap prior to conducting the consent 
discussion. The link may be used by participants as many times as they wish (it is not single-use). Upon 
clicking the link, participants will review the landing page, and continue on to the ICF text.  The entire 
contents of the ICF will be displayed according to the current REB approved consent form, minus the 
signature/attestation page(s). 
Informed consent will be documented using the REDCap e-Consent Framework. Following the consent 
discussion, the participant will be sent a link to the e-consent via email. The participant will complete the 
e-consent and be provided with the option to download and/or email themselves the signed ICF.   
Following the participant signature, the person conducting the consent discussion will complete the Person 
Conducting Consent Discussion Attestation Page. PDF copies of the signed ICFs and Attestation pages will 
be retained in the REDCap File Repository.  The research team will provide the participant with a copy of 
the fully signed ICF via mail and/or email, in accordance with the participant’s wishes. 
CAMH as the sponsor site will have access to participant names on the electronic consent forms (on the 
CAMH REDcap database) All other participating sites will not have access to participant information/e-
consent forms from the other institutions (i.e. UHN would not have access to CAMH e-consents, for 
example).  
 
3) Written Paper Consent: 
 
The consents can occur through tele/videoconferencing or in-person. Prior to the consent discussion, Research 
study staff will provide the prospective participant with the REB-approved ICF, to assist in the consent discussion. 
This provides the prospective participant time to review the material in advance and/or to follow along during the 
consent discussion. The research team will use the REB-approved Initial Contact Script to initiate the discussion. 
Based on the prospective participant’s preference and prior agreement, the ICF can be shared via email, mail, 
courier, or secure file transfer (SFT). If emailed, participants will be given the option to receive a password 
protected ICF. If mailing the ICF to the prospective participant, the research team will either follow-up with the 
participant approximately one week after mailing out the ICF, or have the participant contact them (via email or 
phone) to let them know that they received the ICF.  

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 37 
Regardless of the participant’s preferred method of receiving the ICF document, a 
printed copy will also be mailed to them as the original signed copy will always need 
to be mailed back to the research team. A prepaid postage envelope will be provided 
along with a printed copy of the consent and participants will be asked to mail the signed copy back to the team 
using the prepaid envelop at their earliest convenience.  
Once the virtually emailed or mailed ICF is received by the potential participant, the research team will book a 
scheduled time to go over the consent. The prospective participant must agree in advance to the use of email or 
institutionally-approved teleconferencing/videoconferencing service (this will be documented using the Initial 
Contact Script). As always, prospective participants will be provided with as much time as they need to review the 
consent form, prior to providing informed consent. Research teams will address any questions raised by 
prospective participants prior to documenting informed consent and make a note of the questions on the Informed 
Consent Process Checklist. If the participant asks a question that cannot be answered at that time, a separate 
session should be arranged. 
 
Following the consent discussion, the participant and the person conducting the consent discussion will each 
personally sign and date the ICF.  This process can be conducted in-person or it will be initiated via sending the 
ICF to the participant via mail, email or Secure Fie Transfer (SFT). The participant will sign the ICF, and the 
participant will either mail, email (or SFT), fax, the copy or scan/ send photograph of the consent copy back to the 
study personnel.  Once the copy of the signed consent has been received, research procedures will begin but the 
data obtained will not be used until the original copy of the signed consent has been obtained from the participant. 
The person conducting the consent discussion will also sign the ICF once received and will send a copy to the 
participant via their preferred method (e.g., mail, email SFT).   
In-person consent can be obtained by meeting with the participant to review the REB-approved consent 
script. No study procedures will be undertaken until this in-person visit has occurred and consent is 
obtained and documented from the participant. A copy of the signed ICF will be provided to the participant 
during that same visit. The original copy of the signed ICF will be filed in the Informed Consent binder 
(separate from the participant’s research records).  The Informed consent process will be documented using 
the study’s database on REDcap by filling out a form that will indicate the consent version, date, consent 
options and choices, as well as the person obtaining consent. 
 
Following Informed Consent:  
The participant will receive a fully signed, complete copy of the ICF in a timely manner. A complete copy is all 
pages of the ICF, including the completed signature page(s).  
This may be distributed by mail or email (according to the method the participant agreed to). Alternately, if  
consent is documented via e-signature software or e-consent platform, this distribution will occur via this 
technology where this function is supported.  
 
Research procedures may begin once the consent documentation has been completed in accordance with the 
processes described above. 
 
11.0 Risk/Benefit Ratio 
 
11.1 Risks: 
Venipuncture blood draw: Risks of venipuncture blood draws may include mild discomfort and bruising at 
the venipuncture site and a chance of bleeding, fainting, and/or infection. 
 
Assessments: Assessments may impose some risk emotional discomfort and possible fatigue. 
 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 38 
Suicide Risks: When treating depression there is risk that participants attempt or 
complete suicide. Procedures to manage and mitigate this risk have been carefully 
thought through; they include close monitoring and termination of participants who 
deteriorate and require hospitalization. 
 
tDCS: tDCS has previously been used in multiple studies involving older, frail participants with 
neuropsychiatric disorders such as AD, depression, Parkinson’s disease, or stroke, with no adverse 
sequelae noted. In our own experience, the procedure produces a mild tingling sensation initially which 
usually completely resolves within 30 seconds. In a study that systematically elicited side effects in 77 healthy 
controls and 25 participants who underwent 567 tDCS sessions, participants reported a mild tingling 
sensation (71%), moderate fatigue (35%,), a slight itching sensation under the stimulation electrodes (30%), a 
mild headache (12%), nausea (3%), or insomnia (1%); only 18% as mildly unpleasant. 
 
Some individuals may experience mild headache or shoulder stiffness after testing, however, these symptoms 
usually dissipate within 24 hours. Acetaminophen (Tylenol) is effective in treating these side effects. 
 
It should also be noted that there may be side effects and discomforts that are not yet known. Participants 
will be closely monitored for any adverse effects at each study visit and also on as needed basis. 
 
MRI: Minimal risk except for people with metal or magnetic implants (such as metallic clips in the 
brain or cardiac pacemakers) due to strong magnetic field in scanner. Participants will be screened by the 
study personnel and by personnel at the MR center prior to scanning. If an X-ray is required to rule out the 
presence of metallic fragments,  the maximum  dose to  the involved body area  will  be  0.3  rems  with  
minimal exposure to other body areas. Also, potential risks to pregnant women are not well-known (but 
pregnant women are excluded from this study). Some types of (home-made) tattoos can also heat up and cause 
discomfort. 
Individuals with implanted metallic foreign bodies are excluded because the strong magnetic field in the 
scanner could cause these bodies to change position, injuring participants. In order to assure that MRI 
scanning is safe to undergo, Metal objects can also become projectile when placed near the magnetic field. 
This has been reported on a few occasions, but it is a very rare occurrence. Protection from magnetic objects 
can be safeguarded by the usual safety techniques that are practiced in MRI sessions such has having 
participants and researchers take all metal objects off of their person before entering the environment.  
 
 
 
Another potential risk is psychological distress caused by being in the enclosed magnet bore. Any participants 
who find that they become too anxious or uncomfortable during any part of the procedure will be 
immediately taken out of the scanner and excluded from further scanning. 
 
LP: Potential minimal risks of LP include bleeding and infection and post-spinal headache. It is hard to 
predict which participants will develop the headache. 
 
EEG: EEGs are safe and painless. The only foreseeable risk is experiencing some itchiness or discomfort from 
the electrodes on the scalp. 
 
Steps to prevent or to minimize the severity of the potential risks associated with the experimental 
interventions? 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 39 
The risks and benefits of CR and tDCS will be explained to participants in 
detail. After a psychiatric history, participants will undergo clinical and cognitive 
assessment to assure the clinical appropriateness and safety of their participation. 
Close clinical monitoring will ensure the appropriateness and safety of their continued participation. 
 
Tele/videoconferencing: Using teleconferencing technology presents a new risk to participant privacy and 
confidentially. To mitigate this risk, trained research analysts will be using WebEx and Zoom which are 
approved to be used with participants at CAMH and Sunnybrook respectively. The following mitigation plans 
will also be put in place to ensure the safeguard of participant information.  
- We will ensure that no documents containing personal health information are kept on laptops  
- When/If recording the session, then 
- We will ensure all participants are aware when recording begins and ends, why recording is necessary, 
and whether or how it will be shared with participants or made available elsewhere  
- If participant does not agree to be recorded, then we will not record the session 
- We will remind participants not to discuss, share, or send any identifying information during the session 
- We will store the recording in the secure file location for a minimum of 1 year or according to CAMH 
records retention policy  
-  
In-Person Visits during the COVID-19 Pandemic: Participating in in-person visits may increase potential 
exposure to exposure to coronavirus (SARS-2-CoV). To mitigate this risk, everyone will undergo institutional 
screening procedures prior to and at each visit, adhere to social distancing guidelines of 6 feet, and be required to 
wear a mask. During the booster sessions where the participants will be attending in-person tDCS+CR training at 
CAMH and Sunnybrook, one participant and one RA will become in closer contact than 6ft in order to apply the 
tDCS caps. In addition to a mask, the RA will be required to wear a face shield or goggles when 6 feet distancing 
is not feasible. The tDCS equipment will be wiped down with disinfectant wipes prior to and after each use. Hand 
hygiene will be performed before/after each tDCS session and before/after handling tDCS equipment. Disposable 
nitrile gloves will also be available for use.  
 
 
 
 
 
 
 
Safety Protocol for Remote Visits: 
- 
We will ask participants for an emergency contact number or an alternate phone number to contact 
them if there is an emergency, or if the call/ virtual session ends inadvertently 
- 
We will ask the participant’s address and ask if they are in a fixed location for duration of the call 
- 
Staff will have immediate access to necessary communication technology in order to communicate with 
relevant research supports or emergency services in case of an emergent research situation 
- 
Check on participant(s) who leave/drop off virtual sessions (i.e., if there is a safety concern) by phone 
or separate video-conference. 
 
10.1 Benefits: 
Participants may benefit from the study if the CR and tDCS procedures to which they are assigned to 
works. Participants may also benefit from the careful assessment of cognition and close monitoring they will 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 40 
receive. 
 
12.0   Serious Adverse Events: 
A Serious adverse event (SAEs) is any untoward medical occurrence that results in death, is life-threatening 
(defined as an event in which the patient was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe), results in persistent or significant 
disability or incapacity, requires hospitalization or causes prolongation of existing hospitalization, results in the  
development of drug dependency or drug abuse or is an important medical event [defined as a medical event(s)  
that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate 
medical and scientific judgment, may jeopardize the patient or may require intervention (e.g., medical, 
surgical) to prevent one of the other serious outcomes listed in the definition above. Examples of such 
events include, but are not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization. 
SAEs will be collected during the study and will be followed until event resolution, stabilization, or 60 days 
after the completion of the last participant in the study (whichever comes first). 
13.0 Data and Safety Monitoring Plan 
 
A DSMB will be formed to monitor the conduct of the protocol to ensure the safety of participants and validity 
and integrity of the data. The DSMB will advise the Partners, through the Oversight Committee, on matters 
pertaining to participant safety, data quality, conduct of the study and its continuation. The DSMB may 
recommend suspension of funding in the event of early significance of findings or futility, or the determination  
of unacceptable adverse effects. Dr. Charles Reynolds, Professor of Psychiatry and Neurology at the 
University of Pittsburgh has agreed to chair the DSMB; and Drs. Carl Pieper, Biostatistician at Duke 
University, Stephen Pasternak, Neuropsychiatrist at the Robart’s Institute and Mustafa Husain, expert in Brain 
Stimulation at Duke University have agreed to be members of the DSMB. 
 
Members of the DSMB will agree to keep all information confidential. DSMB will review: (i) the 
number of participants who have been randomized and started treatment, and the number who have 
completed the protocol; (ii) the amount of data lost, including the reason for loss and the steps taken to avoid 
such loss in the future; (iii) adverse consequences (whether minor or severe) to any participants together 
with the short- and long-term remedies to the problem; and (iv) the presence of any new information,  
especially from this study or from other sources, regarding the expected efficacy and safety of study 
intervention (or other procedures) used in the study. From these data, the DSMB will make a 
determination of whether research progress is satisfactory, whether participants' risk/benefit ratio has 
changed (in which case the REBs will be informed), and whether any changes need to be made to any  
protocol or procedure. The DSMB members will also be immediately informed when a serious adverse 
event occur (and is reported to the REBs). The DSMB will also consult with the Data Administrator, 
requesting the assurance that no breach (or potential breach) of participant confidentiality has occurred and 
that data archived and quality control procedures are in place and working. The DSMB will write an annual 
report that will be communicated to the five REBs and the Partners at the annual renewals of the protocol. 
 
14.0 Confidentiality 
 
There is a potential risk of breach of confidentiality that is inherent in all research protocols. Breach of 
confidentiality will be minimized by the staff and by CAMH Neuroinformatics, who will maintain research 
data (identified only by participant code number not related to name, or date of birth) in separate charts 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 41 
and a dedicated password protected electronic database. A list of participant 
names, their ID numbers, and information about how they can be reached will be 
kept in a separate locked cabinet with access only to study personnel authorized 
by the PI. Procedures have been established, and will be followed, to minimize the risk of breach of 
confidentiality. Procedures to maintain confidentially include: (1) formal training sessions for all research 
staff emphasizing the importance of confidentiality; (2) specific procedures developed to protect 
participants’ confidentiality, and (3) formal mechanisms limiting access to information that can link data 
to individual participants. All information obtained from participants will be kept as confidential as 
possible. Computer based files/data will be entered into password-secured databases and paper-based files 
will be stored in a secure location. These data will only be accessible to personnel involved in the study 
and they will abide by confidentiality regulations of the REB. 
Only members of the investigative group will have access to secured files or to master lists for participant 
code numbers and will be well-informed regarding the protection of participants’ rights to confidentiality. 
Identities of participants will not be revealed in the publication or presentation of any results from this project.  
 
Participants will be interviewed specifically to obtain research data. In addition to training and close 
supervision of research staff and a formal quality control mechanism will provide a systematic check on the 
quality of interview data. 
Clinical information obtained at initial evaluation, and clinical treatment notes, will become part of 
participants’ medical records. Participants will not be identified by name in any publication of research 
results. Results will be published as group data without the use of characteristics that would identify 
individual participants. All data pertaining to a participant’s involvement in this study will be coded and 
stored in locked offices. This information will only be accessible to the research team. In unusual cases, a 
participant’s research record may be released in response to a court order. If the research team learns 
that a participant or someone with whom the participant is involved with is in serious danger or harm, an 
investigator will inform the appropriate agencies. 
 
Study personnel at each of the five sites will enter study data via a secure database. At point-of-entry, data 
values will undergo consistency edits (e.g., ID validation, range verification, duplicate detection) and 
personnel will be required to correct errors. Reports will be created via the Web-based program. Data 
management staff will run logic error programs to check for accuracy and irregularities within and across  
 
 
 
data structures and within and across sites. Quality assurance checks will be conducted daily and weekly 
by site personnel, as well as by data management staff. Weekly reports will be generated to monitor site data 
timeliness, completeness, and accuracy as well as participant flow through the study. 
 
15.0 Costs and Payments 
 
Participants will not be charged for research only-services for their participation in this study. All research-
only services, such as cognitive assessments, CR and tDCS will be provided to the participant by the study 
sponsor. Reimbursement will be provided at the end of the study to cover costs of participation ($50 for 
each MRI, $20 for genetics, $80 for neurocognitive assessment battery, $20 per consent/ baseline visit, and 
reimbursements for travel costs using TTC tokens/ tickets (associated monetary value when TTC tokens/ tickets have been 
phased out). 
For remote assessments, participants will continue to be compensated at the rate for the completed assessments 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 42 
and will be provided with an option to receive a cheque via mail or an electronic gift 
card via email.   
16.0 Premature Withdrawal from the Study  
 
Participants are expected to follow all study related procedures and attend all appointments and study visits.  
Participants may be removed from the study at any time by the investigators if they are unable to follow the 
study requirements, such as not attending study clinic appointments.  Participants may also be withdrawn from 
the study, at the discretion of the study investigators, if safety of staff or other study members is at risk or of 
concern.  
 
17.0 Qualifications of Investigators/Staff 
 
Benoit H. Mulsant, M.D., Professor of Psychiatry and clinician scientist at CAMH. He has led or played 
major roles in a series of multi-investigator and multi-site randomized controlled trials in older participants 
with depression or dementia. In the past decade, he has also been involved in new efforts to identify 
biomarkers associated with late-life mental disorders with a focus on pharmacogenetics, neuroimaging, and 
neurophysiology. 
 
Nathan Herrmann, MD FRCPC, Head, Division of Geriatric Psychiatry, Sunnybrook Health Sciences,  
Professor of Psychiatry, University of Toronto. Dr. Herrmann’s expertise are in the areas of the clinical 
pharmacology 
of dementia 
(treatment 
of 
behavioural 
disturbances 
and 
cognition), 
and 
the 
pharmacotherapy of late-life affective disorders. He has published numerous studies on the pharmacotherapy  
of behavioural disturbances in dementia that involve the use of novel agents, which attempt to determine the 
underlying neurobiology of these disorders. He has also participated in studies of post-stroke depression 
examining its neuroimaging and biological correlates. 
 
Bruce Pollock, M.D, PhD, FRCPC., Professor & Head in the Division of Geriatric Psychiatry at the 
University of Toronto. He is a senior scientist at Centre for Addiction & Mental Health & The Rotman 
Research Institute and is internationally recognized for his work in geriatric pharmacology. Dr Pollock has 
vast experience as PI or co-PI of multi-investigator multi-site trials in AD or MDD. 
 
 
 
 
 
Tarek K. Rajji MD, FRCPC, Associate Professor of Psychiatry is the Deputy Physician-in-Chief of the 
Geriatric Psychiatry Division at CAMH. He is also a scientist in the Temerty Centre for Brain Intervention. Dr. 
Rajji is the PI on a psychosocial intervention study in older participants with schizophrenia that includes a 
cognitive remediation and on two brain stimulation studies, one aims at enhancing neuroplasticity in the 
DLPFC of participants with schizophrenia, another in AD. These studies are closely related to the approach 
proposed in this study. 
 
 
18.0 REFERENCES 
1. Daviglus ML et al. NIH Consens State Sci Statements 27:1-30 (2010) 
2. Barnes DE & Yaffe K. Lancet Neurol 10:819-828 (2011) 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 43 
3. Bhalla RK et al. Am J Geriat Psychiat 14:419-427 (2006) 
4. Butters MA et al. Am J Psychia 157:1949-1954 (2000) 
5. Butters MA et al. Archives Gen Psychiat 61:587-595 (2004). 
6. Nebes RD et al. J Psychiat Res 37:99-108 (2003) 
7. Alexopoulos GS et al. Am J Psychiat 150:1693-1699 (1993) 
8. Reynolds CF et al. Archives Gen Psychiat 68:51-60 (2011) 
9. Vinogradov S et al. Neuropsycho-pharmacology 37:43-76 (2012) 
10. Elgamal S et al. Psychol Med 37:1229-1238 (2007) 
11. Naismith SL et al. J Affect Disord 121:258-262 (2010) 
12. Bowie CR et al. J Nerv Ment Dis 201:680-685 (2013) 
13. Brunoni AR et al. Brain Stimul 5:175-195 (2012) 
14. Ferrucci R et al. Neurology 71:493-498 (2008) 
15. Boggio PS et al. J Neurol Neurosurg Psychiat 80:444-447 (2009) 
16. Boggio P S et al. Brain Stimul 5:223-230 (2012) 
17. Grill JD & Karlawish J. Alzheimers Res Ther 2:34 (2010) 
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Appendix 1 – Location of Assessment 
Instruments and batteries 
(text for description) 
Location of 
Assessment 
Baseline 
Randomization/ Treatment 
T0 
T1 
T2 
T3 – T8 T9/TX Other 
Structured Clinical Interview for DSM 5 
Disorders (SCID) (for depression and 
alcohol eligibility) 
All sites 
• 
 
 
 
 
 
Socio-Demographic Information 
All sites 
• 
 
 
 
 
 

 
 
PACt-MD Protocol V20 (December 1, 2020)Page 48 
Montgomery-Asberg Depression 
Rating Scale (MADRS) 
All sites 
• 
 
• 
• 
• 
• 
NPI-Q 
All sites 
• 
 
• 
• 
• 
• 
Beck Scale for Suicidal Ideation (SSI) 
All sites 
• 
• 
• 
• 
• 
• 
Modified Hachinski Ischemic Scale 
All sites 
• 
 
• 
• 
• 
 
Handedness Inventory Scale 
All sites 
• 
 
 
 
 
 
Driving Questionnaire 
All sites 
• 
 
 
 
• 
 
Urine Drug Screen 
All sites 
• 
 
• 
 
 
• 
Review of Medical History 
All sites 
• 
 
 
 
 
 
Vital signs 
All sites 
• 
 
• 
• 
• 
• 
EKG 
All sites 
• 
 
 
 
 
 
CIRS-G 
All sites 
• 
 
 
 
 
 
Family Questionnaire 
All sites 
• 
 
 
 
 
 
E-COG 
CAMH or SHSC 
• 
 
• 
• 
• 
 
Clinical Dementia Rating (CDR) 
All sites 
• 
 
• 
• 
• 
 
Neuropsych. Battery 
CAMH or SHSC 
• 
 
• 
• 
• 
 
EVLT 
CAMH or SHSC 
• 
 
• 
 
 
 
2-item version of PASS 
CAMH or SHSC 
• 
 
• 
• 
• 
 
Intervention 
CAMH or SHSC 
 
 
• 
• 
• 
• 
LP 
CAMH 
 
 
 
 
 
• 
EEG 
CAMH 
• 
 
• 
• 
• 
• 
Genotyping 
CAMH – however if 
subject refuses EEG/ 
MRI /LP, genetics will 
be collected at SHSC 
for the uptown sites 
 
 
 
 
 
• 
MRI 
CAMH 
• 
 
• 
 
• 
 
AE/SAE assessment 
All sites 
 
• 
• 
• 
• 
•