Neuromodulation Plus Cognitive Training to Improve Working Memory Among Individuals With Severe Mental Illness
Phase: NA
Conditions: Schizophrenia, Schizo Affective Disorder, Bipolar Disorder
Sponsor: University of Michigan

i 
 
 
 
FULL PROTOCOL TITLE 
 
Neuromodulation plus cognitive training to improve working memory among individuals with 
serious mental illness 
 
 
Principal Investigator: 
Cynthia Z. Burton, Ph.D., ABPP-CN 
Clinical Assistant Professor, Department of Psychiatry, University of Michigan 
 
Co-Investigators: 
Stephan F. Taylor, M.D.,  
Professor, Department of Psychiatry, University of Michigan 
Ivy F. Tso, Ph.D., 
Assistant Professor, Department of Psychiatry, University of Michigan 
Benjamin M. Hampstead, Ph.D., ABPP-CN 
Associate Professor, Department of Psychiatry, University of Michigan 
 
 
 
 
Other Identifying Numbers: NCT05111548 
University of Michigan IRBMED:  HUM00119204 
Version Day Month Year: 02June2022  
 
 

ii 
 
Table of Contents 
Protocol Summary ................................................................................................................................. iv 
1.0  
Background and Significance ...................................................................................................1 
2.0 
Specific Aims and Study Outcome Measures .........................................................................1 
2.1 
Specific Aims ..................................................................................................................................1 
2.2 
Study Outcome Measures ............................................................................................................1 
3.0 
Study Design ...............................................................................................................................2 
3.1 
Overview of Experimental Design ...............................................................................................2 
3.2 
Interventions ...................................................................................................................................2 
3.3 
Procedures .....................................................................................................................................2 
3.4 
Schematic .......................................................................................................................................3 
4.0 
Study Participants ......................................................................................................................3 
4.1 
Inclusion Criteria ............................................................................................................................3 
4.2 
Exclusion Criteria ...........................................................................................................................3 
4.3 
Strategies for Recruitment and Retention ..................................................................................3 
4.4 
Treatment Assignment Procedures ............................................................................................4 
4.4.1 
Randomization Procedures .............................................................................................4 
4.4.2 
Reasons for Withdrawal...................................................................................................4 
4.4.3 
Handling of Withdrawals ..................................................................................................4 
4.4.4 
Termination of Study ........................................................................................................4 
4.5 
Pre-Screening ................................................................................................................................4 
5.0 
Study Schedule ...........................................................................................................................4 
5.1 
Screening and Initial Assessment Visit ......................................................................................4 
5.1.1 
Informed Consent .............................................................................................................4 
5.1.2 
Initial Assessments ...........................................................................................................5 
5.2 
tDCS Treatment visits ...................................................................................................................5 
5.2.1 
Overview ............................................................................................................................5 
5.2.2 
Treatment Device .............................................................................................................6 
5.2.3 
Stopping Rules ..................................................................................................................6 
5.2.4 
Early Termination Assessments .....................................................................................6 
5.3 
Computerized cognitive training ..................................................................................................6 
5.4 
Subsequent assessment visits (post-treatment and follow-up) ..............................................6 

iii 
 
5.5 
Assessments ..................................................................................................................................6 
5.5.1 Assessment of Suicidality ...................................................................................................7 
5.6 
Concurrent care .............................................................................................................................7 
5.7 
Payment of participants ................................................................................................................7 
6.0 
Assessment of Safety and Regulatory Reporting ..................................................................7 
6.1 
Data Safety and Management Plan ............................................................................................7 
6.1.1 
Data Management ............................................................................................................7 
6.1.2 
Management of withdrawals and drop-outs .................................................................8 
6.1.3 
Adverse Events (AEs) ......................................................................................................8 
6.1.4 
Serious Adverse Events (SAEs) .....................................................................................8 
6.1.5 
Unanticipated Problems...................................................................................................8 
6.2  Event Windows, Missed Assessments/Sessions and Protocol Deviation Reporting ..........9 
7.0 
Clinical Monitoring......................................................................................................................9 
8.0 
Statistical Analysis .....................................................................................................................9 
8.1 
Data Analysis..................................................................................................................................9 
9.0 
Source Documentation ..............................................................................................................9 
10.0 
Quality Control and Assurance:................................................................................................9 
11.0 
Ethics and Protection of Human Participants ....................................................................... 10 
11.1 Ethical Standard and IRB review ............................................................................................. 10 
11.2 Participant Confidentiality .......................................................................................................... 10 
11.2.1 Measures to protect patient privacy ............................................................................ 10 
11.2.2 Minimizing the potential for coercion of patients to participate ............................... 10 
11.3 Potential Risks and Minimization of Risks .............................................................................. 10 
11.3.1 Risk Associated with Screening and Assessments: ................................................. 10 
11.3.2 Risk Associated with Computerized Cognitive Training: ......................................... 11 
11.3.3 Risks Associated with tDCS......................................................................................... 11 
11.4 Potential Benefits and Justification of Risks ........................................................................... 12 
12.0 
Data Handling and Record Keeping ....................................................................................... 12 
13.0 
References ................................................................................................................................. 13 
 
 
 
 

iv 
 
Protocol Summary 
 
Title: Neuromodulation plus cognitive training to improve working memory among individuals 
with serious mental illness 
Abstract: 
Background: People with serious mental illness (bipolar disorder and schizophrenia-spectrum illness) 
often demonstrate impaired neurocognition; in particular, working memory has been proposed as a 
shared neurocognitive endophenotype of these disorders. Novel non-pharmacological treatments have 
shown promise, with some evidence that cognitive remediation confers benefit in terms of neurocognitive 
symptoms and functional performance. The published effect sizes, however, are somewhat modest, 
prompting researchers to focus on potential “cognitive enhancers” to boost the effects of training. 
Neuromodulation, specifically transcranial direct current stimulation (tDCS), is one potential enhancing 
treatment that is considered exceptionally safe and cost-effective.  
Study Design: The proposed study aims to investigate the feasibility, acceptability, and initial efficacy of 
a combined computerized cognitive training and tDCS intervention, using a randomized sham-controlled 
design including individuals with serious mental illness. This study is a critical first step in advancing the 
evidence-base regarding treatments that can improve neurocognitive abilities and functional outcome 
among those affected by psychiatric illness. Examining whether tDCS is a realistic treatment option for 
individuals with psychiatric illness, and whether adding tDCS to a cognitive training paradigm improves 
working memory performance beyond the positive effects of training alone, will lay the groundwork for 
additional investigation with larger samples.    
Objectives:  1) determine the feasibility and acceptability of tDCS treatment and computerized cognitive 
training in this population; 2) examine preliminary efficacy of the combined treatment on main outcome: 
working memory performance.  
 
Population: Patients aged 18-65 diagnosed with schizophrenia, schizoaffective disorder, or bipolar 
disorder 
Site: University of Michigan 
Study Duration: 2 years 
Participant Participation Duration: 2 months 
Study Design:  Randomized controlled trial 
Number of participants:  12 completers for Aim 1, 30 completers for Aim 2, 1:1 randomization 
Description of Intervention: 2mA stimulation to left dorsolateral prefrontal cortex, 10 treatment 
sessions; 10 hours of computerized cognitive training 
Estimated Time to Complete Enrollment: 2 years

1 
 
1.0  
Background and Significance 
Neurocognitive impairment is prevalent among individuals with serious mental illness (SMI; bipolar 
disorder and schizophrenia-spectrum disorders), and is associated with functional disability beyond the 
effects of symptoms alone. Although the magnitude of deficits is typically greater amongst people with 
psychotic illness, the pattern is similar across categorical SMI diagnoses and may represent a 
dimensional, cross-diagnostic feature of those affected by SMI1-4. Among other neurocognitive domains, 
working memory is commonly impaired in both bipolar disorder and schizophrenia, with some evidence 
that it represents a shared neurocognitive endophenotype among individuals with SMI5,6. A burgeoning 
area of research involves neuroplasticity-based treatment called cognitive remediation (also known as 
cognitive training), defined as “a behavioral training-based intervention that aims to improve cognitive 
processes (attention, memory, executive function, social cognition or metacognition) with the goal of 
durability and generalization”7. The current evidence generally supports the efficacy of cognitive 
remediation in mood disorders as well as schizophrenia7,8. However, a broad array of training techniques 
has been reported in the literature, all of which appear to demonstrate some efficacy but none of which 
emerge as clearly superior. Therefore, there is a growing emphasis on applying novel techniques in 
conjunction with remediation paradigms; for example, via a “cognitive enhancer” like transcranial direct 
current stimulation (tDCS) to boost the effects of cognitive training.  
In the context of SMI, tDCS has been identified as a promising treatment to reduce depressive symptoms 
among individuals with bipolar depression, although not all trials have shown significant benefits9,10. 
There is also some limited evidence that tDCS may be effective in treating auditory hallucinations and 
possibly improving cognitive functioning among people with schizophrenia11, although to date most 
published works were case studies, used single tDCS sessions, or did not include cognitive training 
concurrent with stimulation. Researchers have concluded that there is potential utility in use of tDCS for 
cognitive remediation, and have identified the use of tDCS as monotherapy or in combination with 
cognitive training as an area of future emphasis11.  
The proposed study is a critical first step toward a larger RCT, aiming to collect preliminary pilot data on 
the feasibility, acceptability, and initial efficacy of a combined neuromodulation and cognitive training 
intervention for individuals with SMI. Thirty participants diagnosed with SMI will be enrolled; participants 
will be randomized to receive 10 sessions of either active or sham tDCS, and will concurrently complete 
10 hours of computerized cognitive training focused specifically on working memory abilities.  
 
2.0 
Specific Aims and Study Outcome Measures 
2.1 
Specific Aims 
Specific Aim 1: Determine the feasibility and acceptability of delivering a combined neuromodulation 
(tDCS) plus cognitive training intervention to outpatients with SMI (n=12). Individuals with SMI, 
particularly those with neurocognitive impairment, often face barriers to treatment access and retention. 
The proposed study will incorporate various strategies to support participant retention and promote 
acceptability, with the hypothesis that participants will be able to tolerate 10, 20-minute sessions of tDCS 
in the clinic and 10 hours of computerized cognitive training over the course of 4-8 weeks.  
**NOTE: Aim 1 corresponds to NCT03338673 registered on clinicaltrials.gov. ** 
Specific Aim 2: Collect pilot data on the efficacy of the combined intervention, comparing neurocognitive 
performance following active tDCS treatment to performance after cognitive training alone (sham tDCS). 
The proposed analyses will test the hypothesis that active tDCS plus computerized cognitive training will 
produce a synergistic effect, where performance following the combined treatment will be superior to 
performance following sham stimulation/cognitive training alone. 
**NOTE: Aim 2 is registered on clinicaltrials.gov as NCT05111548**  
2.2 
Study Outcome Measures 
Aim 1: Determine the feasibility and acceptability of delivering a combined neuromodulation (tDCS) plus 
cognitive training intervention to outpatients with SMI. 

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Primary outcome: Participant retention, defined as the percentage of enrolled participants who 
complete the combined intervention. 
 
Secondary outcome: Self-reported treatment satisfaction, as measured on a 1-10 scale at study 
completion. 
Aim 2: Collect pilot data on the efficacy of the combined intervention, comparing neurocognitive 
performance following combined treatment to performance after cognitive training alone.  
Primary outcome: change in working memory performance 
 
Secondary outcome: change in non-working memory comparison measures 
 
3.0 
Study Design 
3.1 
Overview of Experimental Design 
Aim 1 (feasibility and acceptability) will include a randomized crossover design, where all 12 participants 
will receive both the combined intervention (active tDCS plus BrainHQ computerized cognitive training), 
and computerized cognitive training alone, with starting condition randomly determined. Aim 2 (efficacy)  
will be a randomized, controlled trial, where half of the participants (n=15) will be randomized to receive 
active transcranial direct current stimulation (tDCS) plus BrainHQ computerized cognitive training, and 
half (n=15) will receive sham tDCS plus BrainHQ computerized cognitive training (Table 1). Participants 
will attend 10 treatment sessions in the clinic. If able to attend daily, participants will complete these 
sessions in 2 weeks; to allow for unanticipated absences or difficulty with attendance, up to 4 weeks will 
be permitted for completion. Following completion of these 10 treatment sessions, participants will return 
after one month of no study contact to complete a follow-up assessment.  
3.2 
Interventions 
Cognitive training: Software licenses for a commercially-available computerized cognitive training 
package titled BrainHQ will be purchased and provided to each participant (http://www.brainhq.com/). To 
date, more than 30 published manuscripts and abstracts reported on the effects of BrainHQ for individuals 
with SMI; it also meets each of the 5 criteria recently published by the Institute of Medicine in support of 
a brain-training program’s scientific merit. This program offers a variety of working memory-specific 
training paradigms, individualized feedback and progress notification, and administrative oversight of 
training exercises as well as detailed usage reports. BrainHQ can be accessed from any web-enabled 
computer and has both tablet and mobile applications available on Apple devices.      
tDCS: There are data suggesting that tDCS can affect functioning in the prefrontal cortex, an area often 
implicated in models of neurocognitive dysfunction. In particular, stimulation of the dorsolateral prefrontal 
cortex (DLPFC) is commonly used; this functional region is believed to underlie executive cognitive 
functions like working memory and cognitive flexibility, which are popular targets of cognitive training 
interventions. Because there is no clear guide from the literature on (1) location of electrode placement, 
(2) frequency of stimulation, or (3) duration of stimulation, the montage and procedures proposed here 
are guided by the general consensus in the published literature, hypothesized neural circuitry of interest, 
and what is presumed to be most acceptable to participants. Based on these features, the anticipated 
montage will include concurrent anodal (excitatory) stimulation of 2 mA over the left dorsolateral 
prefrontal cortex, and cathodal (inhibitory) stimulation over right dorsolateral prefrontal cortex, over a total 
of 10 sessions lasting 20 minutes each. Minor deviations are possible but are not expected to significantly 
increase risk to participants. For example, as new data emerge, we may shift the montage, e.g. cathodal 
stimulation to parietal region. Participants will complete BrainHQ exercises concurrently during 
stimulation. All treatment sessions will take place at the Rachel Upjohn Building (RUB).  
3.3 
Procedures 
Participants will include a total of 42 individuals who are self- or clinician-referred in response to 
advertisements posted in Ambulatory Psychiatry/RUB or in the community. Participants may also be 
recruited from the Prechter Bipolar Longitudinal Study or Dr. Tso & Taylor’s studies. Enrollment will occur 
on a rolling basis, with anticipated enrollment of 1-2 participants per month. Potential participants will 

3 
 
meet with a study coordinator to provide written informed consent; following consent, participants will 
complete a structured diagnostic interview to confirm eligibility; participants not meeting the inclusion 
criterion (below) will be compensated for their time and excluded from further participation. To minimize 
attrition and missing data, participants will be compensated for each visit (up to $200 total); study staff 
will also provide reminder phone calls for appointments, and may arrange transportation via cab if and 
when possible.  
3.4 
Schematic   
Aim 1. 
 
Week 0 
Weeks 1-4 
End of Week 4 
Weeks 5-8 
Week 8 
Group A  
(6 participants) 
Baseline 
assessment 
tDCS + 
BrainHQ 
Mid-point 
assessment 
BrainHQ 
Post-treatment 
assessment 
Group B  
(6 participants) 
 BrainHQ 
tDCS + 
BrainHQ 
 
Aim 2. 
 
Week 0 
Weeks 1-4 
End of Week 4 
Weeks 5-8 
Week 8 
Group A  
(15 participants) 
Baseline 
assessment 
Active tDCS + 
BrainHQ 
Post-treatment 
assessment 
No contact 
Follow-up 
assessment 
Group B  
(15 participants) 
 Sham tDCS 
+ BrainHQ 
 
4.0 
Study Participants 
4.1 
Inclusion Criteria 
(1) age 18-65, (2) diagnosis of bipolar disorder I or II, schizoaffective disorder, or schizophrenia, as 
confirmed by structured diagnostic interview, and (3) willingness to complete computerized cognitive 
training and undergo brain stimulation procedures.  
4.2 
Exclusion Criteria 
(1) history of neurological illness or brain injury (e.g., stroke), (2) history of loss of consciousness > 20 
minutes, (3) diagnosed intellectual disability, (4) current (i.e., past 30 days) substance use disorder, (5) 
current mania (YMRS ≥ 10) or moderate depression (HAM-D ≥ 17) or severe psychosis (PANSS positive 
symptom total ≥ 35), (6) serious suicidal ideation/behavior (endorse questions 4 or 5 or suicide behaviors 
within the past 3 months, according to the C-SSRS), (7) pregnant or trying to become pregnant, or 
currently lactating, (8) presence of metal (except titanium) or electrical implants in the brain or skull (e.g., 
surgical clips, deep brain stimulator, cochlear implants, splinters/fragments, skull plate), (9) presence of 
implanted medical devices elsewhere in the body (e.g., cardiac pacemaker or medical pump).  
4.3 
Strategies for Recruitment and Retention 
Recruitment will be from the outpatient psychiatry programs at the University of Michigan Health System, 
from flyer advertisements, and by clinician referral. The recruitment process is designed to limit 
interference with clinical care and assure the informed participation of patient participants. By obtaining 
a waiver of consent for screening purposes, recruitment is facilitated by pre-review of computer-based 
medical records to identify potential research participants who have contacted the Department of 
Psychiatry. In addition, we will scan umhealthresearch.org, the UM registry of individuals who are 
interested in participating in health research. Study coordinators will make contact with clinic staff to 
interview patients who express an interest in a study, or who appear eligible based on initial review of 
electronic records. For all patients who are screened for the study, we will contact their clinician, if not 
already done during pre-screening (psychiatrist and/or psychotherapist), notify them of their patient's 
interest and verify that the participant is eligible to participate. The patient’s clinician(s) will also be notified 
via a memo when the patient has enrolled and is scheduled for the study treatment. 

4 
 
4.4 
Treatment Assignment Procedures 
 
 
4.4.1 Randomization Procedures  
Following baseline assessment, participants will be randomized to complete either the combined 
treatment (active tDCS plus cognitive training) or cognitive training alone (sham tDCS). Participants and 
clinical assessors will be blinded to condition; at the post-treatment assessment visit, participants and 
the assessor will guess group assignment to evaluate how well the blind was maintained. 
 
 
4.4.2 Reasons for Withdrawal  
During the pre-screening process, participants who are found to be non-eligible, before formal signing of 
a consent form, will be considered not enrolled, and all data related to that participant will be destroyed. 
Participants who consent, and are found not eligible during the assessment and screening will be 
considered screen failures, and all research and identifying data will be destroyed, except for the consent 
form and limited information to document the screen failure (age, gender, diagnosis, specific reason for 
exclusion). Participants who leave the study after signing the informed consent, and after being deemed 
eligible/enrolled/randomized, will be considered withdrawn. Participants may withdraw from the study at 
any time and for any reason. Participants may be withdrawn by the investigator when continued 
participation would present an unacceptable risk to the participant. This would include, but is not limited 
to, significant adverse events related to the device, (e. g., intolerable discomfort), or participants who 
experience severe symptom worsening, including suicidal thoughts or behaviors, which require 
hospitalization. 
 
 
4.4.3 Handling of Withdrawals 
If a participant wishes to withdraw from the study and all assessments, his/her intention will be honored. 
For withdrawn participants, data will be retained and used at the discretion of the investigator.  
 
 
4.4.4 Termination of Study 
This study may be prematurely terminated if, in the opinion of the investigator or the sponsor, there is 
sufficient reasonable cause. Written notification, documenting the reason for study termination, will be 
provided to the investigator or sponsor by the terminating party. Circumstances that may warrant 
termination include, but are not limited to: determination of unexpected, significant, or unacceptable risk 
to participants; insufficient adherence to protocol requirements; data that are not sufficiently complete 
and/or evaluable. If the study is prematurely terminated or suspended, the PI will promptly inform the IRB 
and will provide the reason for the termination or suspension.   
4.5 
Pre-Screening 
Potential participants will be screened informally, usually over the telephone, possibly face-to-face (see 
pre-screening form) in order to make a preliminary assessment of their eligibility. Patients who appear 
eligible and express interest in participating will be scheduled for a screening/assessment visit.  
 
5.0 
Study Schedule   
5.1 
Screening and Initial Assessment Visit  
5.1.1 Informed Consent 
The session will begin by having the participant provide written informed consent.  Informed consent is 
a process that is initiated prior to the individual’s agreeing to participate in the study and continues 
throughout the individual’s study participation. Extensive discussion of risks and possible benefits of 
these treatments will be provided to the participants and any family members or others the participant 
would like to include in the process. Consent forms (written in non-technical language) describing in 
detail the study interventions/products, study procedures, and risks will be given to the participant and 
written documentation of informed consent is required prior to starting the intervention. Consent forms 
will be IRB-approved and the participant will be asked to read and review the document. Upon 
reviewing the document, the investigator (or her designee) will explain the research study to the 
participant and answer any questions that may arise. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. Participants will have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing to participate. 

5 
 
Participants may withdraw consent at any time throughout the course of the trial. A copy of the informed 
consent document will be given to participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study.  
5.1.2 Initial Assessments 
This session will continue with completion of a brief demographic questionnaire and clinical measures to 
confirm eligibility and characterize current symptoms. These include: 
1. Mini-International Neuropsychiatric Interview (MINI), a short structured diagnostic 
interview for DSM-IV and ICD-10 psychiatric disorders 
2. Hamilton Depression Rating Scale (HAM-D) 
3. Young Mania Rating Scale (YMRS) 
4. Positive and Negative Syndrome Scale (PANSS) 
5. Columbia Suicide Severity Rating Scale (C-SSRS) 
Note. To allow for maximal appropriate distancing owing to the ongoing COVID-19 pandemic, these 
interview-based clinical measures may be completed virtually while the participant is physically in the 
building and the clinician is in a remote location, via a secure and approved telehealth platform (Zoom 
for Health). Because the participant will be in the clinic with another study staff member (who will be 
administering the informed consent and the portion of the assessment that requires manipulation of 
materials), there are no anticipated changes to safety or risk-assessment protocols. Any safety concerns 
will be immediately communicated between the study clinician and research assistant, and appropriate 
action will be taken (see section 5.5.1).   
Neuropsychological and functional measures will also be administered to characterize current 
neurocognitive functioning. These include: 
1. Wide Range Achievement Test, reading subtest (WRAT-4) 
2. MCCB: Trails A, letter-number span, spatial span 
3. Trails B 
4. Specific Levels of Functioning (SLOF) clinician-rated questionnaire 
This screening and initial assessment visit is expected to last up to 2.5 hours.  
5.2 
tDCS Treatment visits 
 
 
5.2.1 Overview 
tDCS traditionally uses two electrodes (an anode and a cathode) that are placed according to the 
international 10-20 system (or the extended 10-20 system), allowing for easy replication both within and 
across studies. The neurons underlying the anode become depolarized (“excited”) whereas those 
underlying the cathode become hyperpolarized (“inhibited”). A study team member will be present in the 
room with the participant during the stimulation session. tDCS is administered while the participant sits 
in a chair. Following placement of the electrodes, either active or sham tDCS will commence: in both 
conditions, a brief ramp up period will occur first in which the electrical current is gradually increased. In 
the active condition, the current will reach 2mA and will be sustained at that level for 20 minutes, then a 
ramp down period will take place during which the current is gradually removed. The sham condition 
mirrors the ramp up and ramp down of active stimulation but does not otherwise deliver a current. The 
proposed montage includes anodal (excitatory) stimulation over the left dorsolateral prefrontal cortex, 
and cathodal (inhibitory) stimulation over right dorsolateral prefrontal cortex. The exact duration, 
frequency and amount of stimulation may vary from these procedures based on feedback from 
participants (but will not exceed 2 mA or 20 minutes), so the parameters will always fall within the safety 
guidelines. For example, if a participant reports discomfort, stimulation will be paused and additional 
saline/gel will be added to improve the contact (i.e., reduce resistance), or the current will be incrementally 
reduced to a tolerable level. The participant will concurrently complete BrainHQ working memory 
exercises during and immediately after the stimulation session, for approximately 60 minutes total. 
Treatment will occur in a designated room on the second floor of the Rachel Upjohn Building, department 
of Psychiatry.  

6 
 
5.2.2 Treatment Device 
A Soterix Clinical Trial (CT) stimulator will be used. The unit is powered by standard 9v batteries and has 
a number of built-in safety features that limit the maximum possible current to the programmed 
parameters. The unit includes a switch to select active or sham stimulation. This unit is considered an 
investigational device by the FDA. Based on the scientific literature available to date, this device is 
believed to be of non-significant risk (NSR). 
 
 
5.2.3 Stopping Rules  
In the event that a participant reports discomfort during the tDCS procedure, stimulation will be paused 
and additional saline/gel will be added to improve the contact, or the current will be incrementally reduced. 
The session will be discontinued if the patient reports continued discomfort. Immediately after each 
stimulation session ends, participants will complete a tDCS side effects questionnaire. A study team 
member will review the responses and will immediately consult the PI if a participant reports a moderate-
severe rating for any of the side effects. Those participants, if any, will be given the option of withdrawing 
from the study. The PI will also withdraw participants if the nature of the side effect is unusual (i.e., not 
listed as a common side effect) or concerning (e.g., significant acute mood change). Clinically trained 
study staff will monitor participants closely for mood changes and/or any emergence of suicidal ideation 
throughout the duration of participation. Participants will be withdrawn in the event of significant 
symptomatic worsening, including: 
1. Current mania: YMRS change of ≥ 7 points at mid-point assessment or clinical observation 
indicating current mania 
2. Worsening of depressive symptoms: 25% increase (i.e., greater severity) in HAM-D total 
score at mid-point assessment 
3. Worsening of psychosis: 25% increase (i.e., greater severity) in PANSS positive total 
score at mid-point assessment 
4. Suicide risk evaluated by a clinician to be high and imminent (e.g., current suicide plan 
and intent)  
  
 
5.2.4 Early Termination Assessments  
If early termination occurs and, if the participant is willing and able, all of the outcomes and safety 
assessments noted above for the final experimental visit will be performed. 
5.3 
Computerized cognitive training 
Participants will be provided a personalized login to the BrainHQ website and provided a tutorial to orient 
them to the training program. They will complete a total of 10 hours of working memory exercises 
specifically, as selected and monitored by the study team. BrainHQ can be accessed online on a desktop 
computer, laptop, Apple tablet, or Apple mobile phone. In the event that a participant does not have 
reliable access to one of these devices, arrangements will be made to complete training on an available 
computer at RUB.   
5.4 
Subsequent assessment visits (post-treatment and follow-up)  
Participants will complete follow-up assessments at the conclusion of treatment (post-treatment) and at 
one-month follow-up. Measures will include: 
1. Hamilton Depression Rating Scale (HAM-D) 
2. Young Mania Rating Scale (YMRS) 
3. Positive and Negative Syndrome Scale (PANSS) 
4. MCCB: Trails A, letter-number span, spatial span 
5. Trails B 
6. Specific Levels of Functioning (SLOF) clinician-rated questionnaire 
These visits are expected to last up to 1.5 hours.  
5.5 
Assessments 
Participants will complete assessments at three time points: baseline (pre-treatment), post-treatment, 
and follow-up.  
 

7 
 
Assessment schedule and administration time requirements. 
 
Baseline 
Post-
treatment 
Follow-up 
Administration 
time (mins) 
Clinical measures 
 
 
 
 
     MINI diagnostic interview 
x 
 
 
60 
     HAM-D, YMRS, PANSS 
x 
x 
x 
15-30 
     C-SSRS 
x 
 
 
5 
Neuropsychological measures 
 
 
 
 
     WRAT reading 
x 
 
 
5 
     MCCB (Trails A*; letter-number 
span; spatial span) 
x 
x 
x 
30 
     Trails B* 
x 
x 
x 
5 
Functional measures 
 
 
 
 
     SLOF 
x 
x 
x 
10 
Total estimated time 
≤ 2.5 hours 
≤ 1.5 hours 
≤ 1.5 hours 
 
*Trails A and B will be administered as non-working memory neurocognitive comparison measures 
 
5.5.1 Assessment of Suicidality 
For any potential participant who reports concerning suicidal thoughts/behaviors (defined according to 
the MINI, HAM-D, or C-SSRS), the PI will be notified and a further risk assessment of the patient will be 
conducted, including the identification of risk factors (e.g., substance abuse, active psychosis, 
hopelessness), mitigating factors (e.g., social support, degree of control over suicidal thoughts, religious 
beliefs against suicide) and the level of suicidal ideation/behavior. An intervention plan will be formulated, 
taking into account the level of risk and treatment resources available to the potential participant. This 
could include monitoring by family, contact with a treating clinician (with the patient’s permission), follow-
up phone calls, or urgent evaluation in the psychiatric emergency room. For individuals without a treating 
clinician, referrals to available community resources will be made. 
5.6 
Concurrent care 
Participants may continue to see their current mental health clinicians through the course of the trial in 
order to minimize disruption in existing treatment. Communication with the treating provider(s) will be 
made prior to the onset of treatment with the participant’s knowledge and permission.  
5.7 
Payment of participants 
Participants will be compensated for each assessment visit, with increasing amounts to promote retention 
and study completion. Participants will receive $20 for completing the baseline assessment, $30 for 
completing the post-treatment assessment, and $50 for completing the follow-up assessment, for a total 
of $100 per participant. To offset transportation costs and promote treatment retention, participants will 
be compensated $10 for each tDCS clinic visit, for a total of $100 per participant. The total compensation 
per participant is $200.  
 
6.0 
Assessment of Safety and Regulatory Reporting 
6.1 
Data Safety and Management Plan 
6.1.1 Data Management 
Research data will be maintained on password protected computers, behind UM firewalls. All enrolled 
participants will receive participant identifiers, which will be used to code all research records for this 
project.  Paper records with no identifying data beyond the research code are stored in locked cabinets 
in the PI’s office. Copies of executed consent forms will be stored in separate locked cabinets. 
Demographic data will be entered into spreadsheets, and behavioral data will be merged into files. 
Password-protected electronic files separated from the research data will track consents, including the 
link between the research identifier and individual participants. This tracking file will be the sole link 

8 
 
between participant identifiers and research data. By deleting the field linking identifiers with participant 
names, research records can be effectively anonymized. 
6.1.2 Management of withdrawals and drop-outs 
Procedures for these events are described in sections 4.4.2, 4.4.3, and 4.4.4. 
6.1.3 Adverse Events (AEs) 
An AE is defined as any untoward occurrence in a patient or clinical investigation participant administered 
an intervention regardless of its causal relationship to the study treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of the intervention. The occurrence of an AE may come to the attention 
of study personnel during study visits and interviews of a study participant presenting for medical care, 
or upon review by a study monitor. At each treatment session participants will be questioned about 
putative AEs. Information to be collected includes event description, time of onset, clinician’s assessment 
of severity (mild, moderate, or severe), relationship to study product (assessed by the study clinician, Dr. 
Burton), expected versus unexpected, local versus systemic, and time of resolution/stabilization of the 
event. All AEs occurring while on study will be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution. Adverse event reporting will occur on the standard IRBMED 
timetable. 
6.1.4 Serious Adverse Events (SAEs) 
An SAE is defined as an AE that meets one of the following conditions: 
Death during the period of protocol-defined surveillance 
Life-threatening event (i.e., a participant at immediate risk of death at the time of the event) 
An event requiring inpatient hospitalization or prolongation of existing hospitalization during the 
period of protocol defined surveillance  
Results in congenital anomaly or birth defect 
Results in a persistent or significant disability/incapacity 
Any other important medical event that may not result in death, be life threatening, or require 
hospitalization, may be considered a serious adverse experience when, based upon appropriate 
medical judgment, the event may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse/overdose or cancer. 
All SAEs will be: 
• 
Followed through resolution by a study clinician 
• 
Reviewed and evaluated by a study clinician 
• 
Reported to Soterix, the company supplying the tDCS unit to the investigators 
The study will comply with IRB and FDA reporting requirements and guidelines for SAEs. 
6.1.5 Unanticipated Problems 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• 
Related or possibly related to participation in the research (in the guidance document, 
possibly related means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); and 
suggests that the research places participants or others at a greater risk of harm (including 

9 
 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
• 
An incident, experience, or outcome that meets the three criteria above generally will 
warrant consideration of substantive changes in order to protect the safety, welfare, or 
rights of participants or others.   
Unanticipated problems will be recorded and reported throughout the study.  
6.2  
Event Windows, Missed Assessments/Sessions and Protocol Deviation Reporting   
For the post-treatment and follow-up assessments, a window of ± 10 days will be permitted (not including 
weekends). Any safety-related assessments (HAM-D, YMRS, PANSS, C-SSRS) or primary outcome 
measure (MCCB working memory) which are missed or obtained outside the window will be reported to 
the IRB as a protocol deviation.  However, for the other assessments, missing or late assessments will 
not be reported as protocol deviations unless they constitute > 10% of the total assessments.  In order 
to accommodate inevitable scheduling conflicts, holidays, etc., participants will be allowed to complete 
the 10 tDCS sessions within 4 weeks. Participants who do not complete all 10 tDCS sessions or all 10 
hours of cognitive training will be retained in the study and their outcome data will be compared to those 
participants who completed the full course of treatment. These allowances should affect neither the 
scientific integrity nor the safety monitoring provisions of the protocol.   
7.0 
Clinical Monitoring  
The investigators will meet weekly (as close to that as permitted by travel and holidays) to monitor the 
study activities to ensure that the human participant protection, study procedures, administration, and 
data collection processes are of high quality and meet the appropriate, regulatory guidelines.   
Standard monitoring procedures in place for tDCS therapy will be followed for this protocol. During tDCS 
therapy, operators are trained to monitor patients for any side effects. If a participant reports side effects, 
these are noted and dealt with according to severity. Importantly, tDCS does not directly induce neuronal 
firing and there has never been a reported case of tDCS induced seizure. 
 
8.0 
Statistical Analysis 
8.1 
Data Analysis  
Specific Aim 1: Feasibility will be evaluated through participant retention, and will be calculated as the 
percentage of enrolled participants who complete the combined intervention. Acceptability will be 
evaluated by participant-rated satisfaction with the intervention, as rated on a 1-10 scale (where 1 is low 
satisfaction and 10 is high) collected at study completion. 
Specific Aim 2: Mixed-factorial ANOVA will be used to examine between-group (Group A: active tDCS, 
versus Group B: sham tDCS) and within-group (time) effects on the main outcome measures: MCCB 
letter-number span score and MCCB spatial span score. Mean performance for each group at each time 
point will be plotted and examined.    
9.0 
Source Documentation  
Medical and research records will be maintained to ensure the protection of confidentiality of participants 
(see section 12). Only study staff will have access to these records.  
10.0 
Quality Control and Assurance:  
The PI will review data collection and entry periodically to evaluate compliance with the protocol and for 
accuracy.  

10 
 
11.0 
Ethics and Protection of Human Participants 
11.1 
Ethical Standard and IRB review 
The investigator will ensure that this study is conducted in full conformity with the principles set forth in 
The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Participants of 
Research, as drafted by the US National Commission for the Protection of Human Participants of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 
62 Federal Regulations 25691 (1997) and the Declaration of Helsinki and Good Clinical Practice (GCP). 
All protocol amendments must be IRB approved prior to implementing, except when change is for patient 
safety. 
11.2 
Participant Confidentiality 
11.2.1 Measures to protect patient privacy 
Study staff will make every effort to limit identifiable information on potential participants during 
recruitment. Conversations in which a patient's name must be mentioned (e.g., to determine potential 
eligibility), will occur in private settings of the clinic.  The minimum amount of information will be recorded, 
and staff will be alerted to the dangers of printing, faxing and emailing sensitive information.  Phone 
conversations with potential research participants will occur behind closed doors, and staff will ask callers 
if they are in a location where sensitive information can be discussed without danger of revealing 
confidential information.  Any information gathered on participants who prove ineligible will be destroyed 
as soon as possible (a list of patients who have declined or screened out will be maintained through the 
recruitment phase in order to avoid contacting these participants again). 
11.2.2 Minimizing the potential for coercion of patients to participate 
Because members of the research team are involved in clinical care and research, there is the potential 
that some patients of the study team may be recruited.  It will be made clear to all potential participants 
that participation is entirely optional and not a part of regular treatment. The bulk of the recruitment 
process will occur with the study coordinator, who does not treat patients in any of the clinical venues 
where recruitment will occur. Overall, the research team is experienced in clinical research and very 
mindful of the conflict between the dual roles of clinician and researcher. They firmly believe that the 
safety and desires of the patient take precedence over any research protocol, and work hard to assure 
their patients that research participation is not required for treatment.  In the case where a patient of a 
study team member is recruited, the consent process and signature on the informed consent document 
will be obtained by the study coordinator. 
11.3 
Potential Risks and Minimization of Risks 
 
 
11.3.1 Risk Associated with Screening and Assessments: 
1)  Risk of boredom, fatigue, or discomfort (likely, not serious). It is possible that participants will become 
fatigued, frustrated, or uncomfortable answering sensitive questions about their mental health history.  
To minimize risk: Participants may request a break from the procedures and/or may decline to 
answer any questions, though they will be counseled that this could affect their eligibility to continue their 
participation. If a participant becomes so upset that he/she cannot continue, he/she may be withdrawn 
without penalty. 
2) Loss of confidentiality around sensitive information (rare, not serious).  
To minimize risk: Paper records with identifying personal information (consent form, payment 
records) are stored separately from research records in locked file cabinets behind locked doors, to which 
only authorized research personnel have access. All data will include a subject identifier number and no 
personally-identifiable information. A single tracking file contains links to the research records and 
participant codes. Computer records with identifying information are kept on secure, password protected 
servers. Staff are trained to scrupulously protect the confidentiality of sensitive information, and take care 
to limit the printing of documents with identifying information and to avoid unnecessary discussion of 
participant names. Screening forms for participants who do not qualify for the study will be destroyed, 
except for anonymous information unlinkable to the participants (such as age, gender, and education). 

11 
 
 
 
11.3.2 Risk Associated with Computerized Cognitive Training: 
1) Fatigue or boredom while completing training exercises (likely, not serious). The cognitive training 
exercises used in this study are completed while participants are seated in front of a computer monitor 
or tablet screen. There are no known risks for these procedures, as they are entirely non-invasive and 
painless. It is possible that participants will become fatigued or frustrated while completing the training.  
To minimize risk: Participants may take a break from the procedure or postpone completion to 
another day or time. 
11.3.3 Risks Associated with tDCS. 
Active tDCS may have no benefit. The general consensus is that tDCS is extremely safe. In a meta-
analysis of over 200 tDCS studies conducted from 1998 to 2010, 56% of studies mentioned adverse 
events12. The events were generally minor, including itching, tingling, headache, burning sensation and 
discomfort limited to the scalp site where the tDCS electrodes were applied. To date, there have been 
no reports of seizures or other severe events induced by tDCS12,13. Importantly this is the case in both 
healthy volunteers and in different populations of patients, including patients with disorders where there 
might be an increased risk of seizures (e.g. Alzheimer’s disease, recent stroke, epilepsy). For this study, 
an intensity not to exceed 2 mA will be used, for a duration of 20 minutes; little of this current actually 
reaches the brain since it must first pass through the scalp (skin, fat, etc), skull, and cerebrospinal fluid. 
Few, if any, side effects are reported with these parameters and those that are reported are mild in nature 
(e.g., tingling, itching, burning sensation; Nitsche & Paulus, 2011). Nevertheless, side effects of tDCS are 
possible. The most common side effects associated with tDCS based on the available scientific data are: 
1) Sensations under the electrode: these sensations usually stop shortly after tDCS begins but can 
sometimes continue throughout and for a brief period after tDCS. 
• 
Mild tingling 
• 
Light itching 
• 
Slight burning sensation 
• 
Discomfort 
2) Reported effects that occur only DURING tDCS: 
• 
Visual sensation during switching on and off the stimulation 
3) Other effects that can occur both DURING and AFTER tDCS: 
• 
Fatigue 
• 
Skin redness 
• 
Headache 
• 
Changes in concentration, memory, or other cognitive abilities. This is partially 
what the proposed study will be testing. 
Additionally, the following rare side effects have been described in previous studies that used tDCS: 
1) Nausea 
2) Nervousness 
3) It is also possible that the electric current can cause a burn on the skin. This is unlikely because we 
are using a smaller dose than what is known to cause burns and because we use saline or gel to 
reduce electrical resistance that leads to burns.  
4) A shock-like sensation at the initiation of tDCS was reported in one participant. 
5) Changes in the activity of the prefrontal region (front of the head) have the potential to induce sudden 
changes in mood. Hypomania has been reported in a few patients receiving tDCS for bipolar disorder 
and depression.  
To minimize risk: Clinically trained study staff will monitor participants closely for changes in mood or 
psychosis and/or any emergence of suicidal ideation throughout the duration of participation. In the event 
of significant symptomatic worsening (as detailed in 5.2.3 Stopping Rules), the PI will be promptly notified, 
and plans will be formulated for additional emergency evaluation at the psychiatric emergency room 
(University of Michigan Psychiatric Emergency Services), if appropriate. Similarly, if the evaluation of a 

12 
 
participant uncovers suicidal plans or intentions, the same procedures for emergency evaluation will be 
followed.   
 
Importantly, the majority of the above side effects have also been reported in association with sham (fake) 
tDCS, with similar rates. The table below comes from a recent review of tDCS safety and shows the 
percentage of studies reporting these common sensations12. These data suggest that other factors may 
cause these sensations, such as participant expectations or the pressure of head straps or caps. 
 
Sensation 
Real tDCS 
Sham tDCS 
Itching                     
39.3%                
32.9% 
Tingling                    
22.2%                
18.3% 
Headache                 
14.8%                
16.2% 
Burning                     
8.7%                 
10.0% 
Discomfort                
10.4%                
13.4% 
  
To minimize risk: The researchers will ensure that participants are fully informed of the risks during 
the informed consent process, and will adhere to best-practice standards for tDCS procedures.  
Due to the investigational nature of the study, there may be risks, discomforts, or side effects that are not 
yet known. 
 
For women of child-bearing potential: It is unknown if tDCS can pose a risk to fetuses or if it decreases 
milk production in women who are lactating.  
To minimize risk: Participants are asked during their screening whether they are pregnant or are 
trying to become pregnant, or are currently lactating, and are not enrolled in the study if they are. Urine 
pregnancy screening can be made available to potential participants as requested. Sexually active 
women of child-bearing potential will be asked to use a reliable birth control method for the duration of 
this study. 
 
11.4 
Potential Benefits and Justification of Risks 
Several randomized controlled trials have documented either benefits of tDCS for mental health 
conditions or no effect; we are not aware of any that have reported significant symptomatic worsening. 
tDCS is considered a safe procedure which poses no more than minimal risk. The purpose of this study 
is to investigate whether combined tDCS and computerized cognitive training can improve working 
memory skills; by taking part in this study, participants may demonstrate some improvement. It is also 
possible that participants will experience no change or a worsening of symptoms, which will be clearly 
described during informed consent.  
This study will help clinical researchers develop and test effective interventions for people who 
experience serious mental health symptoms and may demonstrate neurocognitive impairment that can 
limit their everyday functioning. Ultimately, the goal of this research is to better understand the kinds of 
treatments that are feasible, meaningful, and helpful to participants with mental health conditions, in an 
effort to reduce disability and associated personal and societal costs.  
12.0 
Data Handling and Record Keeping  
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. All source documents will be completed in a neat, legible manner to ensure accurate 
interpretation of data. Dark ink is required to ensure clarity of reproduced copies. When making changes 
or corrections, the original entry will be crossed with a single line, initialed, and dated. An electronic 
database will be used to store the coded data, and the key linking to identifiable participant information 
will be kept separate from the database with research data.  

13 
 
13.0 
References 
1. 
Depp CA, Moore DJ, Sitzer D, et al. (2007). Neurocognitive impairment in middle-aged and older 
adults with bipolar disorder: comparison to schizophrenia and normal comparison participants. J 
Affect Disord, 101, 201-209.  
2. 
Schretlen DJ, Cascella NG, Meyer SM, et al. (2007). Neuropsychological functioning in bipolar 
disorder and schizophrenia. Biol Psychiatry, 62, 179-186.  
3. 
Smith MJ, Barch DM, Csernansky JG. (2009). Bridging the gap between schizophrenia and 
psychotic mood disorders: relating neurocognitive deficits to psychopathology. Schizophr Res, 107, 
69-75.  
4. 
Van Rheenen TE, Bryce S, Tan EJ, et al. (2016). Does cognitive performance map to categorical 
diagnoses of schizophrenia, schizoaffective disorder and bipolar disorder? A discriminant functions 
analysis. J Affect Disord, 192, 109-115.  
5. 
Hill SK, Harris MSH, Herbener ES, et al. (2008). Neurocognitive allied phenotypes for schizophrenia 
and bipolar disorder. Schizophr Bull, 34, 743-759.  
6. 
Kim D, Kim J, Koo T, et al. (2015). Shared and distinct neurocognitive endophenotypes of 
schizophrenia and psychotic bipolar disorder. Clin Psychopharmacol and Neurosci, 13, 94-102.  
7. 
Wykes T,Huddy V, Cellard C, et al. (2011). A meta-analysis of cognitive remediation for 
schizophrenia: methodology and effect sizes. Am J Psychiatry, 168, 472-485.  
8. 
Keshavan MS, Vinogradov S, Rumsey J, et al. (2014). Cognitive training in mental disorders: update 
and future directions. Am J Psychiatry, 171, 510-522.  
9. 
Brunoni AR, Ferrucci R, Bortolomasi M, et al. (2011). Transcranial direct current stimulation (tDCS) 
in unipolar vs. bipolar depressive disorder. Prog in Neuro-Psychoparmacol & Biol Psychiatry, 35, 96-
101. 
10. Tortella G, Casati R, Aparicio LVM, et al. (2015). Transcranial direct current stimulation in psychiatric 
disorders. World J Psychiatry, 5, 88-102.  
11. Agarwal SM, Shivakumar V, Bose A, et al. (2013). Transcranial direct current stimulation in 
schizophrenia. Clin Psychopharmacol and Neurosci, 11, 118-125. 
12. Brunoni AR, Amadera J, Berbel B, et al. (2011). A systematic review on reporting and assessment 
of 
adverse 
effects 
associated 
with 
transcranial 
direct 
current 
stimulation. 
Int 
J 
Neuropsychopharmacol, 14, 1133-1145. 
13. Nitsche MA, Paulus W. (2011). Transcranial direct current stimulation – update 2011. Restor Neurol 
Neurosci, 29, 463-492.