Increased Thalamocortical Connectivity in Tdcs-potentiated Generalization of Cognitive Training
Phase: NA
Conditions: Transcranial Direct Current Stimulation, Schizophrenia, Schizoaffective Disorder
Sponsor: University of Minnesota

PROTOCOL TITLE: 
 
Increased thalamocortical connectivity in tdcs-potentiated generalization of cognitive training 
 
PRINCIPAL INVESTIGATOR or FACULTY ADVISOR: 
Kelvin O. Lim 
Psychiatry 
612-626-6772 
kolim@umn.edu 
 
VERSION NUMBER/DATE: 
 
Version 21; December 14, 2022 
 
 

PROTOCOL TITLE: Increased thalamocortical connectivity in tdcs-potentiated generalization of cognitive 
training 
VERSION DATE: January 26, 2023 
 
 
Page 2 of 40 
 
REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
21 
01/26/2023 
● Added compensation for CT scan for MRI safety 
screening 
No 
20 
12/14/2022 
● Added optional CT scan for MRI safety screening 
● Optional consent addendum form for CT scan 
added 
Yes 
19 
4/8/2022 
● Changed randomization groups in Cohort 2 to left 
active only 
No 
18 
2/3/2022 
● Added ResearchMatch as a recruitment source 
No 
17 
11/9/2021 
● Added burns as a side effect of tDCS to consent 
form and protocol 
● Added exclusion iii:  Five or more sessions of 
neuromodulation (such as tDCS) or cognitive 
training in the past 12 months 
● Added mail ads as a source of recruitment 
● Simplified some sections of the consent form, 
removing redundant or confusing language 
Yes 
16 
10/25/2021 
● Added outpatient Psychiatry clinic registry 
database as a method of recruitment 
No 
15 
9/1/2020 
● Changed wording throughout to accommodate 
remote study visit procedures  
Yes 
14 
6/9/2020 
● Added Section 5.7: Remote and Limited Study 
Operations 
● Section 20.0: Added language for administering 
eConsent 
● Added COPRR as a recruitment source 
Yes 
 
13 
4/14/2020 
● Added Suicide Risk Assessment to schedule of 
events tables 
● Corrected definition of “cognitively impaired 
adults” in section 20.5 
● Added specifications regarding fluctuating 
capacity to consent in section 20.5 
No 
12 
2/18/2020 
● Fixed a typo in the compensation schedule 
Yes 
11 
2/3/2020 
● Changed compensation schedule, adding 
information about graded compensation and 
attendance bonus. 
● Added recruitment poster, postcard, contact card 
for participants 
● Updated study phone number and email 
● Added QR codes for recruitment tools 
Yes 
10 
12/27/2019 
● Added Guild and Fairview sites and recruitment 
procedures for Study 2 (letters of support 
attached) 
Yes 

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● Added Release of Information for Guild patients 
to protocol and consent 
● Added assessment audio/video recording to 
protocol and consent 
● Added language describing payments for 
additional visits 
● Added psychosis history questionnaire 
● Removed Department of Psychology database 
from section 16 
● Added CMRR servers to section 16 
● Removed magnetic and optical media from 
sections 6 and 16 
● Modified the estimated IQ inclusion criteria range 
and uploaded updated IQ screen form 
9 
9/30/2019 
● Added compensation to CEDT 
Yes 
8 
9/5/2019 
● Changed exclusion criteria regarding psychiatric 
diagnoses to exclude only Serious and Persistent 
Mental Illness 
● Clarified exclusion criteria regarding conditions 
with neurological sequelae to exclude concussion 
with hospital admission 
No 
7 
7/25/2019 
● Clarified that Cohort 2 participants may be 
recruited and screened using the online portal 
● Explained visit timeline windows 
● Replaced the PANSS with the BPRS and BNSS 
● Clarified that UBACC will be used in both 
cohorts 
● Explained that blinding code will be maintained 
by study statistician 
● Changed randomization procedure description 
● Clarified that some sensitive data is stored on 
secure servers (in addition to locked cabinets) 
● Added consent language about costs of 
participation per updated guidelines 
Yes 
6 
6/20/2019 
● Clarified MRI contraindications and procedure 
for determining MRI safety clearance for subjects 
No 
5 
5/23/2019 
● Removed “6-panel” specification from drug 
screen language. 
No 

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VERSION DATE: January 26, 2023 
 
 
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4 
4/24/2019 
● Added AUDIT, DUDIT and Smoking 
questionnaire 
● Added Cognitive Effort Discounting Task 
● Added TSRQ, BIS/BAS, NFC, and DPA self-
reports 
● Clarified IQ screen procedure 
● Clarified use of online advertising  
● Corrections to payment schedule and total 
● Added graded compensation plan 
● Added MCCB timepoints for cohort 1 (week 6 
and week 12) 
● Added medication review timepoint for cohort 1 
(week 24) 
● Clarified screening procedures for both cohorts 
● Modified MRI N-back and DPX details 
● Clarified that MINI does not assess for sleep 
disorders. 
Yes 
 
 
 
 
 
 
 
 
 
 
3 
3/29/2019 
● Increased age range to 18-60 years 
No 
2 
3/7/2019 
● Added language regarding DNA collection and 
analysis procedures, background rationale, as 
well as several consent form sections on DNA 
collection opt in/out and genetic confidentiality 
risks. 
● Added second tDCS device. 
● Modified task delivery platform description. 
Added notice of video and audio recording to 
consent form. 
● Changed description of resting state MRI 
stimulus 
● Removed language regarding not banking data 
for future use. Explained data banking plan. 
● Changed prescreen IQ test and criteria 
Yes 
1 
11/15/2018 
Added language regarding NDA data sharing to protocol 
and consent form 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1.0 
Objectives 
7 
2.0 
Background 
7 
3.0 
Study Endpoints/Events/Outcomes 
7 
4.0 
Study Intervention(s)/Investigational Agent(s) 
7 
5.0 
Procedures Involved 
8 
6.0 
Data and Specimen Banking 
9 
7.0 
Sharing of Results with Participants 
9 
8.0 
Study Population 
10 
9.0 
Vulnerable Populations 
10 
10.0 Local Number of Participants 
11 
11.0 Local Recruitment Methods 
11 
12.0 Withdrawal of Participants 
13 
13.0 Risks to Participants 
13 
14.0 Potential Benefits to Participants 
13 
15.0 Statistical Considerations 
13 
16.0 Confidentiality 
14 
17.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
14 
18.0 Provisions to Protect the Privacy Interests of Participants 
15 
19.0 Compensation for Research-Related Injury 
15 
20.0 Consent Process 
16 
21.0 Setting 
19 
22.0 Multi-Site Research 
19 
23.0 Resources Available 
20 
24.0 References 
21 
 

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ABBREVIATIONS/DEFINITIONS 
 
FC 
 
functional connectivity 
HC 
 
healthy controls 
MD 
 
modeled dosage 
tDCS  
transcranial direct current stimulation 
WM 
 
working memory 
SZ 
 
schizophrenia or schizoaffective disorder 
DNA  
deoxyribonucleic acid 
BDNF  
brain-derived neurotrophic factor 
 
 

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STUDY SUMMARY 
 
Study Title 
Increased thalamocortical connectivity in tdcs-
potentiated generalization of cognitive training 
Study Design 
Randomized Controlled Trial, Triple Blind 
Primary Objective 
To understand how tDCS with cognitive training 
affect thalamocortical circuitry in individuals with 
and without psychosis and to examine variability in 
response within both groups. 
Secondary Objective(s) 
To associate genotypes and epigenetic changes with 
variations in treatment response and outcome. 
Research Intervention(s)/Investigational Agents 
Transcranial direct current stimulation and magnetic 
resonance imaging 
IND/IDE # (if applicable) 
N/A 
IND/IDE Holder 
N/A 
Investigational Drug Services # (if applicable) 
N/A 
Study Population 
Healthy controls and individuals with schizophrenia 
Local Sample Size (number of participants recruited 
locally) 
180 
 
 
 

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1.0 
Objectives 
1.1 
Purpose:  
The overarching goals of this proposal are to deploy neuroimaging and cognitive testing to understand how 
tDCS with cognitive training affect thalamocortical circuitry in individuals with and without psychosis and to 
examine variability in response within both groups. 
1.2 Secondary objective:  
To associate genotypes and epigenetic changes with variations in treatment response and outcome. 
 
2.0 
Background 
2.1 
Significance of Research Question/Purpose:  
The premise of the proposed work is that tDCS concurrent with multi-session working memory (WM) focused 
cognitive training facilitates durable increases in thalamo-prefrontal cortical (hereafter thalamocortical) 
functional connectivity (FC), and that this in turn enhances generalization to novel tasks. Due to its putative 
effects on plasticity and brain circuitry, tDCS is emerging as an important tool that may eventually be part of 
the next generation of psychiatric and neurological interventions(Andre Russowsky Brunoni et al., 2012). 
However, given the simple and non-focal nature of this intervention, significant questions about the 
mechanisms of action relevant to cognition remain unanswered (Bikson, Name, & Rahman, 2013; Flavio 
Fröhlich & Schmidt, 2013). Given that a 2 mA current from tDCS induces a low electrical field that causes 
subthreshold membrane polarization and does not carry any biological information, how can it potentiate 
improved performance on complex cognitive tasks or reduce diverse symptoms (Andre R. Brunoni et al., 2014; 
Kekic, Boysen, Campbell, & Schmidt, 2016; Trumbo et al., 2016)? Most critically for the current application, 
can understanding the neuroanatomy of tDCS-induced functional changes aid in optimizing tDCS for clinical 
applications?  
2.2 
Preliminary Data:  
We have demonstrated that WM focused training increases left middle frontal gyrus (MFG) activity. This was 
first reported in a sample of n=9 experiment subjects with schizophrenia (compared to n=9 in the active control 
condition (Haut, Lim, & MacDonald, 2010)), and was recently replicated in n=15 patients (compared to n=12 in 
the active control (Ramsay, Nienow, Marggraf, & MacDonald, 2017)). We observed significantly greater 
increases in connectivity following WM training compared to the active control treatment in both right MFG 
(η2=.35) and ACC (η2=.29). These effects were driven by increased thalamocortical connectivity in the 
experimental group. Importantly, those who showed the greatest increases in thalamocortical connectivity also 
had the most general transfer on the MCCB in the experimental group (r=.55, p=.043, but not in controls.  
 
As a proof-of-concept, we have also directly examined thalamo-prefrontal functional connectivity before and 
after tDCS intervention. To determine whether tDCS can directly affect thalamocortical connectivity,  subjects 
were randomized to either  active tDCS(n=6) or  sham tDCS(n=5). Rest fMRI data was collected pre- and post-
intervention. Intervention consisted of either cognitive training + active-tDCS or cognitive training + sham-
TDCS twice a day (two 13 minute sessions per day, each 2mA / 25cm² = 0.08 current density; anode on left 
dorsolateral prefrontal cortex F3, cathode on right dorsolateral prefrontal cortex F4) for five consecutive days.  
Preliminary analyses examining FC between left thalamus and left dorsolateral prefrontal cortex showed that 
subjects assigned to active-tDCS (n=6) showed a within-group increase in FC (t=2.05, p=0.096) while subjects 
assigned to sham-tDCS (n=5) did not show a significant within-group FC change (t=1.103, p=0.332). Group x 
Time effects was eta-square η2=0.353. These pilot data suggest tDCS can improve thalamocortical 
connectivity. 
 
 

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2.3 
Existing Literature:  
Task-dependent Nature of tDCS-enhanced Neuronal Plasticity. A growing consensus suggests tDCS acts as 
a modulator of ongoing synaptic activity to facilitate task-relevant plasticity. For example, anodal tDCS 
enhanced the induction of long-term potentiation (LTP) between concurrently active neurons in slice, but had 
no effect on inactive neurons (Kronberg, Bridi, Abel, Bikson, & Parra, n.d.). In living mice, a combination of 
training with stimulation enhanced both cortical LTP and motor learning in contrast to stimulation alone 
(Fritsch et al., 2010). This underscores the need for ongoing cognitive activity to realize the potential of tDCS. 
 
TDCS-enhanced Cognitive Training. A major limitation of direct tDCS-enhancement of working memory 
(WM) appears to be that, upon meta-analysis, it leads to increased speed without increased accuracy on WM 
tasks (André Russowsky Brunoni & Vanderhasselt, 2014). Given this limitation, protocols interested in broader 
cognitive effects in healthy populations are increasingly using concurrent tDCS stimulation with training, such 
as WM training (e.g. 10 sessions, 2 mA left DLPFC,(Martin et al., 2013); 10 sessions, 1.5 mA left DLPFC, 
(Richmond, Wolk, Chein, & Olson, 2014); 7 sessions, 2 mA right and left DLPFC, (Au et al., 2016)). While 
tDCS- enhanced cognitive training, has only begun to be explored, there is evidence for greater training effects 
when training begins(Ramsay, Nienow, & MacDonald, 2016) and better generalization with right DLPFC 
stimulation (Au et al., 2016). However, as with single session tDCS-enhanced training (Trumbo et al., 2016), 
broad generalization of training with this number of sessions has shown limited results (none (Richmond et al., 
2014) or a few tasks (Au et al., 2016; Martin et al., 2013; Martin, Liu, Alonzo, Green, & Loo, 2014)).  
 
Thalamus and the Role of Thalamocortical Connectivity in Cognitive Generalization. We reject the 
hypothesis that tDCS-enhanced WM focused training works simply by enhancing local prefrontal cortical 
activity. Extensive animal research suggests that thalamocortical connectivity plays a key role in (i) modulating 
the attentional resources of the frontoparietal executive network(Zikopoulos & Barbas, 2007a), (ii) facilitating 
cognitive processes through connectivity throughout prefrontal cortex(Xiao, Zikopoulos, & Barbas, 2009), and 
that (iii) serving as a marker to investigate specific aspects of psychiatric illness(Zikopoulos & Barbas, 2007b). 
Our human studies suggest that WM focused training enhances DLPFC activity without evidence of 
generalization (Haut et al., 2010; Ramsay et al., 2016), which is consistent with local Hebbian mechanisms that 
support specialization (Marsolek, 2008). In contrast, the relationship between the thalamus and prefrontal-
parietal circuitry has long been implicated in the general cognitive ability (or intelligence) literature (Fangmeier, 
Knauff, Ruff, & Sloutsky, 2006; Haier, Siegel, Crinella, & Buchsbaum, 1993; Osherson et al., 1998). While a 
review of thalamic architecture and its reciprocal connections to prefrontal cortex is beyond our scope, it bears 
mentioning that thalamus is the central hub for communication between sensory, association and motor regions, 
with thalamic nuclei projecting to cortical and subcortical areas throughout the brain and in a diffuse manner, 
terminating in various layers of cortex (Jones, 2009). Impairments in this hub function are linked to WM 
failures (Bor et al., 2011). Below we present pilot data suggesting the extent to which thalamocortical 
connectivity is enhanced in WM training predicts the extent to which generalization is observed. Importantly, 
tDCS enhances thalamocortical connectivity: anodal stimulation over left DLPFC or motor cortex (M1) 
temporarily increased thalamocortical cortex connectivity to their respective regions (Polanía, Paulus, & 
Nitsche, 2012)(Keeser et al., 2011)(Sours, Alon, Roys, & Gullapalli, 2014).  
 
Cognitive and Thalamocortical Connectivity Impairments in Patients with Schizophrenia (SZ). Cognitive 
deficits are a prominent feature of schizophrenia and represent a large unmet treatment need with consequences 
for functioning (Barch & Sheffield, 2014; Green, 1996; Sheffield et al., 2014). Cognitive training is an 
intervention designed to improve cognition through repetitive practice with the goal of improving cognitive 
performance such as attention, memory, and problem solving (Cassetta & Goghari, 2016). While cognitive 
training is effective for improving cognitive abilities for some patients (Bosia et al., 2016), the process is time 

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and resource intensive (with as many as 48 1-hour sessions recommended) and many interventions show a lack 
of generalization (Dickinson et al., 2010). At the same time an increasingly compelling literature links 
thalamocortical FC impairments with schizophrenia, suggesting hyperconnectivity between thalamus and 
sensory regions (e.g. (Atluri, Steinbach, Lim, Kumar, & MacDonald, 2014)), and hypoconnectivity with 
prefrontal regions (e.g.(Anticevic et al., 2014)). The magnitude of hypoconnectivity even predicted conversion 
to psychosis among at-risk youth (Anticevic et al., 2015). Our findings, described below, that WM focused 
training improves thalamocortical connectivity in chronic patients with schizophrenia is therefore a hopeful 
advance in need of replication and extension (Ramsay et al., 2016). 
 
Transcranial Direct Current Stimulation (tDCS) Studies in Schizophrenia. Various studies have reported 
promising effects of tDCS on medication-refractory clinical symptoms in schizophrenia (Brunelin et al., 2012; 
Andre R. Brunoni et al., 2014; F. Fröhlich et al., 2016; Goyal, Kataria, & Andrade, 2016; Shivakumar et al., 
2013; Subramaniam et al., 2015), however the literature on tDCS’s independent effect on cognitive deficits is 
quite mixed. Anodal stimulation showed small effects on attention (Smith et al., 2015), WM (Palm et al., 2016; 
Smith et al., 2015) but see also (Hoy, Arnold, Emonson, Daskalakis, & Fitzgerald, 2014) for a negative 
finding), memory (Smith et al., 2015) and general cognitive ability (Rassovsky et al., 2015; Smith et al., 2015). 
Marginal or negative effects were observed for processing speed (Palm et al., 2016; Smith et al., 2015). 
Cathodal stimulation showed comparably small results (Rassovsky et al., 2015). Our quantitative review of 
these findings failed to reject the null hypothesis in any domain of cognition for any modality of transcranial 
stimulation. Consistent with task-dependent nature of tDCS-enhanced neuronal plasticity, tDCS had its largest 
impact on SZ patients’ cognitive impairments when repeatedly paired with concurrent WM cognitive training 
(Nienow, MacDonald, & Lim, 2016). This finding from our group is the clinical lead this study will replicate 
and examine.  
 
Variance in Modeled Dosage. Physiological and behavioral responses to tDCS show high variability between 
participants. One possible source of variability in outcome is a variability in the induced electric field strength 
from participant to participant for identical electrode montages and applied intensities (Laakso, Tanaka, 
Koyama, De Santis, & Hirata, 2015; López-Alonso, Cheeran, Río-Rodríguez, & Fernández-Del-Olmo, 2014; 
Opitz et al., 2016; Wiethoff, Hamada, & Rothwell, 2014). Computational approaches have the potential to 
account for this variability using numerical methods to estimate the electric field distribution on an individual 
level. So far it has been untested whether numerical models can predict subject-specific variability in the 
response to tDCS. Recent intracranial field measurements (Huang et al., 2017; Opitz et al., 2016) and modelling 
studies (Laakso et al., 2015) have shown that applying a fixed intensity of 1mA can lead to large variations in 
the electric field strength in the brain across individuals. This variation in effective dose is a likely cause of the 
large interindividual variations in the physiological response to tDCS across participants (López-Alonso et al., 
2014; Wiethoff et al., 2014). The possibility of computational models to account for this variability arising from 
interindividual anatomical variations (Opitz, Paulus, Will, Antunes, & Thielscher, 2015) has recently been 
recognized (Bestmann & Ward, 2017; Peterchev, 2017). Here we will directly test, whether individual realistic 
finite element method (FEM) models can account for observed variation in physiological and behavioral 
responses to tDCS. 
 
The results from the proposed study on the effect of tDCS on thalamocortical connectivity in the context of WM 
focused training will provide critical information to inform future research work and clinical intervention 
studies. 
 
Genetics and Treatment Response. Another source of treatment response variability could stem from 
differences between participants in baseline genetic profiles or epigenetic changes over the course of treatment. 

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Schizophrenia and associated spectrum disorders have a strong genetic component, with recent studies 
estimating nearly 80% heritability (Hilker et al., 2018). Genetic polymorphisms, particularly in genes relating to 
the dopaminergic and serotonergic systems, have been associated both with the development of the disorder 
(Harrison, 2015) as well as with varied response to pharmacologic treatments (Arranz & De Leon, 2007; 
McClay et al., 2011). Genetic polymorphisms, especially in genes important for neuroplasticity, may also 
mediate neuroplastic changes underlying the effects of tDCS (Chhabra et al., 2016), as has been demonstrated 
with gene BDNF (Antal et al., 2010; Fritsch et al., 2010). In light of these genetic influences on key tenants of 
our study--i.e. treatment response in schizophrenia and physiological effects of tDCS--we will collect genetic 
samples from participants to determine whether genetic or epigenetic variations may affect response to the 
cognitive training and tDCS intervention. This information may help inform the development of more 
individually-tailored treatment protocols in the future. As this is a secondary aim, participants will be given the 
choice in the consent form to opt in or out of the genetic sampling procedure. 
 
Substance use as a moderator and outcome variable of tDCS. Individuals with schizophrenia and related 
disorders tend to exhibit high levels of substance use, particularly nicotine, alcohol, and cannabis (Margolese et 
al., 2004). Use of these substances has been demonstrated to be both an outcome and moderator variable in 
tDCS interventions. Smoking, in particular has been shown to attenuate the effects of a tDCS intervention on 
auditory hallucinations in schizophrenia (Brunelin et al., 2015), but also to restore impaired tDCS-related 
cortical plasticity in chronic smoking schizophrenia patients (Strube et al., 2015). In addition, tDCS 
interventions have proven capable of reducing various substance-related behaviors and craving (e.g. Boggio et 
al., 2008; Boggio et al., 2010; Falcone et al., 2016; Fregni et al., 2008; Klauss et al., 2014; but see Smith et al., 
2015 for a negative finding). In light of the high prevalence of substance use in the schizophrenia population, 
and its potential as a significant moderator and outcome variable (albeit ancillary to our main hypotheses), we 
will track substance use throughout intervention. 
 
3.0 
Study Endpoints/Events/Outcomes 
3.1 
Primary Endpoint/Event/Outcome:  
SA1. Compare the effect of right active-tDCS, left active-tDCS and sham (hemisphere) in HC, the effect of left 
active-tDCS and sham in SZ, length of treatment and measured dosage on brain circuitry. In both HC and SZ, 
greater ipsilateral thalamocortical (prefrontal) FC increases relative to sham are driven by H1.1 active tDCS in 
the ipsilateral hemisphere; H1.2 a longer length of treatment; and H1.3 higher modeled dosage. 
SA2. Establish the effects of hemisphere, length of treatment and modeled dosage on generalization and 
durability. In both HC and SZ, greater generalization and durability are driven H2.1 more by right tDCS 
compared to left tDCS or sham; H2.2 by a longer length of treatment; and H2.3 by higher modeled dosage. 
SA3. Examine how changes in thalamocortical FC in both hemispheres affect generalization and durability. In 
both HC and SZ, greater thalamocortical FC drives H3.1 greater generalization; and H3.2 greater durability. 
SA4. Examine relationships between genetic variants, epigenetic changes and treatment outcome (e.g. 
generalization, durability, functional connectivity). 
 
4.0 
Study Intervention(s)/Investigational Agent(s) 
4.1 
Description:  
This study will include 2 cohorts of participants (healthy controls and patients with schizophrenia) in order to 
evaluate how anodal tDCS with concurrent WM focused training affect thalamocortical connectivity, how this 
may differ from right vs. left (hemisphere) vs. sham stimulation, how the number of sessions (length of 
treatment) and modeled dose impacts proximal transfer and generalization, how they are affected by other 
psychologically and biologically relevant variables, and the durability of these cognitive changes after training. 

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For the proposed project, participants in cohorts 1 and 2 will undergo a similar protocol, consisting of WM 
training concurrent with tDCS. This training will consist of a target of 30 sessions of 45 minutes each in 11-12 
weeks (target average density of 3 sessions/week), with a minimum of 24 sessions (and a minimum average 
density of 2/week). Due to limited reach to the schizophrenia population during the global pandemic, cohort 2 is 
expected to be a smaller sample size than originally anticipated. We will only be studying left hemisphere 
stimulation in cohort 2 subjects. 
 
The tDCS will be performed with Neuroelectrics Starstim8 (Neuroelectrics Barcelona, Spain).  This device has 
been approved for use in research without an investigational device exemption due to meeting criteria for non-
significant risk.  In addition, the device has built in safety mechanisms which allow for the immediate cessation 
of stimulation should the subject become uncomfortable or impedance levels too high. 
 
The Starstim software supports the measurement of electrode impedance (Neuroelectrics, 2016). Before each 
training session, the impedance of the electrodes will be checked and verified to be ≤10 KOhm. During a 
training session, the impedance is measured every second and if found to be > 20 KOhm stimulation will be 
terminated for safety. The current and impedance will be recorded for every session (Ruffini, 2016) 
(implemented in Dec 2016, NIC v2.1). 
 
We will take advantage of the ability of the Neuroelectrics StarStim8 (Neuroelectrics Barcelona, Spain) unit to 
programmatically control stimulation at multiple electrodes.  During the intervention, subjects will wear a 
headband with electrodes at AF4 and AF3 (right and left DLPFC). Three different stimulation montages will be 
programmed: right, left and sham. Stimulation will consist of three periods: RampUp (30 sec), Constant (20 
min), RampDown (30 sec). During the Ramp periods, 2 mA current will be delivered to both AF3 and AF4 with 
an ascending (RampUp) and descending ramp (RampDown) over 30 sec via two saline soaked electrode 
sponges (~ 25cm²; current density = 0.08 mA/cm²). In this way, all subjects experience the same sensation on 
both sides to blind them to condition.  During the Constant period, current will be set based on the Condition: 
Right - 2mA  AF4 anode-AF3 cathode; Left - 2mA applied to AF3 anode-AF4  cathode; Sham - current turned 
off.  We will test and adjust this new blinding approach on healthy subjects prior to beginning the formal study. 
To assess subject perceptions of the intervention, we will ask what treatment they believe they received each 
session. 
 
A second stimulation device will also be available for use in the study. The TaskFlow Transcranial Electrical 
Stimulation  device (TaskFlow-TES)  is a custom brain stimulation device developed in-house at the University 
of Minnesota. The TaskFlow-TES has been designed to provide the same functionality as the commercial 
device we are currently approved to use (Neuroelectrics StarStim8).  Like the StarStim, the TaskFlow-TES is 
battery powered, communicates with the control computer via Bluetooth and monitors impedance and delivered 
current. 
 
4.2 
IND/IDE: N/A 
4.3 
Biosafety: N/A 
4.4 
Stem Cells: N/A 
 
5.0 
Procedures Involved 
5.1 
Study Design: 
This is a triple-blind, randomized placebo-controlled clinical trial (with blinded subjects, experimenters and 
statisticians) with healthy controls (cohort 1) and schizophrenia patients (cohort 2). 90 HCs,  after signing 
consent and determining eligibility will be enrolled and randomized to receive either (i) Active 2mA right (AF4 

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anode-AF3 cathode) or (ii) Active 2 mA left (AF3 anode-AF4 cathode), or (iii) Sham 0 mA tDCS during 
concurrent WM focused training for a total of 12 weeks. 90 SZ patients, after signing consent and determining 
eligibility will be enrolled and randomized to receive either (i) Active 2 mA left (AF3 anode-AF4 cathode), or 
(ii) Sham 0 mA tDCS during concurrent WM focused training for a total of 12 weeks. For the active 
stimulation, current will ramp-up for 30 seconds, remain at 2mA for 20 min and then ramp-down for 30 seconds 
at the end of the stimulation session. For sham stimulation, the electrodes will be placed at the same positions as 
for active stimulation (AF3 and AF4), but current will be turned off immediately after the initial 30 second 
ramp-up period. Thus, participants will feel the initial itching sensation associated with tDCS but will receive 
no active current for the rest of the stimulation period. This method of sham stimulation has been shown to be 
reliable(Gandiga, Hummel, & Cohen, 2006). To test the effects of dosage, we have scheduled a midtest and 
MRI scan after 6 weeks of training (approximately 15 sessions), and a posttest and scan at the completion of the 
protocol after 12 weeks (approximately 30 sessions). The assessment battery will be completed again at follow-
up 12 weeks after the final training session. 
 
5.2 
Study Procedures:  
Pre-Screening for Cohort 1 (healthy controls): Study staff or weblinks will direct interested individuals to a 
HIPAA compliant online portal with a thorough description of the requirements of the study. At this time, 
interested individuals will answer relevant screening questions, including tDCS or MRI contraindications. 
Volunteers will also complete items from a neuropsychological vocabulary test to estimate crystalized IQ. If the 
HC volunteer fulfills inclusion and exclusion criteria, they will be invited to participate and scheduled for the 
pretest assessment.  
Pre-Screening for Cohort 2: Through a voice call or in-person meeting with study staff, or via the HIPAA-
compliant online portal process described above for Cohort 1, interested individuals will be provided with a 
thorough description of the requirements of the study. Interested SZ volunteers will be asked screening 
questions about demographics, likely diagnosis, MRI eligibility and cognitive ability. Volunteers will also 
complete items from a neuropsychological vocabulary test to estimate crystalized IQ. Research staff will then 
inquire about the participant’s transportation needs and offer assistance as needed to attend any in-person study 
appointments. If the SZ volunteer fulfills inclusion and exclusion criteria they will be invited to participate and 
scheduled for a pretest assessment. 
 
 
 
Screening/Baseline Visit for Cohorts 1 and 2: 
After the initial consent form has been signed, all participants will undergo the following assessments: 
● The MINI – to rule out current Serious and Persistent Mental Illness (SPMI) and addictive disorders 
for Cohort 1, and to confirm diagnosis and rule out addictive disorders for Cohort 2. 
 
Prior to randomization, eligible participants in both cohorts will be characterized at baseline and tracked across 
the study (see schedule of events tables) using cognitive tasks, clinical assessments, and neuroimaging. These 
include the following*: 
 
● MATRICS Consensus Cognitive Battery Subtests (including Symbol-Coding, Category Fluency, 
Trailing Making Test, Spatial Span; Letter-Number Span; Hopkins Verbal Learning Test) (Cohort 1 
and 2) 
● UCSD-Performance Based Skills Assessment – Brief (UPSA-B) (Cohort 2 only) 
● Brief Psychiatric Rating Scale (BPRS) (Cohort 2 only) 
● Brief Negative Symptom Scale (BNSS) (Cohort 2 only) 
* In the case that study assessment visits are conducted remotely, some of these measures (e.g. Spatial Span) 
will not be collected. 

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Assessment activities may be audio/video-recorded. These data will be reviewed by the study team in order to 
achieve reliability and consistency between different interviewers and to arrive at consensus ratings for 
assessment scores. Assessment audio/video data will be stored on a secured UMN Box server and will only be 
accessible by the study team. Participants will have the choice to opt out of assessment audio/video recording in 
the consent form. 
 
In addition, all participants will provide a urine or saliva sample in order to complete a drug screen. Results will 
be recorded.  
 
HC participants will be randomly assigned to one of the 3 groups: (i) Active 2mA right (AF4 anode-AFP3 
cathode) or (ii) Active 2 mA left (AF3 anode-AFP4 cathode), or (iii) Sham 0 mA tDCS during concurrent WM 
focused training for a total of 12 weeks. SZ participants will be randomly assigned to one of the 2 groups: (i) 
Active 2 mA left (AF3 anode-AFP4 cathode), or (ii) Sham 0 mA tDCS during concurrent WM focused training 
for a total of 12 weeks. Neither participants nor experimenters will know group assignment. TDCS software 
programming will allow staff selection of the three hemisphere conditions (right, left, sham) corresponding to 
eight random letters (six to be distributed evenly among three conditions for HCs, two to be distributed evenly 
among two conditions for SZs) encoded to preserve the blind. Randomization will be facilitated and the 
blinding code will be maintained by the study statistician. 
 
Neuroimaging Assessments/MRI (Baseline, Week 6, Week 12):  
Participants who are able to do in-person study visits will complete MRI sessions using the 32 channel head coil 
on a 3T Siemens Prisma scanner (Siemens Erlangen, Germany) located in the Center for Magnetic Resonance 
Research (CMRR) at the University of Minnesota at baseline, midway through the intervention and post-
intervention, at 12 weeks. MRIs will not be completed if there is any concern for participant safety. This 
includes safety concerns during the COVID-19 pandemic. 
 
If the research team suspects that a participant may have metal in their body, the participant may have the 
option to undergo a low-dose, partial- or whole-body Computed Tomography (CT) scan prior to the MRI in 
order to ensure their safety and eligibility. The CT scan will take place at the CMRR at the University of 
Minnesota. Minnesota. A CMRR Safety Officer will determine the level of risk to the subject and whether they 
are approved for MRI scanning. If approved for scanning by professionals, all risks will be conveyed to the 
participant so they can decide whether they wish to complete the procedure. Any concerns from the review 
committee will be conveyed to the participant at that time. If a participant chooses to undergo a CT scan and is 
subsequently found to be ineligible for the MRI scan, they will still be compensated accordingly for their time. 
 
 
The MRI scan (3T) takes about 75 to 80 minutes. MRI involves taking pictures of the participant's brain, from 
which the properties of certain brain tissues can be measured.  While sometimes MRI scans are done for clinical 
purposes, the scans the participant will receive are being done for research purposes.  Since these scans are not 
designed for clinical or medical reading, the participant's scans will not receive a clinical or medical 
interpretation. For the scan, the participant will be asked to lie down quietly on a bed, and the bed will slide into 
the scanner. Once the participant is inside the scanner, it will start to take the pictures. During the scan, the 
participant will simply lie quietly in the scanner with eyes closed while the scanner takes images of the 
participant's brain. The MRI scan will be performed at the University of Minnesota’s Center for Magnetic 
Resonance Research.   
 
The MRI protocol: 

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● Structural Imaging. High resolution whole brain anatomical T1 weighted (MPRAGE) and T2 weighted 
(SPACE) scans will be acquired using scan parameters matched to the HCP-lifespan protocol. Scan parameters 
are: T1: TE/TI/TR = 3.65/1100/2530 ms, flip angle = 7º, voxel size = 0.8 mm isotropic, scan time ≈ 7 min. T2: 
TE/TR = 564ms/3200 ms, variable flip angle, voxel size = 0.8 mm isotropic, scan time ≈ 6 min. The structural 
images will be processed through the Human Connectome Project (HCP) minimal preprocessing stream and are 
used in the data analysis for (a) image registration purposes and (b) structural volumetric measures for use as 
covariates in fMRI analysis. 
● fMRI scanning. fMRI data will be collected using the HCP (http://www.humanconnectome.org/) multiband 
(MB) echo-planar sequence with parameters that closely match those used by the HCP-Lifespan project: echo 
time (TE) = 37 ms; repetition time (TR) = 800 ms; MB factor=8, flip angle = 52º; 72 oblique axial 2 mm thick 
slices; field of view (FOV) = 208 mm; 2 x 2 mm in-plane resolution (104 x 104 matrix size). The first 10 
volumes will be discarded from data analysis to ensure that magnetization reached steady state. To avoid 
carryover task-related effects, rest will be collected before the other tasks (the order of which will be 
counterbalanced). 
● Rest. Participants will keep their eyes open while they look directly at a small animated square 
which periodically rotates 45 degrees approximately every 60 to 180 seconds. Participants press a button 
whenever they perceive this change. This low-demand activity is used to objectively ensure that the participant 
is awake during the resting fMRI scan. The rest scan will have 900 volumes for a total scan time of 12 minutes. 
● N-back Tasks. N-back tasks (Haut et al., 2010) will switch between 0-back and 2-back trials. A picture n-back 
will be done in scanner, and a word n-back will be performed the day of scan outside of the scanner. The word 
n-back includes one run, and the picture n-back includes two runs. Each run lasts approximately 6 minutes.  
● DPX (Henderson et al., 2012; Poppe et al., 2016)  task will be performed in several blocks. Each trial consists 
of a cue dot pattern followed by a probe dot pattern. One dot pattern was identified as a valid cue (“A” cue), and 
another as a valid probe (“X” probe). All other cues were invalid (“B” cues), and all other probes will be invalid 
(“Y” probes). Besides the valid “AX” target trials, 3 other possible combinations of cues and probes (“AY,” 
“BX,” and “BY”) made up 3 distinct non-target trial types enabling the identification of a specific deficit in a 
subject’s ability to maintain goal-relevant information throughout a trial. Timing will be jittered and each block 
of the DPX task will consist of 40 trials: 24 AX (6 0%), 6 AY (15%), 6 BX trials (15%), and 4 BY (10%). Each 
block will last approximately 6 minutes (Poppe et al., 2016). 
● Field map Imaging. A pair of reverse phase encode spin echo EPI field map scans with the same prescription 
and voxel size as with the fMRI and with a total scan time ≈ 1 min. The field map images are used to correct the 
fMRI data for geometric distortions caused by magnetic field inhomogeneities as part of the HCP fMRI 
minimal preprocessing pipeline. 
 
 
WM Training with tDCS (Weeks 1-12): 
All participants will undergo WM training concurrent with tDCS. This training will consist of a target of 30 
sessions of 45 minutes each in 12 weeks (target average density of 3 sessions/week), with a minimum of 24 
sessions (and a minimum average density of 2/week). Individuals with fewer than 24 sessions will not be 
considered “complete”. The training protocol is described below: 
 
 
TDCS Protocol 
 
Before each training session, the impedance of the electrodes will be checked and verified to be ≤10 KOhm. 
During a training session, the impedance is measured every second and if found to be > 20 KOhm stimulation 

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Page 16 of 40 
 
will be terminated for safety. The current and impedance will be recorded for every session. During the 
intervention, subjects will wear a headband  with electrodes at AF4 and AF3 (right and left DLPFC)). Three 
different stimulation montages will be programmed: right, left and sham. Stimulation will consist of three 
periods: RampUp (30 sec), Constant (20 min), RampDown (30 sec). During the Ramp periods, 2 mA current 
will be delivered to both AF3 and AF4 with an ascending (RampUp) and descending ramp (RampDown) over 
30 sec via two saline soaked electrode sponges (~ 25cm²; current density = 0.08 mA/cm²). In this way, all 
subjects experience the same sensation on both sides to blind them to condition. During the Constant period, 
current will be set based on the Condition: Right - 2mA AF4 anode-AF3 cathode; Left - 2mA applied to AF3 
anode-AF4 cathode; Sham current turned off. We will test and adjust this new blinding approach on healthy 
subjects prior to beginning the formal study. To assess subject perceptions of the intervention, we will ask what 
treatment they believe they received each session. 
 
WM Focused Cognitive Training Protocol.  
 
WM focused training occurs on a computer and consists of a variety of exercises selected to i) place demands 
on the executive and storage functions of working memory ii) adapt to challenge the participant’s current ability 
level, iii) provide ongoing feedback, and iv) present novel stimuli across verbal, visual and spatial modalities. 
Training tasks are developed in-house. Tasks for each subject are delivered from our AHC-IS server 
(cnc2.med.umn.edu).  Responses of subjects and session audio and video are saved on our AHC-IS server for 
analysis of training performance and engagement. The aim of using multiple tasks that require WM functions is 
to engage thalamocortical connectivity in a number of different ways to promote generalization. The 
intervention will be provided by the experimenter in small groups of four or fewer participants (4:1 ratio of 
participants to experimenters) working under the supervision of Drs. MacDonald and Lim, in consultation with 
Co-I Dr. Nienow, following a protocol developed by Drs. MacDonald and Nienow. In this scheme, 
experimenters will monitor each participant's’ training and customize the intervention to balance challenge and 
engagement. In addition, each week participants will perform 4-minute versions of a word and a spatial 3-back 
task that will remain the same across all weeks (but differ from the assessment versions) to allow us to track 
training improvements using a constant difficulty level. 
 
Participant effort will be rated by experimenters at each session using the Work Behavior Inventory (Bryson, 
Bell, Lysaker, & Zito, 1997). Just before the end of each training session, subjects will complete a brief 
questionnaire that also asks about their perceived engagement in the training that day, as well as their mood, 
previous night’s sleep, discomfort, and their perceived experimental condition. Finally, at the end of each 
session, the participant will select the final task from an array of fun games, which we have found promotes 
agency and improves attendance. 
 
Genetic sampling procedures (Baseline and Week 12): 
At the baseline and post-test visit, all participants will be given the option to provide a saliva sample for genetic 
analyses. A study staff member will provide the participant with written step-by-step instructions for the 
collection of a saliva sample using the Oragene DISCOVER saliva self-collection kit (DNA Genotek, Ottawa, 
ON, Canada, Catalog number OGR-500) and ask the participant to not eat, drink, smoke or chew gum for 30 
minutes before giving a saliva sample. The total amount of saliva collected is approximately 2 milliliters (about 
half a teaspoon) and will take approximately 5 minutes to complete.  
 
Nucleic Acid (DNA) Extraction: 
 

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Collected samples will be stored in the laboratory of Dr. Jeffrey R. Bishop at the University of Minnesota (516 
Delaware Street S.E. Phillips-Wangensteen Building room B150 Minneapolis, MN 55455). Saliva samples will 
be processed for DNA using the prepIT extraction kit following the manufacturer’s standard protocol (DNA 
Genotek, Ottawa, ON, Canada, catalog number PT-L2P-5). Extracted DNA will be quantified by the Quant-
iT™ PicoGreen™ dsDNA Assay Kit (Invitrogen, Waltham, MA USA, Catalog number P7589) using the 
Synergy HTX mult-imode plate reader (BioTek Instruments, Winooski, VT, USA). 
 
Genetic analyses: 
 
DNA extracted from saliva specimens will be standardized to a working concentration of 10-25ng/l prior to 
analyses. Targeted gene variants will be genotyped using TaqMan SNP Genotyping assays and the Applied 
Biosystems 7500 Real Time PCR system (Applied Biosystems, Foster City, CA, USA), Restriction Fragment 
Length Polymorphism (RFLP) performed by fragment analysis on the 3730 Genetic Analyzer (Applied 
Biosystems), or multiplexed genotyping assays performed on the MassARRAY System (Agena Bioscience) at 
the University of Minnesota Genomics Core facility (UMGC). Genome-wide scale genotyping will be 
performed using microarray or sequencing techniques in consultation with the University of Minnesota 
Genomics Core (UMGC)  For methylation detection studies, DNA extracted from saliva specimens will be 
bisulfite-converted using the EZ DNA Methylation Kit (Zymo Research, Irvine, CA, USA). Bisulfite-modified 
DNA will be PCR-amplified using primers designed to cover target gene regions for CpG site DNA methylation 
detection, and sequenced using the Illumina MiSeq system following a standardized protocol at the University 
of Minnesota Genomics Core facility (UMGC). Genome-wide methylation assessments will be performed using 
the Infinium MethylationEPIC BeadChip Kit (Illumina) (or comparable alternative) which interrogates over 
850,000 methylation sites quantitatively across the genome at single-nucleotide resolution. 
 
Motivation Questionnaires (optional): 
At the baseline, week 6, week 12, and week 24 visits, participants in both cohorts will be given the option to 
complete a set of several questionnaires which assess motivation: the Treatment Self-Regulation Questionnaire 
(TSRQ) (based on Williams, Freedman, & Deci, 1998), the Defeatist Performance Attitude scale (DPA) (based 
on Weissman & Beck, 1978), the Need for Cognition Scale (NFC) (Cacioppo & Petty, 1982), and the 
Behavioral Avoidance/Inhibition Scale (BIS/BAS) (Carver & White, 1994). Individual differences in these 
traits may moderate performance and engagement with the study intervention. Participants who complete these 
questionnaires will be compensated an additional $10 for each visit they complete them (up to $40 additional 
compensation). 
 
Cognitive Effort Discounting Task (CEDT; Baseline, Week 6, Week 12, Week 24): 
Individual differences in motivation for cognitive effort may moderate performance in the cognitive training 
intervention (i.e., inadequate effort could impede performance). In order to assess motivation for cognitive 
effort in a performance-based manner, participants will be given a numbers task, adding up the sum of two 
displayed numbers and answering via keypress if the sum starts with T, S, F, or E. Participants will choose 
between receiving $5 (as a metric of points, not money paid out; hypothetical only except for random payout 
described below) for the harder version of this task or a value ranging from below $5 and above $0 for an easier 
version of this task. Harder tasks will range from 16 trials of the numbers task down to 4 trials. Easier tasks will 
range from 16> trials to >0 trials. Participants will be informed in the task instructions that they will be paid 
based on one of their choices in the task, selected at random. This amount will range between $0-5 based on the 
task parameters. The task will last approximately 10 minutes. 

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Assessment of Substance Use (Baseline, Week 6, Week 12, Week 24): 
Alcohol, drug, and smoking behavior in both cohorts will be assessed at each timepoint using the Alcohol Use 
Disorder Identification Test (AUDIT; Saunders et al., 1993), Drug Use Disorders Identification Test (DUDIT; 
Berman et al., 2007) as well as several questions about smoking history and behaviors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of Events for Healthy Controls 
 
Pre-screen
Screening/ 
Baseline 
Visit 
Sessions 1-
15  
Weeks 1-6 
(2-3 times/ 
weekly) 
Mid-Test 
Week 6 
Sessions 
16-30 
Weeks 7-
12 
(2-3 times/ 
weekly) 
Post-test 
Week 
12 
Follow-up 
Week 24 
Online screening 
questions 
X 
 
 
 
 
 
 
IQ screen 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
MATRICS 
Consensus Cognitive 
Battery Subtests 
 
X 
 
X 
 
X 
X 
MINI1 
 
X 
 
 
 
 
 
Suicide Risk 
Assessment 
 
X 
 
X 
 
X 
X 
Drug Screen 
 
X 
 
X 
 
X 
X 
Medication Review 
 
X 
X 
X 
X 
X 
X 
Neuroimaging 
Assessment (MRI)4 
 
X 
 
X 
 
X 
 
                                                 
1 The MINI will be administered prior to randomization. 

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WM Training with 
tDCS 
 
 
X 
 
X 
 
 
Genetic specimen 
collection (saliva)2 
 
X 
 
 
 
X 
 
CEDT 
 
X 
 
X 
 
X 
X 
AUDIT, DUDIT, & 
Smoking 
questionnaire 
 
X 
 
X 
 
X 
X 
TSRQ, BIS/BAS, 
NFC, DPA33 
 
X 
 
X 
 
X 
X 
 
 
 
                                                 
2 Participants will indicate in consent form whether they choose to opt in or out of genetic sampling 
3 Optional questionnaires 
4 MRIs may not occur if in-person visits are a safety concern 

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Schedule of Events for SZ patients 
 
 
Pre-screen Screening/ 
Baseline 
Visit 
Sessions 1-
15  
Weeks 1-6 
(2-3 times/ 
weekly) 
Mid-
Test 
Week 6 
Sessions 
16-30 
Weeks 7-12 
(2-3 times/ 
weekly) 
Post-test 
Week 12
Follow-
up Week 
24 
Screening Questions 
(phone) 
X 
 
 
 
 
 
 
IQ screen 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
MATRICS Consensus 
Cognitive Battery 
Subtests 
 
X 
 
X 
 
X 
X 
UPSA-B 
 
X 
 
X 
 
X 
X 
BPRS 
 
X 
 
X 
 
X 
X 
BNSS 
 
X 
 
X 
 
X 
X 
MINI4 
 
X 
 
 
 
 
 
Suicide Risk 
Assessment 
 
X 
 
X 
 
X 
X 
Psychosis history 
questionnaire 
 
X 
 
 
 
 
 
Drug Screen 
 
X 
 
X 
 
X 
X 
Medication Review 
 
X 
X 
X 
X 
X 
X 
Neuroimaging 
Assessment (MRI)7 
 
X 
 
X 
 
X 
 
WM Training with 
tDCS 
 
 
X 
 
X 
 
 
Genetic specimen 
collection (saliva)45 
 
X 
 
 
 
X 
 
CEDT 
 
X 
 
X 
 
X 
X 
AUDIT, DUDIT, & 
Smoking 
questionnaire 
 
X 
 
X 
 
X 
X 
TSRQ, BIS/BAS, 
NFC, DPA6 
 
X 
 
X 
 
X 
X 
Visit windows: We will attempt to schedule study visits within approximately a one-week window (+/- one 
week) from the of the intended timeline. The time between a participant’s screening/baseline visit and the start 
of their WM training (i.e., Session 1) may vary more flexibly, however. This timeframe is less critical than the 
timing of other visits, as it occurs before the participant receives the study intervention. 
                                                 
4 The MINI will be administered prior to randomization. 
5 Participants will indicate in consent form whether they choose to opt in or out of genetic sampling 
6 Optional questionnaires 
7 MRIs may not occur if in-person visits are a safety concern 

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5.3 
Study Duration:  
● An individual will be enrolled in the study for approximately 24 weeks total to provide 
complete data.  
● We anticipate requiring 4 years to enroll all subjects needed for this trial 
 
5.4 
Individually Identifiable Health Information:  
 
We have submitted the University’s Privacy Office online application for data privacy and security review. We 
will print and upload the application with this protocol. 
 
5.5 
Use of radiation: N/A 
 
5.6 
Use of Center for Magnetic Resonance Research:  
Participants will complete three MRI sessions using the 32 channel head coil on a 3T Siemens Prisma scanner 
(Siemens, Erlangen, Germany) located in the Center for Magnetic Resonance Research (CMRR) at the 
University of Minnesota. This study will obtain CMRR PARS approval. Structural Imaging and fMRI scanning 
protocols included in Section 5.2.  
 
5.7 
Remote and Limited Study Operations 
In the event of research constraints that reduce our capacity for face-to-face contact with subjects, or in cases 
where MR scanners are not available, we will still carry out as much of the original project as possible. This 
will be done by completing research procedures using remote data collection and task administration. We will 
provide subjects with the necessary software and hardware to support remote research procedures.  
 
Remote study operations will proceed according to protocol, with the following differences: 
 
Study visits that would usually occur in-person will occur via a HIPAA-compliant video connection 
platform (such as Zoom) or via phone call. 
 
MRI procedures will not be necessary 
 
The MATRICS “Spatial Span” task will be dropped due to impracticality of remote administration 
 
tDCS cognitive training will be self-administered using remote contact with research staff. Training will 
proceed according to the current protocol, including regular communication with research staff. 
 
Consent, HIPAA authorization, and UBACC will be collected prior to the baseline visit (see section 20.0 
for information on eConsent). 
 
After the consent, research staff will provide a package(s) to the participant containing the following: 
o 1 Linux appliance with a custom desktop application will be provided to the subject for 
conducting assessments and training. The custom desktop application running on the Linux 
appliance does not store any data locally. Collected data is stored on an HST supported server, 
cnc2.med.umn.edu. The appliance will have the capacity to provide computerized assessment, 
tDCS training, training tasks, and an integrated HIPAA-compliant video connection platform 
o 1 tDCS stimulation device and headband 
o Sufficient saline vials for the anticipated duration of remote training 
o Sufficient saliva drug screens for the anticipated duration of the study 
o 2 DNA saliva sample kits (if applicable) 
o 1 payment card to be activated and “charged” as appropriate according to the payment schedule 
o Any materials necessary for remote paper-and-pencil assessments (e.g. MATRICS test booklets, 
pencils, etc.) 

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o Other materials as may be needed to complete the protocol, including return labels and 
packaging as needed for DNA saliva samples, laptop, and tDCS device  
 
Saliva drug screens and DNA sample kits will be done over Zoom so study staff can verify they are 
being done correctly by the participant 
 
All materials will be disinfected before and after shipping 
 
 
6.0 
Data and Specimen Banking 
6.1 
Storage and Access:  
Data collected for this study will be maintained and stored in REDCap, Box and AHC-IS password protected 
servers.  
 
Only research staff will have access to subject information. Records containing identifying information will be 
stored in a private research office in a locked file cabinet or on a secure server and will be accessible only by the 
principal investigator and study staff. The passwords for accessing this information will be available to only 
select staff that need access to the information to conduct their research duties.  
 
All biological specimens for genetic analyses collected through this protocol will be stored in the laboratory of 
Dr. Jeffrey R. Bishop at the University of Minnesota (516 Delaware Street S.E. Phillips-Wangensteen Building 
room B150 Minneapolis, MN 55455). All specimens will be labeled and stored with a study specimen number, 
not with any personal or protected health information. 
 
6.2 
Data: List all of the data elements to be collected and banked for future use.  
 
Data will be uploaded to the National Institute of Mental Health Data Archive (NDA) (see section 6.3 below). 
 
Genetic data may be banked for future studies. Participants will choose on the consent form whether or not they 
wish for their specimens to be banked for future studies. 
 
 
6.3 
Release/Sharing:  
The data collected may represent a unique resource for some investigators. We will make the de-identified data 
available to interested investigators who contact us for access to the data. As the proposed work is a clinical 
trial, the most appropriate database for our collected data appears to be clinicaltrials.gov.  The investigator, co-
investigator, and research staff will permit trial-related monitoring, audits, IRB/IEC(s) review and regulatory 
inspection(s) by providing direct access to source data/documentation. 
 
Data will also be uploaded to the National Institute of Mental Health Data Archive (NDA), a repository run by 
the National Institute of Mental Health (NIMH) that allows researchers studying mental illness to collect and 
share information with each other. All personal information about research participants such as name, address, 
and phone number will be removed from these data and replaced with a code number before uploading to NDA. 
Research participants will be informed about NDA data sharing in the consent process and notified that they 
may choose to not participate in the study if they do not wish for their data to be shared with NDA. 
 
7.0 
Sharing of Results with Participants 
 

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7.1 
Individual and group results, including results from genetic analyses, will not be directly shared with 
research participants. Participants will be informed that they can learn more about the outcome of this study 
upon completion at clinicaltrials.gov or on the investigators’ personal laboratory research. 
 
8.0 
Study Population 
8.1 
Inclusion Criteria:  
Cohort 1:  
(i) ability to provide consent and comply with study procedures; (ii) age 18 to 60 years old; (iii) estimated IQ 
range within the specified range (70 <= IQE <= 115); (iv) no Serious and Persistent Mental Illness (SPMI) or 
addictive disorder diagnosis as measured by the MINI (Mini International Neuropsychiatric Interview; (Sheehan 
et al., 1998)), or sleep disorder; (v) ability to participate in three weekly 45’ training sessions over 12 weeks and 
participate in four assessments. 
Cohort 2:  
(i) Ability to provide consent and comply with study procedures; (ii) age 18 to 60 years old; (iii) estimated IQ 
within the specified range (70 <= IQE <= 115); (iv) schizophrenia or schizoaffective disorder as assessed by the 
MINI (Mini International Neuropsychiatric Interview)(Sheehan et al., 1998); (v) not having a current addictive 
disorder as measured by MINI (Mini International Neuropsychiatric Interview), or a sleep disorder; and (vi) 
ability to participate in the intervention and assessments, as above; (vii) clinically stable and on stable 
medications for at least one month before start of study. 
 
8.2 
Exclusion Criteria:  
Exclusion Criteria for Cohort 1 and 2:  
(i) any medical condition or treatment with neurological sequelae (e.g. stroke, tumor, loss of consciousness >30 
min, concussion involving hospital admission, HIV); (ii) contraindications for tDCS or MRI scanning (tDCS 
contraindication: history of seizures; MRI contraindications: The research team will utilize the CMRR Center’s 
screening tools and adhere to the screening SOP during enrollment of all research participants in this 
protocol.  The CMRR Center’s screening tools and SOP are IRB approved under the CMRR Center Grant 
(HSC# 1406M51205) and information regarding screening procedures is publicly available on the CMRR 
website (CMRR Policies / Procedures); (iii) Five or more sessions of neuromodulation (such as tDCS) or 
cognitive training in the past 12 months 
 
8.3 
Screening:  
Individuals interested in participating will be screened using a series of questions probing for inclusion and 
exclusion criteria.   
 
Cohort 1: Study staff or weblinks will direct interested individuals to a HIPAA compliant online portal with a 
thorough description of the requirements of the study. At this time, interested individuals will answer relevant 
screening questions, including tDCS or MRI contraindications. If a volunteer appears eligible based on their 
answers to the online screening questions, study staff will call the volunteer on the phone to answer additional 
screening questions and to complete items from a neuropsychological vocabulary test. Alternatively, Cohort 1 
volunteers can complete the entire screening process over the phone if needed. If the HC volunteer fulfills 
inclusion and exclusion criteria, they will be invited to participate and scheduled for the pretest assessment. 
 
Cohort 2: Through a voice call or in-person meeting study staff will ask potential participants in Cohort 2 
screening questions about demographics, likely diagnosis, MRI eligibility and cognitive ability. Alternatively, 
potential participants may complete elements of the prescreening process through the HIPAA-compliant online 

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portal described above. Volunteers will also complete items from a neuropsychological vocabulary test. 
Research staff will then inquire about the participant’s transportation needs and offer assistance as needed to 
attend any in-person study appointments. If the SZ volunteer fulfills inclusion and exclusion criteria below, they 
will be invited to participate and scheduled for a pretest assessment. 
 
Vocabulary test and IQ ranges: The purpose of the neuropsychological vocabulary test is to screen out 
individuals in both cohorts who are likely to fall outside the desired IQ range of 70 < IQE ≤ 115. Importantly, 
scores on the vocabulary test do not represent actual IQ per se, but will be used to efficiently estimate a range 
within which a volunteer’s IQ is likely to fall.  
 Cohort 1 (HC): because the mean IQ of the university community is approximately 115, we will use an 
estimated IQ (IQE) range 70 < IQE ≤ 115 for inclusion. This screening will substantially reduce the 
number of eligible participants, and is accounted for in our recruitment strategy.  
 Cohort 2 (SZ): our goal is to study the portion of the SZ population that is most cognitively impaired 
and may therefore gain significantly from generalization of cognitive training, however we will also 
wish to rule-out cognitive disabilities.  SZ mean performance on cognitive batteries is approximately 1 
SD below the mean (85 IQ)(Dickinson, Ramsey, & Gold, 2007). We will use the estimated IQ range 70 
< IQE ≤ 115 as appropriate for inclusion. We anticipate that this screening will not substantially reduce 
the number of eligible SZ participants as this is a large proportion of the population. 
 
If potential participants in both cohorts meet the pre-screening criteria, they will be invited to participate and 
scheduled for a screening visit, where they will review and sign a consent prior to completing the screening 
assessment, which includes the MINI. The MINI will be administered in order to rule out current Serious and 
Persistent Mental Illness (SMPI) and addictive disorders for Cohort 1, and to confirm diagnosis and rule out 
current addictive disorders for Cohort 2. 
 
 
9.0 
Vulnerable Populations 
9.1 
Vulnerable Populations:  
☐ Children 
☐ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☒ Adults lacking capacity to consent and/or adults with diminished capacity to consent, including, but not 
limited to, those with acute medical conditions, psychiatric disorders, neurologic disorders, developmental 
disorders, and behavioral disorders 
☐ Approached for participation in research during a stressful situation such as emergency room setting, 
childbirth (labor), etc. 
☐ Disadvantaged in the distribution of social goods and services such as income, housing, or healthcare 
☐ Serious health condition for which there are no satisfactory standard treatments 
☐ Fear of negative consequences for not participating in the research (e.g. institutionalization, deportation, 
disclosure of stigmatizing behavior) 
☐Any other circumstance/dynamic that could increase vulnerability to coercion or exploitation that might 
influence consent to research or decision to continue in research 
☐ Undervalued or disenfranchised social group 
☐ Members of the military 
☐ Non-English speakers 
☐ Those unable to read (illiterate) 

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☐ Employees of the researcher 
☐ Students of the researcher 
☐ None of the above 
9.2 
Adults lacking capacity to consent and/or adults with diminished capacity (IQ 70-75) to consent: 
One of the hallmark features of psychotic illnesses is diminished cognitive functioning. To date, there are 
relatively few treatments available for cognitive deficit. This study is a minimal risk trial and those with 
diminished cognitive functioning will not face greater risks by participating. In fact, we are matching the 
cognition level of the healthy comparison group in Cohort 1 (IQ 70-115) to  that of the SZ group in Cohort 2. 
This is being done so that both groups will have the headroom to improve with the intervention.  All 
participants must have capacity to provide informed consent at enrollment and throughout the study. Please 
refer to section 20.5 for the procedures to determine capacity to consent. 
9.3 
Additional Safeguards:  
This research project is examining a potential treatment for impaired cognition in psychotic illnesses (Cohort 2); 
therefore it is necessary to include individuals with diminished cognitive functioning to evaluate the 
effectiveness of the proposed therapy. Both Cohort 1 and Cohort 2 will have the same range of cognition (IQ 
70-115).  All participants must have capacity to provide informed consent at enrollment and throughout the 
study. Please refer to section 20.5 for the procedures to determine capacity to consent. 
 
 
10.0 Local Number of Participants 
10.1 
Local Number of Participants to be Consented:  
We anticipate screening 300 healthy controls in order to enroll 90 participants in Cohort 1. We anticipate 
screening 130 SZ Patients in order to enroll 90 participants in Cohort 2. 
 
11.0 Local Recruitment Methods 
11.1 
Recruitment Process:  
Cohort 1: Healthy community (HC) sample:  
Advertisements and postings announcing the study will be placed in University newspapers, organizational and 
departmental newsletters, online, and in public places. Study staff or weblinks will direct volunteers to a 
HIPAA-compliant online portal (REDCap) with a thorough description of the requirements of the study, such as 
the 3-day per week training for 12 weeks, and will allow them to answer relevant screening questions, such as 
tDCS or MRI contraindications. This mechanism is maintained through the College of Liberal Arts and has 
already been used in IRB approved studies.   
 
Cohort 2 Patients with schizophrenia or schizoaffective disorder (SZ) sample:  
SZ volunteers will be recruited directly from Guild Incorporated community mental health agency and Fairview 
Riverside Adult Day Treatment Center. Both organizations have provided letters of support, which are attached 
in ETHOS. SZ volunteers will also be recruited through referrals from other researchers at the University of 
Minnesota and from community and mental health agencies, paper and online postings, and in-person and 
telephone announcements made to support and advocacy groups. Through a call or in-person meeting study 
staff will provide a thorough description of the requirements of the study for SZ volunteers. Interested SZ 
volunteers will be asked screening questions about demographics, likely diagnosis, MRI eligibility and 
cognitive ability. 
 
Patients from the Fairview Riverside Adult Day Treatment Center will primarily learn about our study through 
an IRB-approved flyer posted on a board (IRB approved) placed on a hallway wall at their treatment program. 

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They may also be told of the study by treatment program staff. If a patient is interested in participating in the 
study, they will be instructed to contact the study at a provided a study phone number or email address. 
Alternatively, we may provide a physical opt-in form (IRB approved) and instruct patients to return it with their 
name and signature to a locked box installed next to the flyer board. Only research staff have a key to access 
that locked box to ensure privacy, and will check the locked box regularly. Research staff will follow up with 
interested participants and set up a phone conversation or in-person meeting where the patient can learn more 
about the study and complete screening procedures. 
 
All outpatients seen at the UMP Psychiatry Clinic are asked to complete a Consent to Contact for Research 
form to indicate if they are interested in being contacted for research opportunities. Study staff will request the 
contact information for those who have signed the consent form and meet basic inclusion criteria for the study, 
namely clinical diagnosis of a psychotic illness. Additionally, we have kept lists of previous participants or 
interested individuals who did not pass phone screens, who have consented to being contacted again in the 
future for further research opportunities. Individuals in both of these lists will be contacted by study staff, who 
will ask to describe the study to the individual on the phone and determine interest.  
The Psychiatry Department has hired a Research Advocate who will be available to UMP clinic staff as a 
neutral party who can discuss research opportunities with patients. During a regularly scheduled clinic visit, the 
Research Advocate may briefly meet with the patient and ask them if they are interested in hearing about any 
research opportunities at the University of Minnesota. If the patient agrees, the Advocate will describe available 
studies which the patient may qualify for and if they are interested, provide contact information and recruitment 
materials to the patient. The Advocate may also ask if it would be okay to provide the patient’s contact 
information to the study team or introduce them to study staff if they are available. The Advocate may also be 
responsible for asking patients to sign the consent form mentioned above which indicates if the patient may be 
contacted for research opportunities in the future.  
 
Clinicians who see patients with psychotic illnesses within recruiting clinic locations may also discuss this 
study with their clients to see if they are interested in participating. If the client agrees, the provider may request 
that the client fill out a Consent to Contact for Research form, may ask to share their contact information with 
the study staff, or may provide them with IRB approved recruitment materials with contact information for the 
study.  
 
The outpatient Psychiatry Clinic in the Department of Psychiatry & Behavioral Health at the University of 
Minnesota provides patients with the opportunity to indicate whether they are interested in being contacted to 
learn about research studies or whether they prefer to not be contacted. This is accomplished through provision 
of a secure electronic REDCap consent form. Access to the voluntary contact information is managed by the 
Department of Psychiatry & Behavioral Health and securely stored and accessed by the Institute for Health 
Informatics Data Warehouse (BPIC) at CTSI (UL1TR002494). The department’s Research Recruitment 
Specialist partners with BPIC to request a registry database for specific, IRB approved studies. We are 
requesting permission to receive this contact information to recruit participants for study #STUDY00003506. 
We will only contact patients who have indicated an interest in hearing about research. 
 
The Department of Psychiatry and Behavioral Sciences provides information about research opportunities for 
the public on a University of Minnesota webpage. Our study will be listed for public information and interest 
and include information about the study, including contact information, inclusion/exclusion criteria, IRB 
approval number, and purpose of study. 
 

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The Research Recruitment and Outreach Specialist (RROS), employee of the Department of Psychiatry, 
describes research opportunities to patients and provides study contact information to interested individuals. 
Potential participants may also provide confidential contact information to the RROS for the study coordinators. 
We will use advertisements on digital media platforms to reach our research population via demographic 
(geographically central to study site) and key words. Clicking the link will bring them to a link them to the 
informative REDCap database.  
 
We will be using ResearchMatch as an additional source of recruitment. ResearchMatch.org is a national 
electronic, web-based recruitment tool that was created through the Clinical & Translational Science Awards 
Consortium in 2009 and is maintained at Vanderbilt University Medical Center. Potential volunteers will be 
contacted using the IRB-approved website recruitment language. Volunteers will then have the option of 
replying yes or no through a set of quick links available in the notification. If a volunteer chooses to respond in 
the affirmative, they will authorize ResearchMatch to release their contact information to me and we will be 
responsible for managing that information according to institutional guidelines. 
 
We will use Quick Response (QR) codes on all printed and digital materials which will direct potential 
participants HIPAA compliant registry in REDCap.  
 
We will utilize the Consortium of Psychosis Research Recruitment (COPRR) in the Department of Psychiatry 
& Behavioral Sciences. COPRR provides research participants with the opportunity to be added to a registry 
that contains their demographic and contact information, some assessment results, and study participation 
updates. The goal of COPRR is to reduce participant burden by centralizing recruitment and sharing assessment 
data that is collected in most studies. Data is stored in a secure REDCap database. Access to the database is 
controlled by the department’s Research Recruitment & Outreach Specialist and is only granted after sufficient 
approval is confirmed. We will only use COPRR for its intended purposes and will follow guidelines from the 
COPRR PI for use of the database. 
 
Email Communication with Potential Participants and Consented Participants: Potential participants may 
communicate with the study via email throughout the recruitment process. After signing the consent form and 
entering the study, however, if participants wish to continue communicating via email they must opt-in by 
signing a “Guidelines and Consent for Unsecured Email Correspondence for Research Participants.” This form 
notifies participants of the confidentiality risks entailed in using unsecured emails, documents their consent to 
use this form of communication, and instructs them as to how to withdraw their consent at a later time should 
they choose to do so. 
 
11.2 
Identification of Potential Participants:  
Healthy Controls: Potential participants will self-identify in response to advertisements and postings. 
SZ cohort: Potential participants will self-identify in response to advertisements and postings, as well as through 
referrals from other researchers at the University of Minnesota. Potential participants will also be identified 
directly from Guild Incorporated community mental health agency and Fairview Riverside Adult Day 
Treatment Center (letters of support are attached in ETHOS) and from community and mental health agencies. 
 
11.3 
Recruitment Materials:  
● Flyer (paper and online versions)  
● Posters, contact cards, and rackcards 
● Mail ads 
● Newspaper ads 

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● Online portal (REDCap) 
● Digital media ads 
● QR codes linked to IRB approved contact portal 
● Department of Psychiatry research opportunities website 
 
11.4 
Payment: subjects will be compensated according to the following schedule:  
Baseline evaluation = $30 
Follow-up at 6 weeks = $50  
Follow-up at 12 weeks = $75 
Follow-up at 24 weeks = $100 
Intervention - 36 sessions (3 visits/week x 12 weeks) = up to $396 if all sessions are completed ($11  
average per session)* 
Attendance bonus = up to $60** 
3 scans = $150 
4 Motivation questionnaires (optional): $40 
Cognitive Effort Discounting Task (optional): $0-5 per visit (x4 visits = maximum of $20) 
 
Total possible compensation = $921 
 
* Graded compensation for WM/tDCS sessions: Compensation for WM/tDCS sessions increases as a 
participant progress through the study. Sessions will be compensated at rates of $8, $10, $12, and $14 
per visit. Payment tiers increase $2 every 9 completed sessions (if a participant attends 9 sessions at a 
given rate payment will increase to the next tier). If a participant misses a session, the payment does not 
go up until they have completed 9 sessions at a given rate.  
 
** Attendance bonus: Additionally, if a participant completes 3 sessions in a week, they will receive a 
$5 attendance bonus for that week. Research staff will track participant attendance using a punch card 
and increase payment accordingly. 
 
Participant travel and parking expenses: additional funds have been allocated in the budget to assist 
participants with travel and parking expenses on an as-needed basis. Participants will be informed in the 
consent form that these funds are available and to ask the research staff if they are interested in utilizing 
them. 
 
Compensation for additional visits: Additional visits may be scheduled in order to recollect or finish 
collecting data (e.g. in the event that a standard study visit is disrupted by a technical issue such as equipment 
malfunction). In such cases, participants will be compensated for the additional time spent completing these 
study activities according to the following guidelines: 
 
For additional visits at involve assessment activities (activities normally completed at the Baseline or 
follow up visits at week 6, 12, or 24), participants will be compensated at a rate of $15/hr. 
 
For additional visits that involve training session activities (activities normally completed at the tDCS + 
cognitive training sessions), participants will be compensated for a full training session at the rate 
corresponding to their progress through the graded compensation plan mentioned above. A participant 
must still complete 3 successful sessions at a given rate in order to progress to the next compensation 
tier. 
 
If a participant terminates a visit early resulting in incomplete data, their compensation for that visit may 
be prorated according to the time spent during that visit. 

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 
For other cases, compensation for additional visits or activities will be commensurate to the time and 
demands required of the participant for that visit/activity. 
 
An additional $10 will be provided as compensation for CT scans to confirm clear orbits as an MRI 
safety measure. CT scans will only be offered as needed for participants who have a history of 
metalworking and cannot be cleared to safely proceed with an MRI scan unless we have documentation 
of no metal fragments in the eyes. Only these participants will complete a separate consent form 
addendum which includes information about the additional $10 compensation.  
 
 
 
12.0 Withdrawal of Participants 
12.1 
Withdrawal Circumstances:  
● Participants will be able to discontinue study participation at any time.  
● If at any time the study staff or clinical care team of the participant believes that it is 
unsafe for the participant to continue in the study, they will be removed. 
● If the participant is not compliant with study procedures, they may be removed from the 
study at the discretion of the PI.  
● If the participant is unable to tolerate the tDCS stimulation, technical adjustments will be 
made to improve tolerance. If these do not work, they will be withdrawn from the study. 
● To protect vulnerable populations, if a patient that was deemed capable of providing 
consent goes through unforeseeable situations that may affect their capacity to consent, 
their capacity will be reassessed, and if not deemed capable, they will not be withdrawn 
from the study.  
 
12.2 
Withdrawal Procedures:  
If participants are withdrawn from the study, the investigators will make a case-by-case determination as to 
whether they will collect any final assessment data after terminating the intervention. If it is unsafe for the 
participant to continue participating in the study, follow up data will not be collected. Any previously collected 
data will continue to be used in the data analysis. 
 
12.3 
Termination Procedures:  
If at any point research staff is concerned about participant’s welfare or behavior, they will notify participant 
that their participation in the study needs to terminate because of safety reasons.  The participant will be paid for 
their time until their last active participation day. Data collected until the termination date will be used and 
considered incomplete. 
 
13.0 Risks to Participants 
13.1 
Foreseeable Risks:  
TDCS is considered to be a safe brain stimulation technique that rarely results in adverse events. The FDA has 
determined that it is a non significant risk device and consequently will not provide an IDE. There is currently 
no evidence of serious side-effects. Mild side-effects that typically resolve upon discontinuing tDCS include 
light itching or tingling under the electrode at the beginning of administration, skin redness, headache, fatigue, 
and nausea. A rare side effect of tDCS is a burn on the skin underneath the electrodes (less than 1 out of 500 
sessions). The subject may choose to discontinue stimulation at any time during the session if experiencing 
excessive discomfort or side effects. Although seizures are not a known risk of tDCS intervention, anyone with 
a history or a risk for seizures will be excluded from the study. No other risks related to tDCS are anticipated. 

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To minimize risks regarding tDCS, study staff will be using standards of administration that have been shown 
as safe in numerous other studies using transcranial direct current stimulation. The length of administration of 
the current, size of electrode sponges used, and method of applying stimulation are the same as methods of 
administration that have been demonstrated as safe.  
 
The other potential risks pertain to the maintenance of confidentiality. Participants will be probed for personal 
information during the interviewing process. As noted in the consent form, participants will be told that all 
diagnostic and other sensitive raw data will be kept in a locked file or secure server and available only to 
authorized investigators involved in this study. To minimize confidentiality risks, as noted in the consent form, 
all diagnostic and other sensitive raw data will be kept in a locked file or secure server and be available only to 
authorized investigators involved in this study. Genetic and epigenetic information will be for research purposes 
only and will not be included in participants’ medical records. Genetic specimens and data will be labeled with 
the participant’s study ID number and will not contain personally identifying information. Participants may opt-
in to communication via email by signing a form, “Guidelines and Consent for Unsecured Email 
Correspondence for Research Participants”, notifying them that unsecured emails pose a risk to confidentiality. 
 
MRI risks. Individuals will complete a screening questionnaire for contraindications of MRI scanning. Any 
affirmative responses on the questionnaire will result in an interview regarding the possible contraindication. 
An attempt will be made to secure any records of the nature of the possible contraindication and this 
information will be reviewed by the PI and/or CMRR staff at the University of Minnesota. A determination will 
be made regarding the level of risk to the subject and whether they are approved for scanning. If approved for 
scanning by professionals, all risks to the subject will be conveyed to him or her so they can deliberate as to 
whether or not they want to complete the procedure. Any concerns from the review committee will be conveyed 
to the participant at that time. If the subject is not approved for scanning, the subject may not have the scan and 
will be excluded from that part of the study. 
 
There are no known risks to humans due to the static magnetic field. Subjects, operators, and guests are 
carefully screened prior to entering the magnetic environment, and frequently reminded of the potential danger 
of introducing magnetic objects to the controlled area.  Subjects are carefully screened and excluded from the 
study if they have any implanted devices.  Subjects are always accompanied when near the magnet, and 
reminded to move slowly and carefully as they enter and leave the magnet. 
 
The risk of tissue damage by energy emitted by the MRI device is controlled by compliance with FDA 
guidelines for commercial MRI devices.  Safety devices are in place so that the magnet will cease to operate 
should any parameters begin to exceed their preset safety limits. The risk of peripheral nerve stimulation by 
dB/dt is limited by safety devices. The noise levels generated by each scan are monitored to ensure adherence to 
guidelines. In addition, subjects are provided with earplugs and secondary protection (foam covering or 
headphones) to increase comfort during the scan. 
 
CT Risks. If a participant is suspected to have metal in their body and undergoes a CT scan, the CT scan 
involves exposure to ionizing radiation in the form of x-rays. Everyone receives a small amount of unavoidable 
radiation each year from space and from naturally occurring radioactive materials in the environment. The 
amount of radiation exposure received from a CT scan varies according to the size of the patient and the portion 
of the body that is scanned. The low dose CT scan performed for this study gives the body the equivalent of 
about 1 year or less of natural background radiation. The radiation discussed here does not include any exposure 
a participant might receive from their regular medical care. Generally, at such low radiation exposures, 
scientists disagree about the amount of risk and there may be no extra risk at all. 

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13.2 
Reproduction Risks:  
Since the MRI risks to fetuses are unknown, pregnant women are excluded from the study. The radiation from a 
CT scan may involve risks to an infant, embryo, fetus, or nursing infant which are not known at this time. 
Female subjects in child-bearing years are asked to confirm they are not pregnant. 
13.3 
Risks to Others: N/A 
 
14.0 Potential Benefits to Participants 
14.1 
Potential Benefits: There is no guarantee of direct benefit to subjects. 
 
15.0 Statistical Considerations 
15.1 
Data Analysis Plan: 
Analyses to test SA1, whether ipsilateral thalamocortical (prefrontal) FC changes are affected by hemisphere, 
length of treatment or modeled dosage will be conducted separately for Studies 1 and 2. We will use FSL 
Randomise (“Randomise/UserGuide - FslWiki,” n.d.) using non-parametric thresholding (5000 permutations, p-
value 0.001) to avoid inflated false positive rates (Eklund, Nichols, & Knutsson, 2016), and threshold for 
significance using threshold free cluster enhancement (TFCE). Randomise design matrix files and contrast files 
(“GLM - FslWiki,” n.d.) will model specific contrasts to compare the effect of right v. left active-tDCS or sham 
on thalamo-prefrontal FC. Main effects of hemisphere (right active-tDCS vs left active-tDCS and sham-tDCS 
H1.1), length of treatment (H1.2), and modeled dosage (H1.3) will be examined for each fMRI dataset (rest, N-
Back, and DPX). Group x Time (pre-intervention, mid-intervention, post-intervention) interactions will also be 
examined for each fMRI dataset. In addition to motion correction and motion-related artifact removal, 24-
parameter motion estimates will be included as regressors of noninterest (Power, Schlaggar, & Petersen, 2015). 
Rest. Rest will provide the most straightforward use of the regressor, which is to detect whether changes in 
thalamocortical connectivity exists. Since this test is in the absence of particular task demands any changes 
noted suggest trait-related functional connectivity changes. N-Back. Task-dependent connectivity associated 
with N-back task performance will be identified by modeling the block task design together with the thalamic 
regressor (similar to psychophysiological interaction (PPI) analysis (Friston et al., 1997)). Blocked fMRI 
analysis will allow us the best power to detect hemodynamic changes within brain networks related to working 
memory. The primary analysis for the N-Back tasks will consider the 2-back conditions alone. Subsequent 
analyses will examine the 2 > 0-back contrast to strengthen interpretation of any observed changes in task-
dependent thalamocortical connectivity. DPX. Task-dependent connectivity associated with the DPX task 
demands will be identified by analyzing cue and probe events together with the thalamic regressor. Preliminary 
analysis for the DPX task will examine B-cue related connectivity alone, as this draws the most on proactive, 
WM-dependent, control. Subsequent analyses will strengthen interpretation by examining both B-cue > A-cue 
related connectivity, as well as connectivity changes associated with response-related, or reactive, control 
(during the AY condition). These analyses can all be completed before the blind is broken, with direction of any 
effects to be resolved after breaking the blind. 
 
Analyses to test SA2, that generalization and durability are driven by right tDCS more than left tDCS or sham 
(H2.1), longer treatment length (H2.2) and higher modeled dosage (H2.3) will be conducted both between and 
within groups (for both Studies 1 and 2). The first step will establish the existence of between-group training 
effects using repeated-measures ANOVA’s on the key performance outcome variables (d’ scores for the word 
and picture N-backs, d’-context for the DPX, and the composite score for MCCB). We will also evaluate 
differences in self-rated engagement and experimenter-rated Work Behavior Inventory (Bryson et al., 1997), 
sleep patterns, age, baseline IQ, and these will be used as covariates of non-interest as appropriate.  

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To examine SA3, the relationship between thalamocortical FC change and generalization and durability, we will 
examine the nonparametric relationships between changes in thalamocortical connectivity and improvements on 
the trained task (word N-back d’), proximal transfer (picture N-back d’), and more distal generalization (DPX 
d’, MCCB composite score) and durability (H3.1 and H3.2 respectively). If analysis of covariates suggest that 
there are important sources of within-group variance in learning (e.g. age, baseline IQ, etc.), then hierarchical 
regressions will be used on Fisher’s transformed z-scores of thalamocortical connectivity. In addition, to 
determine whether thalamocortical FC changes predict stability in learning and generalization, task performance 
at 24 weeks will also be subjected to hierarchical regressions. The regression model will enter covariates on step 
1, and thalamocortical connectivity on step 2. The statistician will be blind to condition until analyses are 
completed.  
 
In all cases, these relationships will be tested separately for Cohort 1 and Cohort 2, as changes associated with 
improvement are likely to be different for groups with different mean levels of ability. Follow-up analyses will 
determine the extent to which these observed differences suggest actual differences between these populations. 
However, the current study is not designed to directly compare the populations. 
 
15.2 
Power Analysis: 
75 completers in cohort 1 and cohort 2 will provide power of .80 to detect effects as small as η2=.03 for key 
confirmatory analyses (tested at α = .05) and η2=.05 for other analyses (tested at α=.005), with nearly as strong 
power for the analysis of the 24 week follow-up. The more conservative approach of intent-to-treat analysis 
(n=90) will also be conducted for Cohort 2, for which the study will be sensitive to η2=.027 (tested at α = .05) 
and η2=.042 (tested at α = .005). These effect sizes are much smaller than the group x time effect for 
generalization as measured by the MCCB in our pilot tDCS data (η2=.08), suggesting the proposed study is 
well-powered. While power analyses for neuroimaging studies are challenging due to the interactions of 
voxelwise-thresholds, brain-wise error correction and spatial smoothness, the proposed studies will be well-
powered to detect group x time voxel differences as small as η2=0.07 (tested at α = .001), and in any case the 
samples are twice the size of our previous, successfully replicated, neuroimaging studies of brain change 
following cognitive remediation. Within-group responder analyses conducted for completers (n=25 per cell) 
will have power of .80 to detect correlations r ≥ .34, a lower magnitude that we already observed (r=.55). 
 
15.3 
Statistical Analysis:  
 
See section 16.1 
 
15.4 
Data Integrity:  
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data 
reported. To enhance scientific rigor, avoid bias and enhance reproducibility, our triple-blind randomized design 
will use a stratified permuted block randomization procedure (Matts & Lachin, 1988) to roughly equate age and 
baseline WM performance across groups with a block size of 6. Neither participants nor experimenters will 
know group assignment. TDCS software programming will allow staff to randomly select one of the three 
hemisphere conditions (right, left, sham) corresponding to eight letters (six to be distributed evenly among three 
conditions for HCs, two to be distributed evenly among two conditions for SZs) encoded to preserve the blind. 
Randomization will be facilitated and the blinding code will be maintained by the study statistician. 
 
16.0 Confidentiality 
16.1 
Data Security: 

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Only research staff will have access to subject information. All records, including those containing identifying 
information, will be stored in one of the following manners: 
● in a private research office in a locked file cabinet; 
● in the University of Minnesota supported REDCap database; 
● University of Minnesota secured BOX files 
● AHC-IS maintained server 
● CMRR servers (imaging data) 
● secured laboratory (biological samples) 
Passwords will be required to access study data stored electronically or in a database.  Study data will be 
available only to select staff that need access to the information to conduct their research duties and to computer 
system administrators via password.  
 
To minimize the volume of documents containing identifying information, all study documents or data will 
contain a unique participant ID that will be used when possible.  
No copy of the consent form or other research study information will be placed in the participant’s medical, 
employment, or educational records.  
 
17.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
17.1 
Data Integrity Monitoring.  
The PI will be responsible for data accuracy and quality assurance (e.g., data collection, entry, transmission, and 
analysis), and study management (e.g., enrollment, integrity of study procedures). 
The  study will be monitored by CTSI in accordance with its institutionally approved monitoring plan. 
 
17.2 
Data Safety Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study. This safety monitoring will 
include careful assessment and appropriate reporting of adverse events.  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events. 
 
18.0 Provisions to Protect the Privacy Interests of Participants 
18.1 
Protecting Privacy: 
 The study consent form will describe in detail any intrusive, uncomfortable, or unfamiliar questions, 
procedures, or interactions with researchers or study personnel that the participant will be asked to complete. 
Furthermore, the study consent form will communicate that it is the participant’s right to opt-out of any study 
procedures or the study as a whole or withdraw from the study at any time and this information will be 
reiterated and revisited periodically throughout the study in advance of intrusive, uncomfortable, or unfamiliar 
questions procedures or interactions. Participants will not be compelled or pressured to provide information or 
specimens or study data that they do not wish to provide. 
18.2 
Access to Participants:  
The research team will not access any medical records from participants. 
 
 
19.0 Compensation for Research-Related Injury 
19.1 
Compensation for Research-Related Injury:  
In the event that this research activity results in an injury, treatment will be available, including first aid, 
emergency treatment and follow-up care as needed.  Care for such injuries will be billed in the ordinary manner, 
to the participant or his/her insurance company. 

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19.2 
Contract Language: N/A 
 
20.0 Consent Process 
20.1 
Consent Process (when consent will be obtained):  
Prior to the baseline visit, all subjects participating in this study will be required to provide informed consent 
and HIPAA authorization using an eConsent (electronic consent) form. Only the staff obtaining consent, the 
subject, and any family members invited by the subject will be present. The research coordinator or other 
trained research staff will explain the study to the participants. After explaining the study, the participants will 
be allowed as much time as needed to review the consent document and ask any questions that might arise 
before making the decision to participate. If necessary, participants can delay participation and return to sign the 
consent form at a later time. Subjects will be allowed to review the consent form in private for as long as they 
need. Subjects will be encouraged to ask any and all questions prior to providing consent. Study personnel 
obtaining consent will emphasize first and foremost that the study is voluntary and will not influence that 
subject’s clinical care or their relationship to the University of Minnesota. No participant will be under legal 
commitment at the time of their consent or during their participation in the study, and surrogate consent will not 
be allowed.  
The IRB-approved eConsent form will be administered as a REDCap survey. We will follow SOPs from the 
Psychiatry department on carrying out remote eConsent. 
 
Participants will be offered a physical and/or electronic copy of the consent form and HIPAA authorization to 
read through during the consent discussion. If the participant agrees to participate, they will sign the consent 
form and HIPAA authorization.  
 
Participants recruited from Guild Incorporated will be asked to sign an optional Release of Information form 
provided by Guild Incorporated (attached in ETHOS) as well as to initial an additional, optional section of the 
informed consent form (provided in ETHOS) that grant permission for the study team to confirm eligibility 
criteria with the participant’s case manager at Guild Incorporated.  
 
Consent to continue in the study will be addressed before each scheduled visit. The participant will be reminded 
that their participation in this study is completely voluntary and they do not have to continue unless they want to 
do so. In addition, if at any point during the study the staff has reason to suspect that the individual’s capacity to 
provide consent has diminished (e.g., the participant has increased psychotic symptoms), the study staff may 
choose to re-administer the UBACC to confirm that the participant has capacity to provide ongoing consent. If 
the participant does not show capacity to consent, the PI will review their case and determine whether it would 
be best to withdraw them from the study completely or pause their participation until capacity to consent 
returns. 
 
20.2 
Waiver or Alteration of Consent Process (when consent will not be obtained): N/A 
 
20.3 
Non-English Speaking Participants: We will not enroll participants who do not speak English 
 
20.4 
Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years of age): We 
will not enroll participants under 18 years of age. 
 
20.5 
Cognitively Impaired Adults (IQ 70-75), or adults with fluctuating or diminished capacity to 
consent:   

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● Cohort 1 subjects are healthy community volunteers.  
● Cohort 2 will be subjects who have a psychosis disorder but are clinically stable.  
● We will use the UBACC to assess capacity to consent for both cohorts. 
● The UBACC will be re-administered at any point if we have reason to believe that there 
has been a change in capacity to consent due to any of the following: 
 Confusion or disorientation (i.e. not knowing the current time or date) 
 Inability to complete training and tasks that had been done previously 
Inability to understand or follow directions 
20.6 
Adults Unable to Consent: We will not enroll adults unable to consent. 
 
 
21.0 Setting 
21.1 
Research Sites:  
● Research visits will take place in the Department of Psychology, CTSI Delaware Clinical 
Research Unit, 717 Delaware Ave. building, Psychiatry Dept Ambulatory Research Center, 
the Center for Magnetic Resonance Research (CMRR) and Guild Incorporated in St. Paul. 
● Biological samples for genetic analyses will be stored and processed at the laboratory of 
Dr. Jeffrey R. Bishop at the University of Minnesota (516 Delaware Street S.E. Phillips-
Wangensteen Building room B150 Minneapolis, MN 55455). 
  
21.2 
International Research: N/A 
 
22.0 Multi-Site Research 
N/A 
 
23.0 Resources Available 
23.1 
Resources Available:  
● We propose to enroll 180 participants (90 HC and 90 SZ). We have conducted longitudinal 
studies with similar recruitment numbers without issue. We will use recruitment 
approaches available through our University Clinics, Clinical Translational Science 
Institute, community partners, advertisements (online and print), flyers and university 
community resources. We will monitor our recruitment progress and expand outreach if the 
recruitment goals are not meeting project targets. 
● Our study staff are all equipped with desktop computers to conduct data entry and other 
study related tasks. All desktop computers are connected to dedicated secure Ethernet 
cords connected to the UMN secure networks and require passwords to log on. No 
identifying information will be stored on desktop computers. Additionally, we have two 
laptops for tDCS administration which will also be connected to the UMN secure 
networks. We have the necessary facilities to print subject binders. We have a StarStim 
tDCS system.  
 
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