The Effects of Transcranial Direct Current Stimulation on the Neuronal Mechanisms of Cognitive Control in Schizophrenia
Phase: NA
Conditions: Schizophrenia
Sponsor: University of California, Davis

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
1) 
Protocol Title 
Title: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
Protocol Version Date: 9/23/2019 
 
2) 
Objectives 
The purpose of this study is to better understand the neural correlates of cognitive 
control (CC) deficits in schizophrenia and determine how these mechanisms can 
be modulated by transcranial direct current stimulation (tDCS). CC is a critical 
neurocognitive process that is required for flexible, directed thought and action 
based on goals and intentions. Identifying and developing paradigms to improve 
CC is therefore a mental health priority. Current theories of CC postulate that 
recruitment of the dorsolateral prefrontal cortex (DLPFC) is essential for this 
process by maintaining high-level information that it can then use to orchestrate 
patterns of activation in other brain networks to support optimal performance. tDCS 
is a safe, noninvasive method of modulating regional brain excitability via brief (15-
20 m) application of a weak (1-2 mA) current. The goal of the proposed 
experiments is to combine tDCS with functional magnetic resonance imaging 
(fMRI) or electroencephalography (EEG) to test the hypotheses that 1) acute tDCS 
over the DLPFC can improve performance during a CC task (the dot pattern 
expectancy (DPX) variant of the AX-CPT) in schizophrenia, and 2) acute tDCS 
over the DLPFC can increase recruitment of the DLPFC during the DPX. Sham 
stimulation over the DLPFC and acute stimulation over the somatomotor cortex 
(SMC) will also be performed as control conditions.  Effects of tDCS on brain 
functional connectivity (during CC as well as during the resting state) will also be 
examined, as well as effects on an episodic memory task. EEG recordings will be 
incorporated into this study in order to better understand the physiological 
mechanisms associated with cognitive function, as well as with non-invasive 
stimulation The current study will be the first to use fMRI to examine the effects of 
tDCS on the neuronal mechanisms of CC in schizophrenia, and has potentially 
important implications for therapeutic development for this treatment refractory yet 
disabling aspect of the illness. 
 
This study is solely intended as basic research in order to understand brain 
function in healthy individuals and brain function in patients with schizophrenia. 
This study is not intended to diagnose, cure, or treat schizophrenia or any other 
disease.  
 
3) 
Background 
Cognitive deficits in schizophrenia are not only the single greatest determinant of 
functional disability in the illness (Green, 1996) but also the least well-treated 
symptom. To that end, increased understanding of the neurobiology of cognitive 
symptoms of schizophrenia as well as developing new treatments for these 
symptoms remains a priority for neuropsychiatric research. Of these symptoms, 
CC is one of the most readily measured, consistently observed, and translational 
deficits in the illness. Indeed, for these and other reasons the 2007 CNTRICS 
meeting recommended CC be emphasized for treatment development (Carter et 
al., 2012). Unfortunately, as yet no FDA-approved treatment exists to improve CC 
in schizophrenia.  
 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
CC is a critical neurocognitive process that is required for flexible, directed thought 
and action based on goals and intentions, allowing us to direct behavior from the 
“top down” rather than automatically and reflexively from the surrounding 
environment. CC helps us override prepotent responses, select amongst 
competing stimuli, control our emotions, perform multiple tasks at the same time, 
and accomplish long-term goals in the face of adversity. Longitudinal studies 
demonstrate that "grit" and "conscientiousness," personality traits closely related 
to CC, are significant predictors of career success and future income (Duckworth 
et al., 2007; Sutin et al., 2009). Indeed, CC influences a myriad of cognitive 
functions such as attention, sensory perception, learning and memory, processing 
speed, and reasoning/problem solving. As may be expected, performance 
impairment during CC is a significant predictor of functional outcome in 
schizophrenia (Chang et al., 2014; Sheffield et al., 2014). 
 
Based on this evidence, it follows that developing treatments for CC deficits in 
schizophrenia is expected to markedly improve functional outcomes and quality of 
life in the disease, alleviating the suffering of millions. The overall hypothesis tested 
here is that transcranical direct current stimulation (tDCS) will improve 
performance and restore normal recruitment of brain networks during a CC task in 
schizophrenia patients.  
 
Neuronal Mechanisms of CC. 
The neurobiology of human CC has received 
considerable focus since the advent of fMRI. Two brain networks are believed to 
be essential for CC. One network, called the frontal-parietal network (FPN), 
consists of the dorsolateral prefrontal cortex (DLPFC) and dorsal parietal cortex. 
This network (especially the DLPFC hub) is thought to store neuronal 
representations of task goals in order to bias attention and responses in order to 
facilitate the achievement of those goals (Cocchi et al., 2013; Dosenbach et al., 
2008; Dosenbach et al., 2007). The second network, the cingulo-opercular network 
(CON), includes the anterior cingulate and insula. This network is involved in trial-
by-trial control and performance monitoring during cognitive tasks. Through its 
connectivity to other networks including the FPN, the CON may then use this 
information in order to help maintain goal-representations, adjust strategies, and 
maximize task performance (Cocchi et al., 2013; Dosenbach et al., 2008; 
Dosenbach et al., 2007). 
 
Disrupted CC Mechanisms in Schizophrenia. 
In his early descriptions of 
schizophrenia (or "Dementia Praecox") Kraepelin referred to the mind of a 
schizophrenia patient as like "an orchestra without a conductor" (Kraepelin, 1919), 
strongly suggestive of a loss of CC. Subsequent behavioral studies of executive 
function reinforced his suppositions (Cameron, 1939; Rappaport et al., 1945/1946; 
Vigotsky, 1934), but it has only been since the advent of fMRI that researchers 
have been able to noninvasively understand the neuronal mechanisms that 
underlie loss of CC in schizophrenia. 
 
Consequently, abnormal neuronal response during CC has become one of the 
most widely replicated neuroimaging findings in schizophrenia. The most 
consistent result in patients is reduced response (relative to healthy controls) 
during CC in the DLPFC (Lesh et al., 2011; Lesh et al., 2013; Perlstein et al., 2003; 
Poppe et al., 2016; Ragland et al., 2015; Snitz et al., 2005; Yoon et al., 2008a; 
Yoon et al., 2008b) (Figure 1 ). Hypoactivation of the parietal cortex and anterior 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
cingulate (ACC) has also been observed (Poppe et al., 2016; Snitz et al., 2005). 
Consistent with these findings, a meta-analysis of 41 neuroimaging studies of 
executive function in schizophrenia reported reduced activation of the DLPFC, 
ACC, and parietal cortex, and thalamus in patients (Minzenberg et al., 2009). 
Adding to these findings, a study in first-episode patients found reduced functional 
connectivity of a frontoparietal network consisting of the DLPFC and inferior 
parietal cortex during CC (Yoon et al., 2008a).  
 
Reduced DLPFC activation has also been observed during CC in unaffected first-
degree relatives of schizophrenia patients (Becker et al., 2008) and persons at 
high risk for psychosis (Colibazzi et al., 2016). Interestingly, the relative inability to 
recruit the DLPFC during CC also may predict conversion to psychosis in at-risk 
individuals (Colibazzi et al., 2016). In regards to drug effects, our lab has observed 
improved performance and increased recruitment of the DLPFC during the AX-
CPT task in patients treated with atypical antipsychotics, although PFC function 
and CC performance were not restored to healthy levels (Lesh et al., 2015). These 
results suggest that 1) disrupted CC in schizophrenia is associated with DLPFC 
and frontoparietal circuit dysfunction, and 2) a manipulation that effectively targets 
this system may improve CC in the illness. 
 
Transcranial Direct Current Stimulation. 
Ideally, a treatment for cognitive 
symptoms of schizophrenia should be able to precisely target the underlying 
dysfunctional neuronal systems while minimizing financial cost and side effects. 
Transcranial direct current stimulation (tDCS) is a promising technique that offers 
these advantages and therefore has recently gained considerable attention for the 
treatment of schizophrenia as well as many other psychiatric and neurological 
diseases (Aparicio et al., 2016; Bikson et al., 2016; Cho and Hallett, 2016; Elsner 
et al., 2016a, b; Gschwind and Seeck, 2016; Hsu et al., 2015; Kekic et al., 2016; 
Naro et al., 2016; Palm et al., 2014; Sauvaget et al., 2015; Zaghi et al., 2009). 
 
In tDCS, saline-soaked electrodes are temporary affixed to the scalp and 
connected to a battery-powered current generator. A weak (1-2 mA) constant 
current is then briefly applied (e.g. 20 minute) to stimulate the targeted brain area 
(e.g. the DLPFC). To control for placebo effects, studies may utilize a sham 
stimulation protocol that consists of very brief constant stimulation (e.g. 1 minute). 
Subjects usually cannot discern the difference between the sham and 
experimental stimulation protocols due to habituation (Poreisz et al., 2007).  
 
 
The primary effect of tDCS is to alter neuronal excitability by increasing the 
neuronal membrane potential but not inducing action potentials (Fertonani and 
Miniussi, 2016). Notably, tDCS effects persist beyond the stimulation period, 
perhaps due to persistent enhancement of glutamate receptor signaling in a 
mechanism conceptually akin to long-term potentiation (Liebetanz et al., 2002). 
The neurocognitive effects of tDCS are enhanced if stimulation occurs concurrently 
with a task that engages the neuronal systems to be targeted (e.g. a working 
memory task during DLPFC stimulation). This is thought to be due to tDCS 
primarily affecting neurons close to the discharge threshold (i.e. "active" neurons) 
(Fertonani and Miniussi, 2016).  
 
 
tDCS is generally agreed to be safe and well-tolerated (Bikson et al., 2016). 
Indeed, a recent meta-analysis of tDCS clinical trials did not find a single severe 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
adverse event across 33,200 sessions (Bikson et al., 2016). The most common 
side effect is skin erythema that resolves soon after stimulation (Guarienti et al., 
2015). No evidence exists that suggests tDCS may cause tissue damage or 
another irreversible form of brain injury (Bikson et al., 2016). The likelihood of 
inducing seizures is also low due to the fact that tDCS current strengths are almost 
always administered at least an order of magnitude lower than that required to 
induce epileptiform activity, even during gamma oscillations (Bikson et al., 2016; 
Bikson et al., 2004).  
 
Effects of tDCS in Schizophrenia.
 The great majority of tDCS studies in 
schizophrenia have targeted the DLPFC. Most studies have observed reduced 
positive and/or negative symptoms, with no studies reporting severe adverse 
events (reviewed by Kekic et al., 2016). To date, however, few studies have 
examined the effects of tDCS on cognition in schizophrenia. A 2014 study by Hoy 
et al. observed improved working memory in patients after a single 20 minute, 2 
mA session of tDCS over the left DLPFC (Hoy et al., 2014). This effect was later 
shown to be associated with increased gamma synchrony in the region (Hoy et al., 
2015). Rassovsky et al. reported improved performance on a social cognition task 
after bilateral DLPFC stimulation (Rassovsky et al., 2015), and Reinhart and 
colleagues have observed enhanced task learning and adaptive control after 
stimulation of the medial PFC in schizophrenia (Reinhart et al., 2015a, b). The 
most comprehensive neurocognitive study to date was conducted by Smith et al., 
who reported increased overall score on the MATRICS Consensus Cognitive 
Battery after 2 mA DLPFC stimulation (Smith et al., 2015). The effect was driven 
by improvement in working memory and attention-vigilance (Smith et al., 2015). 
 
 
The fact that evidence is limited for pro-cognitive effects of tDCS in schizophrenia 
is likely because the technique has been underutilized from a cognitive 
perspective. Few tDCS (or any other noninvasive stimulation) studies in 
schizophrenia have included cognitive processes as primary outcome measures 
(Hasan et al., 2016). As a result, studies may be 1) underpowered to detect group 
differences, and/or 2) do not examine cognitive domains relevant to the brain area 
being targeted (Fertonani and Miniussi, 2016). The fact that many previous studies 
have demonstrated pro-cognitive effects of tDCS in other patient and control 
populations suggests that tDCS may also ameliorate cognitive dysfunction in 
schizophrenia (reviewed by Dedoncker et al., 2016). 
 
To sum up, we plan to explore how tDCS affects brain response during CC in 
schizophrenia.  We will conduct a series of experiments using active or sham tDCS 
and measure the effects on brain response (measured by fMRI) on CC in both 
patients with schizophrenia and healthy control subjects. This project will help us 
understand basic questions about the role of brain response in CC and if tDCS 
may be purposed to improve CC in schizophrenia. 
4) 
Inclusion and Exclusion Criteria 
Healthy subjects and patients with schizophrenia between the ages of 18-35 will 
be recruited for this study. Participants will be carefully screened and will be 
excluded if they do not adhere to our criteria.  
• 
Participants must be able to sufficiently speak and understand English so as 
to be able to understand and complete cognitive tasks.  
• 
All subjects must have the ability to give valid informed consent.   

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
• 
No children under the age of 18 will be recruited.   
No pregnant women will be recruited. Although there is no known significant risk 
associated with study procedures for pregnant participants, they will be excluded 
as an extra precautionary measure.  
No prisoners will be included. 
 
EEG 
• 
Hairstyles that hinder the placement of electrodes 
MRI and tDCS 
Exclusion criteria include:  
• 
Pacemakers 
• 
Implanted electrical (brain and spinal) stimulators 
• 
Implanted defribrillator 
• 
Metallic implants 
• 
Skin damage or skin conditions such as eczema at the sites where electrodes 
will be placed 
• 
Subjects with dreadlocks or other hairstyles hindering the placement of tDCS 
electrodes will also be excluded. 
• 
Cranial pathologies 
• 
Head trauma 
• 
Epilepsy 
• 
Mental retardation 
• 
Encephalitis or history of encephalitis 
• 
Any known history of neurological disorders (including epilepsy, ALS, MS, 
stroke, cerebral palsy, any DSM-5 axis I psychiatric disorder (for healthy control 
subjects), autism) 
• 
Uncorrected vision problems that would hinder cognitive testing (this also 
pertains to subjects with color blindness in tasks where discriminating colored 
objects/items is necessary for successful performance).   
• 
Pregnant women: There is no known risk of MR brain scanning of a pregnant 
woman to the developing fetus for scanning at 4T or less, and no known 
mechanism of potential risk under normal operating procedures. Nonetheless, 
the possibility that risks may be discovered in the future cannot be completely 
ruled out. Therefore, as a general precaution, pregnant women will be 
excluded. If subjects are unsure if they are pregnant and still wish to participate, 
a pregnancy test will be provided. In keeping with human subjects protocols 
currently used by other MRI research groups at UC Davis, each female 
participant will be asked if there is a possibility that she could be pregnant. 
These measures also apply to brain stimulation research. There is no known 
significant risk associated with noninvasive stimulation procedures in 
pregnancy. Excluding pregnant women is simply as an extra precautionary 
measure.  
 
Other than nicotine, no subjects reporting substance dependence in the past six 
months and no substance abuse in the past month will be recruited.   
 
The tDCS and MRI pre-screening forms are included in the IRB application.   
 
For studies of patients with schizophrenia:  
Our inclusion criteria will be:  

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
• 
Diagnosis of schizophrenia, schizophreniform or schizoaffective disorder;  
• 
No medication changes in the prior month;  
• 
No medication changes anticipated in the upcoming month;  
• 
Stable outpatient or partial hospital status;  
• 
Normal IQ (>70; IQ will be measured by administering the Wechsler 
Abbreviated Scale of Intelligence (WASI) test).  
• 
Must not be currently taking the antipsychotic clozapine 
 
In addition, all exclusion criteria listed above for healthy controls also apply to 
recruitment of patients (except for being diagnosed with schizophrenia, 
schizophreniform or schizoaffective disorder;). 
 
5) 
Study Timelines 
This study will enroll approximately 250 patients with schizophrenia and 50 
demographically (age/gender) matched control subjects. Depending on the 
success of our methods, the overall study is projected to last up to 5 years. An 
individual subject’s participation will generally consist of six visits (a 
screening/questionnaire/interview visit, three stimulation visits with fMRI or EEG 
and two non-stimulation visits with fMRI or EEG).  
 
In addition to a clinical/screening visit, this study will incorporate a crossover 
design consisting of 5-10 sessions separated by at least 24-48 hours.  
For these sessions, the tDCS protocol (sham with task, DLPFC with task, sham 
without task, DLPFC without task, or SMC stimulation) may be followed by fMRI or 
EEG. Up to 4 tDCS sessions (2 sham, 2 stim) may be conducted without fMRI or 
EEG afterwards. The order of sessions (sham with task, DLPFC with task, sham 
without task, DLPFC without task,or SMC stimulation) will be randomized and 
counterbalanced for each group (patients and controls). 
 
The estimated study completion date is March 1, 2022, with all subjects expected 
to be enrolled by March 1, 2021, and all primary analyses complete by March 1, 
2022. 
 
6) 
Study Endpoints 
Participation for each subject is considered complete following participation in all 
of the tDCS conditions and sessions (sham with task, DLPFC with task, sham 
without task, DLPFC without task, and SMC stimulation) for an experiment. 
Although we do not anticipate any safety concerns, studies may be terminated 
prior to completion in the case of any skin irritations, lesions or other adverse 
reactions to stimulation. Subjects may also choose to withdraw at any point during 
the study. 
 
7) 
Procedures Involved 
Recruitment Methods. Healthy young adult participants will be recruited by ads 
and word of mouth from the UC Davis community; ads will be placed in the 
Department of Psychology, Center for Neuroscience, or UCDMC as well as around 
the community (grocery stores, churches, community centers, coffee shops, etc). 
These flyers are included in the IRB application.  Ads will also be placed on our 
lab web page. Additional subjects will be recruited through the Sona system paid 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
participation website. Studies of volunteers who are directly supervised by the 
investigator(s) or who are the investigator's students will be avoided. Students who 
choose to participate will be freely chosen. 
 
Patients with schizophrenia will be recruited from two primary sources: 1) UCDMC 
EDAPT (Early Diagnosis and Preventative Treatment of Psychotic Illness) clinic 2) 
present and former participants in studies conducted in the Translational Cognitive 
and Affective Neuroscience Laboratory directed by Dr. Cameron Carter. The two 
protocols we will recruit from are the “Understanding Early Psychosis” (Protocol # 
226043-1) and “Cognitive Neuroscience Task Reliability & Clinical Application 
Consortium” (Protocol # 219516-2). Only subjects who have consented to be 
contacted 
for 
future 
studies 
will 
be 
recruited 
from 
these 
two 
protocols.  Participation of potential schizophrenic subjects from EDAPT will be 
attained through direct communication to patients by personnel at the EDAPT 
clinic. The EDAPT clinic is staffed by Faculty and staff within the Department of 
Psychiatry at UC Davis. Upon entry to the EDAPT clinic, patients are told that 
EDAPT is a research clinic and that they are welcome to take part in research 
activities if they are interested, but that participation is voluntary and that whether 
or not they participate in this or any other study will not affect their care at UCDMC. 
Recruitment will take place at potential subjects’ initial entry into the EDAPT clinic 
as well as during later clinical visits. Subjects will be given a recruitment letter 
explaining the study to take home and review. We have included a screening form 
to be used by study personnel to screen potential participants to see if they qualify. 
We have also created a patient flyer that can be posted in EDAPT clinic so that the 
potential subjects may contact us if they are interested. Subjects from other studies 
who have consented to be contacted about other studies will be called to see if 
they are interested in participating and screened. The phone script, recruitment 
letter, and patient flyer are included in this IRB submission.  
 
 
Pre-screening forms would be used on the basis of exclusion and inclusion. When 
prospective subjects contact the lab, the experimental procedures and scheduling 
requirements will be explained, and a brief phone/e-mail screening questionnaire 
will be administered to determine eligibility. For phone screening, we will continue 
screening only after obtaining their consent. For e-mail screening, we will send 
them the pre-screening form only after receiving their e-mail confirmation. They 
can skip any questions they don’t want to answer and they can stop at any time. 
These documents are included in our IRB application. 
 
The items in the pre-screening forms aim to identify any contraindications to the 
participant’s participation in the study with regards to safety and comfort (see Risks 
below). It also aims to verify whether participants are neurologically healthy, 
screening out participants with any history of neurological or psychiatric (for 
healthy controls) problems, such as epilepsy, head trauma, mental retardation, and 
neurological disorders. For the MRI study, additional questions ask whether 
participants are taking any medication that can make them drowsy. The proposed 
experiments require that the participant be alert throughout the duration of the 
study. This question is intended to screen out participants who may fall asleep in 
the scanner. Finally, the questionnaire will also be used to determine whether 
participants can participate in experiments involving vision (i.e., do they have 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
normal visual acuity and color vision?). The pre- screening and consent forms are 
included in the IRB application. 
 
The pre-screening forms will be kept strictly confidential and will remain on 
password- protected computers or password encrypted lab web space. Health 
information in the pre- screening form is used only for recruitment purposes. It will 
not be reused for other purposes or disclosed to another person or entity. A code 
that carries no personal identifiable information will be used to label pre-screening 
forms. Keys to identities will be kept separately from experimental records, and 
pre-screening consents will be stored separately from the pre- screening forms. 
Only individuals on the Research Personnel List will have access to the system.  
 
No identifiers, used for recruitment purposes, will be disclosed to a third party 
except as required by law or for authorized oversight of the research project.  
 
General Procedure . Overall, during testing sessions subjects will first undergo 
the tDCS protocol assigned to that session (sham with task, DLPFC with task, 
sham without task, DLPFC without task, and SMC stimulation) immediately 
followed by MRI scanning, or EEG recording. MRI scanning will consist of (in 
order): prescanning procedures (e.g. high order shim, anatomical (T1) scan), a 
CC task (the Dot-Probe Expectancy (DPX) task), an episodic memory task (The 
Relational and Item-Specific Encoding (RISE) task) and a 10 minute resting state 
scan.  
 
Prior to the start of each experiment, the participant will be properly consented and 
fill out a demographic form. This demographic form may be a paper version or a 
Google form. We will record subject number, gender, age, racial background, and 
ethnic background on the form. Completion of the form is entirely optional and 
subjects can choose not to answer any of the questions on the form. The subject 
number is a code that carries no personal identifiable information. Only 
researchers on the Research Personnel list have access to the answers stored on 
the Google Drive. All demographic forms will be stored in locked file cabinets in 
lab space. Only researchers on the Research Personnel list have access to the file 
cabinets.   
 
 
Subjects 
without 
previously 
confirmed diagnoses 
of 
schizophrenia 
or 
schizoaffective disorder will then undergo the Structured Clinical Interview for 
DSM-V (SCID), and a complete psychiatric history will be taken. 
 
Subjects will then undergo diagnostic (clinical) interviews if no current clinical 
ratings/information are available (ratings < 1 month old are considered current). 
These rating scales will include the Brief Psychiatric Rating Scale (24 item), the 
Scale of the Assessment of Positive Symptoms, the Scale for the Assessment of 
Negative Symptoms, and may also include the following (see attached packets for 
actual questionnaires): 
 
The Global Functioning Scales 
The Global Functioning Scale: Social (GFS: Social; Auther et al., 2006) and Global 
Functioning Scale: Role (GFS: Role; Niendam et al., 2006a) provide ratings of 
functioning in social and role domains, respectively, on two separate 10-point 
Likert scales, which are scored independently of symptom severity. 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Psychosocial Treatment Survey 
The psychosocial treatment questionnaires evaluates social adjustment of 
subjects. 
 
Medication Summary 
This survey provides a comprehensive assessment of medication history. 
 
Family History of Mental Illness 
This survey provides a comprehensive history of mental illness. 
 
Modified Mini-Mental Status Exam 
This survey provides a brief assessment of acute mental status. 
 
Calgary Depression Scale 
The Calgary Depression Scale is a valid and reliable interview-based 9-item scale 
for measuring risk factors for suicide in schizophrenia, and at present is the only 
scale that is valid for assessing depression in schizophrenia. Items are rated on a 
4-point scale, assessing symptoms of depression such as self-deprecation, guilt, 
hopelessness and suicidal thoughts. 
 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is an interview-based 
scale to assess suicide risk that assesses the content and intensity of suicidal 
thoughts, and suicidal and self-injurious behaviors, and also allows the investigator 
to characterize the nature and severity of past suicidal acts. This scale is rapidly 
emerging as the standard for suicide risk assessment and has been informally 
recommended by a committee of the American Federation for Suicide Prevention. 
 
Strauss-Carpenter Outcome Scale (SCOS) 
The Strauss-Carpenter Outcome Scale (SCOS, Strauss & Carpenter, 1972) 
contains 4 items assessing duration and frequency of hospitalizations, social 
contacts with individuals outside of the family, useful employment or participation 
in school, and severity of symptoms 
 
Young Mania Rating Scale (YMRS) 
The YMRS is a valid and reliable measure of symptoms related to mania. Eleven 
items are rated on a 0-to-4 scale, assessing symptoms such as elevated mood, 
increased motor activity, changes in sleep, and pressured speech. 
 
Premorbid Assessment Scale (PAS) 
The PAS is a widely used unconstructed instrument to retrospectively assess 
premorbid adjustment.  It contains a 28 item rating scale that measures social 
isolation, peer relationships, functioning outside the family and school 
performance, as well as social-sexual aspects of life starting at age 15.  As a 
supplement the PAS includes a section of 9 general items relating to educational 
and job achievement, work and school performance immediately preceding the 
onset of psychosis, the highest level of independence achieved from family, the 
highest level of social personal adjustment, and the degree of interest in life and 
energy level. 
 

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Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
Fagerstrom Nicotine Dependence and Smoking History Questionnaire 
The Fagerstrom test for nicotine dependence (Heatherton, et al., 1991) is a self-
report questionnaire that can be completed in less than five minutes.  
Participants are asked to answer questions related to frequency and history of 
nicotine use as well as assessing current symptoms of dependence. 
 
Self-Report Measures:   
The Barratt Impulsivity Scale 11th version 
The Barratt Impulsivity Scale 11th version is a questionnaire that assesses various 
forms of impulsive thinking and behavior. 30 items are rated on a 4-point scale by 
subjects, and assess non-planning, attentional and behavioral impulsivity with 
items such as "I plan tasks carefully" and "I do things quickly without thinking." This 
is one of the most widely-used scales in the study of impulsive behavior, across a 
range of clinical and non-clinical populations. 
 
Cannabis Use Problems Identification Test (CUPIT) 
The 16-item CUPIT (Bashford, 2007) was developed as a screening tool to capture 
signs of dependence, abuse and risk for dependence/abuse of cannabis in 
adolescents and young adults. Individuals answer questions about their amount of 
cannabis use and related difficulties. In addition to the CUPIT, an additional 7 
questions re: cannabis dependence (the CANNEX) will be asked that are based 
on information gathered re: cannabis use in the SCID. 
 
Drug Use Screening Inventory 
The DUSI (Tarter & Kirisci, 1997) is a self-report measure of 10 domains of 
substance use, psychological functioning, and social functioning. We are using the 
substance abuse section (labeled DUSI-SU-Self Report) of this measure only to 
assess participant’s use of various substances and alcohol. Questions examine 
amount of use over the lifetime and recently (past 6 months, past month) and its 
impact on functioning. 
 
Barkley ADHD Scales (Childhood/Current Symptoms Scale-Self Report) 
The Barkley ADHD Scales assess severity of self-reported current and childhood 
ADHD symptoms, including inattention, hyperactivity and oppositional behaviors. 
Individuals rate the severity of symptoms or impact on functioning on a 4-point 
Likert scale from “never or rarely” to “very often”. 
 
 
 
Wender Utah Scale 
 
The Wender Utah Rating Scale can be used to assess adults for Attention Deficit 
 
Hyperactivity Disorder with a subset of 25 questions associated with that 
 
diagnosis. 
 
Participant Health and Treatment History: 
Parents or caregivers will be asked to provide information on the participant’s 
developmental, medical, school, family, substance use and treatment history. If a 
parent or caregiver is not available, adult participants will be asked to complete 
this form. 
 

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Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Beck Anxiety Inventory (BAI) 
The BAI is a 21-item self-report assessing the cognitive and physical symptoms 
associated with anxiety. Participants rate how much each item bothered them in 
the past month on a 4 point scale: 0 = Not at all; 1 = Mildly but it didn’t bother me 
much; 2 = Moderately – it wasn’t pleasant; and 3 = Severely – it bothered me a lot.  
 
Rejection Sensitivity Questionnaire (RSQ): 
Participants may be asked to complete the Rejection Sensitivity Questionnaire-
Personal (RSQ-Personal) (Downey & Feldman, 1996). This measure asks 
participants to assess how anxious or angry they would feel and what they would 
expect to happen in various hypothetical social situations. 
 
Affective Reactivity Scale (ARI) – Self Report 
The ARI contains s six items related to feelings/behaviors specific for irritability and 
one question assessing impairment due to irritability (‘overall, irritability causes 
him/her (or ‘‘me’’ by self-report) problems’). Each item has a three-level response 
category: ‘not true’, ‘somewhat true’, ‘certainly true’ – scored as ‘0’, ‘1’, ‘2’, 
respectively, giving a range of possible scores of 0–12. The total score is the sum 
of the first six items. The impairment item is not counted in the total score. 
 
Positive Urgency Measure (PUM) 
The PUM is a 14-item self report scale that examines an individual’s ability to 
control their thoughts and emotions during elevated mood states. Individuals rate 
their agreement with the items on a 4 point scale (1= Agree Strongly, 2 = Agree, 3 
= Disagree, 4 = Disagree Strongly). 
 
Buss-Perry Aggression Questionnaire (BP-S) 
The BP-S is a 29 item self report survey that examines personality traits associated 
with 4 dimensions of aggression: physical aggression, verbal aggression, anger 
and hostility.  Participants rank certain statements along a 5 point continuum from 
"extremely uncharacteristic of me" to "extremely characteristic of me." The scores 
are normalized on a scale of 0 to 1, with 1 being the highest level of aggression. 
 
Reactive-Proactive Questionnaire (RPQ) 
This 22 item self report examines both reactive and proactive motivations behind 
aggressive behavior, including verbal and physical aggression. Participants rate 
the frequency that they have demonstrated certain behaviors on a scale: 0=Never; 
1= Sometimes; 2 = Often. 
 
Levenson’s Self-Report Psychopathy Scale (LSRPS) 
This 26-item self report for ages 18 and older examines personality characteristics 
associated with psychopathy. Participants rate their agreement with the items on 
a 5 point likert scale from “strongly disagree” to “strongly agree.” 
 
During the first session the subject will be given instructions for the cognitive tasks 
to be completed at later sessions, and some time to practice the tasks. These tasks 
will involve looking at a computer screen where different types of stimuli will be 
presented. These will be figures, symbols, numbers, letters, words or sentences. 
The subject will be asked to respond to these by pressing a button, reading aloud 

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Revised: September 23, 2019 
what you see on screen or generating your own verbal responses, or picking from 
among a group of answers on the screen. 
 
The participant will also fill out a standard MRI screening questionnaire he or she 
can be safely included in the study. If the researcher is using electronic consent 
forms, the subject will be asked to use the mouse or sign pad to place their 
electronic signature, and we will email an electronic copy of the signed consent. 
Then, they will be explained all of the experimental procedures by the 
experimenter. Because it is not clear whether tDCS has any reliable effects on CC 
or brain activity, we may adjust tDCS stimulation parameters during the study. 
More specifically, tDCS may vary with the type of current (direct current or sham 
stimulation), magnitude of current (up to 2 mA), time of stimulation (up to 20 
minute) and stimulation sites. The difference between sham and direct current 
stimulation is that sham stimulation only persists for the first minute of stimulation 
(after which it is removed) whereas direct current stimulation will last up to 20 
minute. Only sites designated by the Starstim cap will be used. The Starstim cap 
only has standard electrode sites from the 10-20 system. Note that, although 
different stimulation parameters may be utilized, these differences will not affect 
the safety or tolerability of the procedure.  
 
Subjects will undergo sham and direct current stimulation on separate visits 
separated by at least 24-48 hours. Subjects will be blinded to their condition on 
each visit. During the first visit, we will inform the subjects the number of visits and 
all the stimulation conditions they will be doing for the specific experiments. 
However, they will not know which visit is for which condition (the active tDCS or 
sham conditions) and we will give the same instructions for every visit. The order 
of the active versus sham conditions will be fully counterbalanced across subjects. 
Many participants can feel the onset of the stimulation (which leads to a brief 
tingling or itching sensation), but people cannot generally feel the continued 
stimulation beyond one minute. By beginning the active and sham stimulation 
conditions with a period of stimulation, we can ensure that participants will not 
know if they are receiving either type of active or sham stimulation. 
 
We will use tDCS to stimulate specifically the DLPFC or SMC, and we will 
concurrently measure the effects of the stimulation on CC by means of behavioral 
measurements of accuracy and reaction time. These may be combined with fMRI 
or EEG after some of the stimulation sessions to measure brain response during 
a CC task as well as the resting state. The fMRI and EEG measurements are 
noninvasive. The CC paradigm we will use is described below. 
 
Prior to the start of an experiment, the experimenter will explain all of the 
experimental procedures to the participants, and the participants will read and sign 
consent forms if they agree to participate. To familiarize subjects with test 
procedures, prior to tDCS stimulation subjects will complete a short practice 
session on the DPX task on a computer screen outside of the MRI scanner. 
Subjects unfamiliar with MRI scanning procedures may also participate in a mock 
scanning session (mock scanner that visually resembles the actual MRI scanner) 
prior to tDCS.  
 
For fMRI sessions, subjects will perform the DPX and RISE tasks while lying 
supine in the MRI scanner.  For EEG sessions, subjects will be seated in a 

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Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
comfortable chair in front of a computer screen. Participants will be presented with 
visual (e.g., a picture of an object) stimuli. Participants will be asked to make 
responses to the series of visual stimuli using a numbered pad or keyboard. To 
constrain learning strategies, participants may be asked to make a simple 
perceptual or semantic judgment about each stimulus. See below for further details 
regarding the DPX and RISE tasks. At the end of the session, participants will be 
debriefed and they will remain in the laboratory in a relaxed state until mood and 
mental state return to baseline.  More details about the experimental design are 
highlighted below.   
 
Following the completion of each experiment, participants will be fully debriefed on 
the goals and hypotheses of the experiment and be given the opportunity to 
provide feedback regarding their experiences and strategies that they used in the 
study. Below is a table summarizing the possible stimulation parameters that may 
be used in the proposed experiments: 
 
Stimulation 
sites  
Number of 
stimulation 
electrodes  
Stimulation 
electrodes  
Current parameters  
SPONSTIM-8 
8 cm2 sponge 
electrode 
Any electrode sites 
from the standard 
10-20 EEG system  
 
Up to 39 
The first 30 -60s: up to 
2 mA 
Active stimulation:
 
continue to receive up to 
2.0 mA stimulation 
Sham stimulation : 
reduce to 0.0-0.1 mA for 
remainder of the 
session 
Time: Up to 20 minutes 
SPONSTIM-25 
25 cm2 sponge 
electrode 
PISTIM 
Pi cm2 Ag/AgCl 
electrodes 
PISTIM 
Pi cm2 
Ag/AgCl 
electrodes 
 
MRI. For MRI scans, a brief phone/e-mail pre-screening form will be 
administered when prospective participants contact the lab (see Recruitment 
Methods). The items in the form aim to identify any contraindications to the 
subject's participation in the study with regard to their safety and comfort. This 
pre- screening form is applied only during initial subject contact to determine 
eligibility. 
During the scan, the participant will lay supine on the MRI table, with an RF coil 
placed over his/her head, and will be put into the center of the magnet.  This 
protocol does not involve any contrast agents, drugs, or other invasive procedures, 
and uses established MRI sequences. Typical scan parameters are as follows: 
(Precise pulse sequence settings may be changed to test specific hypotheses.) 
 
• 
For echo planar imaging (EPI) scans during the DPX: gradient recalled echo, 
voxel size 3.75 x 3.75 x 4.55 mm, slice gap=0 mm, TR=2 sec, TE=29 ms, 
FA=75 degrees, matrix=64x64, FOV=240x240 mm, images per slice=150-200; 
• 
For echo planar imaging (EPI) scans during the resting state: gradient recalled 
echo, voxel size 3.75 x 3.75 mm2, slice gap=0.5 mm, TR=2 sec, TE=32 ms, 
FA=70 degrees, matrix=64x64, FOV=240x240 mm, images per slice=180-300; 
• 
For high resolution anatomical scans: fast spin echo, slice thickness=3.4 mm, 
gap=0 mm, TR=3.1sec, TE=36 and 136 ms, echo train=8, matrix= 256x256, 
FOV=240x240 mm. 

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Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
 
All MRI studies will be performed on a 3T Siemens Skyra (at the MRI Facility for 
Integrative Neurosciences at the UC Davis Center for Neuroscience) or 3T 
Siemens Time Trio (at the IRC) scanner with a 32-channel phased array head coil. 
T1, T2, and proton-density weighted structural MRI scans will be obtained.  In 
additional to these structural scans, images sensitive to BOLD contrast may be 
acquired with an echoplanar imaging sequence. We will carefully monitor subject 
motion, employing scrubbing techniques (Power et al., 2014) and, when 
necessary, excluding data from participants with excessive motion. In the scanner, 
visual stimuli may be presented on a magnet-compatible monitor placed behind 
the scanner, which participants will view via a mirror. Any responses by the subject 
will be made with 2 custom-built 5-button fiber- optic response devices. We 
anticipate that the total time to prepare a participant, run structural scans, and 
complete any EPI scanning will be approximately 90-120 minutes, which includes 
initial setup time, the anatomical scans, any functional scans, and rest time 
between the scans.  Data processing is done after the session is finished.  
 
Note that the MRI pictures of subjects’ brains are for research purposes. The MRI 
data are not meant to evaluate subjects’ health, as they would be if they were part 
of a clinical (non-research) visit to the doctor or hospital. The pictures will not 
receive any routine clinical review by specifically trained physicians (radiologists) 
who interpret MRI scans. This means that all abnormalities may not necessarily be 
noticed. However, if in the routine administration of the MRI pictures, the research 
staff notices any possible abnormalities, they will notify Cameron Carter, M.D. If 
Dr. Carter deems it appropriate, he will discuss these possible problems with the 
subject, and will help to obtain a more complete review of the MRI scans by a 
trained physician who can determine if any clinical health condition is present. If 
the physician thinks that there may be a clinical problem, we will provide the subject 
with a copy of the MRI picture to take to the physician of their choosing. If they 
prefer, we can send the pictures electronically, but there is a small risk that 
someone else could view electronically sent files. 
 
EEG Recording:  
The participant’s electroencephalogram (EEG or “brain waves”) will be recorded 
using conventional methods that we have used in a number of our other protocols. 
We will use the Starstim device (Neuroelectrics), while they perform a cognitive task 
and/or remain at a resting state. Electrodes (metallic disks with wires attached) are 
used to sample the electrical signals of the brain at the scalp.  
During EEG recording, the participant sits comfortably in a chair in a sound-
attenuating, electrically shielded room (dimensions: 10’x 8’ with a ceiling height of 8’) 
while viewing visual stimuli or listening to auditory stimuli. Electrodes and caps are 
sterilized between uses and dried completely prior to next use. Application materials 
are discarded after every use and new materials are utilized for each participant. 
 
StarStim system: 
The electrodes used for EEG recording with the StarStim device will be the “EEG 
Only” or “Stimulation and EEG” electrodes listed below.  The electrodes are worn in 
an elastic cap that is commercially available from Neuroelectrics. The scalp is 

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Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
cleansed (alcohol may be used) and prepared using a non-toxic electrically 
conductive gel (except in the case of dry electrodes- see below) that is placed 
between the electrode surface and the scalp. Standard EEG recording equipment 
protects the participant from any hazard of electrical shock using isolated grounding 
procedures. In addition to electrodes in the cap, external STICKTRODES may be 
placed on the mastoid bones (for references), or above/below/to the side of the eyes 
in order to measure eye blink and movement artifacts.  
StarStim Electrodes: 
 
 
 
 
DPX Task. The DPX task has been utilized previously by our lab, including in an 
fMRI study (Lopez-Garcia et al., 2016).  
 

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Revised: September 23, 2019 
The DPX is a more challenging (less 
susceptible to ceiling effects) variant 
of the AX-Continuous Performance 
Task (CPT), in which the letter (A, B, 
X, Y) cues found in the AX-CPT are 
replaced by Braille stimuli. Subjects 
are asked to respond (button press) to 
a target probe (“A”) after it follows a 
target cue (“X”), but not otherwise 
(“AY”, “BX”, or “BY” trials) (Figure 1) . 
AX targets occur with high frequency 
(69%), setting up the tendency to 
make the target response to the X 
probe. An intact goal-maintenance 
system of CC influences performance 
on this task by decreasing BX errors 
(processing the absence of context 
associated 
with 
the 
prepotent 
response) and increasing AY errors 
(processing the presence of context 
associated 
with 
the 
prepotent 
response). The goal maintenance aspect of CC, therefore, is measured by the 
difference between AY and BX errors. Previous work from our lab has shown 
deficits in this aspect of the task in schizophrenia (Henderson et al., 2012). 
 
RISE Task. The RISE tests an individual’s recognition memory for a list of visual 
objects. Objects are presented during two learning conditions. During item-specific 
encoding, the subject will see an object and decide whether it is living or non-living. 
During relational encoding they view two objects and decide whether one can fit 
inside the other. They are then presented with a longer list of items, including the 
items that they just studied as well as new items, and are asked to judge whether 
the item is old or new, and provide a 3-point confidence judgment. The task ends 
with an associative recognition task, where the subject is presented with the 
original pairs of items that were studied during the relational encoding condition 
along with re-arranged pairs of items which combine items that were studied during 
different encoding trials, and the subject is asked to decide if the item pair is the 
same as the pair that they originally studied, of if the pair has been re-arranged. 
The RISE takes approximately 20 minutes to administer. 
 
tDCS. We will use the Starstim device (Neuroelectrics) prior to having subjects 
complete the DPX, RISE, and resting state fMRI scans. Electrodes (metallic disks 
with wires attached) are used to stimulate the brain at the scalp. During stimulation, 
the participant sits comfortably in a chair in a sound-attenuating, electrically 
shielded room (dimensions: 10’x 8’ with a ceiling height of 8’) while performing a 
working memory task (n-back, see below) to engage the DLPFC. Electrodes and 
caps are sterilized between uses and dried completely prior to next use. 
Application materials are discarded after every use and new materials are utilized 
for each participant. 
 
StarStim system.  The electrodes used with the StarStim device will be or 
“Stimulation Only” or “Stimulation and EEG” electrodes listed above. The 
Figure 1. The DPX task. Subjects button
press in response to the target cue followed 
by the target probe (AX trial) but not the
other 
cue/probe 
combinations. 
CC 
is
measured by the difference between AY and
BX percent correct. 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
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Revised: September 23, 2019 
electrodes are worn in an elastic cap that is commercially available from 
Neuroelectrics. The scalp is cleansed (alcohol may be used) and prepared using 
a non-toxic electrically conductive gel (except in the case of dry electrodes- see 
below) that is placed between the electrode surface and the scalp. Standard 
StarStim equipment protects the participant from any hazard of electrical shock 
using isolated grounding procedures.  
 
 
 
tDCS/Sham Stimulation Session 
Procedure  
 
Mood and Mental State Assessment (5 minutes
). A 1-page questionnaire (see 
attached) will be administered. This brief mood and mental state questionnaire 
will serve as a baseline for the subject’s mood and mental state. 
 
tDCS preparation  (~10 minutes ). Prior to electrode placement, the skin at the 
electrode sites will be inspected to ensure that it is free of abrasions or irritation. 
The area will then be gently cleaned with rubbing alcohol, but not abraded.  
 
“Stimulation Only” or “Stimulation and EEG” electrodes may be used (see 
electrode chart above). Note, for ease of these experiments, the “Stimulation Only” 
electrodes will be used in most cases. For these electrodes, sponge electrodes will 
be moistened (with saline), prior to placement on the subject’s scalp. Alternatively, 
“Stimulation and EEG” electrodes (PISTIM) will be applied using conductive 
electrode gel. See chart above for electrode sizes and specification.  Up to 8 
electrodes may be used at any given time (in addition to external/reference 
electrodes. See above). Only scalp electrode sites designated on the Starstim cap 
will be used. The cap only uses standard electrode sites from the 10-20 system.  
 
tDCS stimulation (~25 minutes).  During this phase, participants will first receive 
a few minutes of training on the DPX task and complete a brief practice session. 
Subjects will also be familiarized with the working memory task (see below). After 
practice, stimulation (or sham stimulation) will begin.  
 
Following the practice session, subjects will undergo sham with task, DLPFC with 
task, sham without task, DLPFC without task, or SMC active stimulation. The order 
of the conditions will be fully counterbalanced across subjects. This experiment 
involves five tDCS visits, and may include tDCS at any of the designated scalp 
electrode sites in the Starstim cap. Each stimulation visit will be separated by at 
least 24-48 hours.  
 
Subjects will receive up to 20 minutes of tDCS stimulation or sham, in addition to 
a few seconds of ramp up and ramp down time at the beginning and end of each 
session, using the Starstim device. All subjects will receive up to 2.0 mA for the 
first 30-60 s of stimulation. Current strength will be ramped down, and then 
reduced to 0.0-0.1 mA in subjects receiving sham stimulation for the remainder of 
the session. The active stimulation subjects will continue to receive up to 2.0 mA 
stimulation. Many participants can feel the onset of the stimulation (which leads to 
a brief tingling or itching sensation), but people cannot generally feel the continued 
stimulation beyond one minute. By beginning both the active and sham stimulation 
conditions with a period of stimulation, we can ensure that participants will not 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
Page 18 of 36 
 
Revised: September 23, 2019 
know if they are receiving active or sham stimulation. The sham conditions serve 
as an important control, which is similar in procedure and results in similar initial 
sensations, but does not provide a significant level of stimulation.  The SMC 
stimulation condition is another important, "active" control that controls for the 
effect of stimulation at a location other than the DLPFC area of interest for which 
tDCS is hypothesized to have effects on CC. 
 
A sensation questionnaire will be administered at 3 separate time points during 
stimulation, starting at approximately 5 minutes after the beginning of stimulation, 
and then approximately every 10 minutes during stimulation. In this assessment, 
subjects will be asked to report the level of sensation arising from the stimulation 
on a 10 point scale, with 1 meaning no sensation and 10 meaning mild pain. 
Stimulation will be terminated immediately if the reported sensation level is 7 or 
higher at any assessment. Participants—who will be in constant communication 
with an experimenter—will also be instructed to inform the experimenter if pain is 
experienced at any other time, which will lead to immediate termination of 
stimulation. Additionally, the experimenter will monitor the electrodes to ensure 
that they do not dry out or otherwise cause discomfort.   
 
No-Task Sessions: While subjects are undergoing sham without task or direct 
current stimulation without task they will rest quietly while seated at a computer 
desk. The experimenter will be available to chat with the participants and 
administer the sensation questionnaires as described above. The purpose of the 
No-Task sessions is to be able to compare the effects of sham/stimulation without 
task to sham/stimulation with a concurrent task, as previous work has suggested 
that there may be a benefit to completing a concurrent task during tDCS (see 
below).  
 
Concurrent Visuospatial N
-Back Working Memory Task: 
While subjects are 
undergoing sham or direct current stimulation they will concurrently perform a 
simple “n-back” (three-back) working memory task. This is because tDCS effects 
on tasks that engage the prefrontal cortex (e.g. the DPX) are enhanced if the 
stimulation occurs at the same time as either the same task or another task that 
also engages the prefrontal cortex (i.e. “state-dependent” effects) (Tremblay et al., 
2014).  
 
In the three-back task, subjects will be asked to remember the location of an object 
presented three objects previously on a computer screen. To register a match, a 
key on a keypad, keyboard, or mouse will be pressed. No response is required for 
non-targets. 
 
Wash up: The stimulating electrodes will be removed, cleaned, and disinfected 
according to the manufacturers instructions. As the electrodes are removed, the 
experimenter will inspect the skin at and near the electrode sites for redness, 
irritation, or damage and note if present. 
 
For sessions that include fMRI scans, scanning will begin immediately following 
wash-up and will last up to 1 hour (Stimulation will only last for 20 minutes).  See 
above for specific imaging procedures.   
 
Mood Assessment  (30-90 minutes):  

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Revised: September 23, 2019 
After imaging is complete, participants will undergo a relaxation period (~30 
minutes) during which the electrodes will be removed and the participants will relax 
(by sitting quietly or watching a video). Subjects will then take the mood and mental 
state questionnaire again to make sure that they have no lingering effects of the 
stimulation. In the unlikely case that a subject still has any lingering effects, the 
subject will relax for an additional 15 minutes, and then repeat the mood/mental 
state assessment. This will be repeated until the participant returns to baseline. 
There are no known reports of lingering effects of tDCS after 90 minutes, so we 
anticipate that the relaxation period will be complete within 90 minutes in all 
participants.  We will also perform a 48-hour follow-up call or email to ensure that 
subjects have not experienced any additional adverse effects. 
 
Compensation. 
Subjects will be compensated $25 for completing the 
questionnaires and clinical interview, $25 for each tDCS session that does not 
include fMRI or EEG afterwards, $75 for each tDCS session that is followed by 
fMRI or EEG, and given a $50 bonus for completing all sessions of a given modality 
(EEG or fMRI). 
 
8) 
Data and/or Specimen Management and Confidentiality 
The Biomedical Informatics Program of the UC Davis Clinical and Translational 
Science Center will be used as a central location for data management. Vanderbilt 
University, with collaboration from a consortium of institutional partners, has 
developed a software toolset and workflow methodology for electronic collection 
and management of research and clinical trial data. REDCap (Research Electronic 
Data Capture) data collection projects rely on a thorough study-specific data 
dictionary defined in an iterative self-documenting process by all members of the 
research team with planning assistance from the Biomedical Informatics Program. 
The iterative development and testing process results in a well-planned data 
collection strategy for individual studies. The REDCap system provides secure, 
web-based applications that are flexible enough to be used for a variety of types 
of research, provide an intuitive interface for users to enter data and have real time 
validation rules (with automated data type and range checks) at the time of entry. 
These systems offer easy data manipulation with audit trails for reporting, 
monitoring and querying patient records, and an automated export mechanism to 
common statistical packages (SPSS, SAS, Stata, R/S-Plus) REDCap servers are 
housed in a local data center at UC Davis Health System and all web-based 
information transmission is encrypted. REDCap was developed specifically around 
HIPAA-Security guidelines. REDCap has been disseminated for use locally at 
other institutions and currently supports 240+ academic/non-profit consortium 
partners on six continents and over 26,000 research end-users (www.project-
redcap.org).   
 
Access to REDCap is limited to research personnel who are on the IRB-approved 
study personnel list.  Some study questionnaires may be administered 
electronically through REDCap Survey, a secure web application for building and 
managing online surveys for research.  Additionally, data that is not easily stored 
in REDCap (i.e. raw MRI data and some behavioral testing files) will be stored de-
identified on password-protected servers at the Imaging Research Center that are 
protected by an institutional firewall or in locked filing cabinets.   
 

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Revised: September 23, 2019 
Under no circumstances will individually identifiable data be released to anyone 
without the written consent of the subject, and study results will be reported as 
group findings only. Behavioral and imaging data will be labeled with a code that 
carries no personal identifiable information; keys to identities will be kept 
separately from experimental records on a secure computer, and consent forms 
with subjects’ names will be stored separately in a secure filing cabinet. Only 
individuals on the IRB personnel list will have access to the system. 
 
9) 
Data and/or Specimen Banking 
Select data from this study may be submitted to the National Institute of Mental 
Health Data Archive (NDA). NDA is a data repository run by the National Institute 
of Mental Health (NIMH) that allows researchers studying mental illness to collect 
and share de-identified information with each other. The data repository is 
accessible only to qualified investigators. All subject data will be de-identified 
(subject names will not be used) and each subject will have a separate identifier 
called a Global Unique Identifier (GUID) to remove any possibility that “the 
identities of the subjects cannot be readily ascertained or otherwise associated 
with the data by the repository staff or secondary data users.” (45 CFR, 46.102). 
The GUID is a universal subject ID that allows researchers to share data specific 
to a study participant without exposing personally identifiable information. The 
following information will be collected and entered into the study database to 
generate a GUID: First name, Last name, Middle name (if applicable), Month of 
birth, Day of birth, Year of birth, Physical sex at birth, and Name of city/municipality 
of birth. Once GUID is generated, all personal information will be deleted from the 
study database.   
 
10) Provisions to Monitor the Data to Ensure the Safety of Subjects 
N/A this study does not involve more than minimal risk to subjects. 
 
11) Withdrawal of Subjects 
There may be circumstances in which some participants miss sessions or show 
unexpected adverse effects (e.g. severe allergic reactions to tDCS). In these 
cases, the study may be terminated for those subjects. In this case, subjects will 
be informed that the study is being terminated, and they will be paid in a pro-rated 
manner for the time in which that participated. If a subject decides that they do not 
wish to continue with the study for any reason they will be paid in a prorated 
manner. Additionally, if during the study timelines a subject no longer meets our 
inclusion and exclusion criteria the study will be terminated. The subject will be 
paid in a prorated manner for their time. 
 
12) Risks to Subjects 
Because the protocol involves multiple methods, we separately list potential risks 
associated with each method below. 
 
Magnetic Resonance Imaging
 
An MRI scan is a painless radiology technique, which has the advantage of 
avoiding x- ray radiation exposure. There are no known side effects of an MRI 
scan. Typical fMRI pulse sequences without any contrast agents will be used in an 
FDA- approved scanner. As the scanner produces a loud noise during the 

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Revised: September 23, 2019 
scanning procedure, participants will be required to wear earplugs as protection 
against hearing damage.  Pre-screening for metal, pacemakers and other risk 
factors will be pre-screened prior to the study.  No subjects with these 
contraindications will be allowed to participate in MRI scans. 
 
EEG Recording  
Potential risks are minimal. Standard, commercially purchased equipment is used 
for recording the EEG (Starstim). The equipment uses isolated ground procedures 
to minimize the possibilities of electrical shock to the participants, and all current 
safety guidelines are met (e.g., recessed electrode leads to prevent accidental 
contact of electrodes with sources of electric current). Sterilization procedures 
conform to published guidelines for protection of participants from transfer of viral 
or bacterial agents via electrodes. Briefly, the electrode caps and any loose- lead 
electrodes are washed using detergent and warm water, then rinsed thoroughly 
and towel-dried. Caps are then rinsed thoroughly, and hung to dry.  
 
Use of tDCS Equipment (e.g. Electrodes)
 
Potential risks are minimal. Standard, commercially purchased equipment is used 
for stimulation (Starstim). The equipment uses isolated ground procedures to 
minimize the possibilities of electrical shock to the participants, and all current 
safety guidelines are met (e.g., recessed electrode leads to prevent accidental 
contact of electrodes with sources of electric current). Sterilization procedures 
conform to published guidelines for protection of participants from transfer of viral 
or bacterial agents via electrodes. Briefly, the electrode caps and any loose- lead 
electrodes are washed using detergent and warm water, then rinsed thoroughly 
and towel-dried. Caps are then rinsed thoroughly, and hung to dry.  
 
 
Brain Stimulation  
Uncommon Risks: 
• 
Sensations ranging from tingling to itching 
• 
Physical discomfort, including (but not limited to) pain or burning at the 
electrode site and/or headache. 
• 
Skin irritation, redness or itching. 
Very Rare Risks: 
• 
Tissue discomfort, redness, or damage at the electrode site. 
• 
Allergic skin reactions 
• 
Changes in mood 
• 
Seizure 
 
tDCS involves very minimal risks to subjects. Several investigators have examined 
the safety aspects associated with tDCS. For example, Iyer et al. (2005) applied 1 
and 2 mA and sham stimulation to the left prefrontal cortex for 20 minutes in 103 
subjects, while clinical electroencephalography (EEG) was recorded in 9 of the 
subjects. Subjects were encouraged to report any discomfort or subjective 
sensations while undergoing stimulation. These researchers observed no aversive 
EEG abnormalities resulting from DC stimulation, and no subjects asked to stop 
the study or reported any significant discomfort. Differences in mood between 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
sham and stimulation were assessed using the Visual Analog Mood Scale (VAMS) 
that measures subjective reports of anger, anxiety, confusion, energy, fright, 
happiness, sadness, tension, and tiredness. The investigators found no 
measurable effects of stimulation on subjects' VAMS scores. Based on their 
findings, they concluded that limited exposure to direct current stimulation between 
1 and 2 mA is a safe procedure in healthy subjects.  
 
In another study conducted by Gandiga et al. (2006) tDCS and sham were 
compared in healthy volunteers and chronic stroke victims. Discomfort was 
measured using a 10-point scale, where 1 represented no discomfort and 10 
represented extreme discomfort and pain. These researchers report transient and 
mild discomfort of sensations (1-2 on the 10 point scale) that were not significant 
between sham and stimulation conditions, or between healthy volunteers and 
stroke victims. Most subjects from both groups only reported a slight tingling 
sensation associated with both stimulation and sham conditions. These 
investigators concluded that tDCS can be successfully used in neurorehabilitative 
and cognitive neuroscience settings, and is safe for both stroke victims and healthy 
volunteers.  
  
Poreisz et al. (2007) reported on their extensive experience (567 sessions) with 
tDCS to multiple brain regions in healthy subjects and patients. None of the 
subjects asked for a session to be terminated or required any medical assistance. 
102 of their subjects completed a questionnaire inquiring about potential adverse 
effects. Subjects included healthy subjects (75.5%), migraineuers (8.8%), post-
stroke patients (5.9%) and patients with tinnitus (9.8%). A mild tingling sensation 
was the most common symptom, occurring in 71% of subjects; the mean rating of 
the tingling was 1.74 ± .84 on a 1-5 scale. Moderate fatigue was noted in 35% of 
subjects during the stimulation; the mean rating was 2.17 ±1.11. Itching under the 
electrode was reported by 30%; the mean rating was 1.6 ±.72.  
 
Clark et al. (2012) have assessed safety during 30 minutes of tDCS (ranging from 
0.1 to 2.0 mA) tDCS. We have been consulting with Dr. Clark, and have based 
many of our experimental parameters on his work. The following is a statement 
from Dr. Clark: “(as of 2010) we only found two subjects who developed a rash out 
of the 83 tested using tDCS, and one of these was in the low-current sham control 
group (likely an allergic reaction to the electrode holder).  We have tested an 
additional 120+ subjects in our ongoing study, roughly half using the 2.0 mA 
current for 30 minutes.  Of these, only one subject asked to be removed for 
excessive sensation, but he was in a car accident earlier that day and was still 
emotionally upset. Not one subject has reported phosphenes (visual disturbances) 
resulting from tDCS.” Overall, sensations were minimal.  Most commonly, subjects 
reported tingling or itching as the dominant sensations, with no serious adverse 
side effects.  
 
Additionally, tDCS has demonstrated safety at UC Davis. Using similar stimulation 
parameters that we propose, Emily Kappenman, research personnel in Dr. Luck’s 
lab at UC Davis is currently acquiring data using tDCS. She submitted the following 
statement regarding their experiments:   
 
“Using IRB Protocol #2550573-3, we have used the approved tDCS procedure in 
PI Dr. Luck’s laboratory in 164 subjects (approximately half in the sham condition 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
and half in the stimulation condition).  Of the 164 subjects we have tested, only 1 
person has requested to discontinue the procedure, citing excessing itching.  
During the stimulation/sham, sensations reported across subjects included: a 
tingling sensation at the electrode location, arm aching at the cathode electrode 
location, a prickling sensation that felt like small needles, weird taste in mouth, and 
itching at the electrode site.  In all of these cases, the reported pain level on a scale 
from 1 (no pain) to 10 (extreme pain) never exceeded a value of 7. At the end of 
the procedure, self-report measures showed no adverse effects on mood or 
attention, no dizziness, persisting pain or discomfort, or confusion at the end of the 
procedure compared with the reported measures before the session.”  
 
Furthermore, a review by Nitsche et al. (2008) presented the behavioral, cognitive 
and side effects of tDCS in over 90 studies that had been conducted between 
1998-2008.  In summary, these reports have indicated that tDCS is a noninvasive 
procedure with strong promise for improving learning and memory across a wide 
population.  The majority of tDCS studies that were reviewed reported no side 
effects.  Approximately one third of these studies reported mild itching or tingling 
under the electrodes as the most severe and common side effect.  Of more than 
90 studies, less than 10 of these papers indicated that subjects experienced 
headache, and in most cases only one participant reported headache in those 
studies. 
 
In our collaborator Dr. Ranganath’s laboratory, using Protocol #468198-3, a tDCS 
experiment was completed in 21 individuals. No adverse events have occurred 
during this experiment. Sensations reported across subjects included an itching or 
tingling sensation at the electrode location, a prickling sensation that felt like small 
needles, or mild heat sensations at the electrode site.  In all of these cases, the 
reported pain level on a scale from 1 (no pain) to 10 (extreme pain) never exceeded 
a value of 6. The median self reported pain value was a 2. At the end of the 
procedure, self-report measures showed no adverse effects on mood at the end 
of the procedure compared with the reported measures before the session.  
 
Since the Nitsche review in 2008, the field of tDCS has quickly expanded, and to 
date a PubMed search of “transcranial direct current stimulation” results in 2705 
published articles. In these studies there have been almost no reported seizures, 
loss of consciousness or persistent neurologic signs or symptoms. Therefore, the 
evidence to date suggests that the main risk associated with tDCS is a mild 
burning/tingling sensation. After approximately 10 years of experience and 
hundreds of publications with the technique, there have only very rarely been 
reports of serious adverse effects in subjects who have participated, including 
those studies involving multiple sessions (a rare case report was recently 
published by Ekici (2015) that described a seizure in a boy diagnosed with spastic 
tetraparesis induced after 3 consecutive days of direct stimulation to the motor 
cortex).  The likelihood of inducing seizures is low due to the fact that tDCS current 
strengths are almost always administered at least an order of magnitude lower 
than that required to induce epileptiform activity, even during gamma oscillations 
(Bikson et al., 2016; Bikson et al., 2004). For example, our colleagues, Lauren 
Richmond and Ingrid Olson at the University of Pennsylvania, reported that 10 
sessions of tDCS (with 2 weeks of 5 sessions over consecutive days) did not result 
in any serious adverse effects, and the repeated exposure to stimulation did not 

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Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
result in an increased incidence of adverse effects when compared to shorter-term 
studies (Richmond et al., 2013). 
 
Given that itching, tingling, and burning tend to be the most likely adverse effects 
associated with noninvasive stimulation studies, protocols have been outlined to 
help minimize the risk of skin damage or burning. In a paper by Loo et al. (2011) 
they outlined a protocol to address the potential risk of skin burns during tDCS 
experiments.  They suggested that skin burns are attributed to drying out of 
electrodes and/or uneven skin abrasion.  In order to prevent skin burns they 
suggested incorporating a few simple steps, including screening subjects for any 
skin conditions, inspecting skin at stimulation site for cuts, rash, etc. prior to placing 
electrodes, cleaning but not abrading skin prior to electrode placement, disinfecting 
electrodes, dampening sponges with saline when using single-use sponge 
electrodes (and monitoring them so that they do not dry out), periodically 
questioning subjects about sensations at the electrode site, stopping stimulation 
or adjusting electrodes if the subject reports discomfort, and inspecting skin for 
redness or damage following stimulation. In order to minimize skin burning in our 
experiments, we have incorporated these steps into our protocol (see 11. 
Procedures).  Loo et al. (2011) reported that, by following these procedures, they 
were able to conduct over 2000 experiments without the incidence of any skin 
burns.  This is the most extensive report on 2 mA stimulation. In addition, they 
reported that skin burns are usually preceded by pain.  By asking the subjects to 
report any instance of pain, as well as periodic sensation questionnaires, the 
occurrence of skin burns can be minimized. 
 
Noninvasive stimulation techniques such as tDCS have also been used safely to 
study cognitive function in several patient populations, including Parkinson’s 
Disease (Boggio et al., 2006), stroke (Jo et al., 2009), Alzheimer’s Disease (Boggio 
et al., 2009), and schizophrenia (reviewed by Kekic et al., 2016). Most relevant to 
this protocol, Brunelin et al. (2012) conducted a pilot study to explore the safety 
and efficacy in refractory schizophrenia.  In this experiment patients received 2 mA 
of current for 20 minutes twice a day with a 3-hour interval, across 5 consecutive 
days.  Patients improved on measures of symptoms, particularly in auditory 
hallucinations. No adverse events occurred.  Patients only described a transient 
mild tingling or a slight itching sensation associated with the onset of stimulation. 
Additionally, the tolerability of tDCS in childhood-onset schizophrenia has been 
assessed (Mattai et al., 2011). In this study, patients received 2 mA or sham 
stimulation in 20-minute sessions, across 10 sessions (over 2 weeks).  tDCS was 
well tolerated in all subjects, and no serious adverse events were reported.  Again, 
the most common effect reported was tingling and itching, and a few reports of 
mild fatigue. 
 
The great majority of tDCS studies in schizophrenia have targeted the DLPFC. 
Most studies have observed reduced positive and/or negative symptoms, with no 
studies reporting severe adverse events (reviewed by Kekic et al., 2016). These 
studies involve a range of patients, including patients with childhood-onset 
schizophrenia, catatonic schizophrenia, and treatment-resistant schizophrenia. 
There have been no reports of serious adverse effects, and no reports of seizures 
in any of these patient studies. 
 

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Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
Finally, the risk of excitotoxic damage is not applicable to tDCS. Stimulation levels 
of 1 or 2 mA do not directly induce firing in cells that are not spontaneously active. 
Instead, it has been shown in animals that tDCS increases spontaneous neuronal 
firing rates only to a moderate degree and did not reach the threshold for 
excitotoxicity (Bindman et al., 1964). At 1 or 2 mA, it has been shown that tDCS 
does not increase levels of serum neurone-specific enolase (Nitsche et al., 2003; 
Nitsche and Paulus, 2001) a sensitive marker of neuronal damage (Steinhoff et 
al., 1999). In rats, only at doses 100 times higher than those used in humans was 
neural pathology evident. Whereas 800 mA is used in humans for 
electroconvulsive shock therapy (ECT), which is intended to induce seizures, we 
only intend to use a maximum of 2 mA. Therefore, it is highly unlikely that this dose 
will produce seizures in a non-epileptic population.  Furthermore, we would like to 
re-emphasize that non-invasive stimulation techniques such as tDCS and tACS 
are not at all similar to ECT, and therefore, the risks are quite different.  In addition, 
tDCS is also quite different from, and considered less invasive than, other 
stimulation techniques such as transcranial magnetic stimulation (TMS). The risks 
associated with tDCS and tACS have been shown to be minimal. 
 
Some additional potential risks have been identified, and although these events 
rarely (if ever) occur, every precaution will be made to prevent these risks. These 
risks include tissue damage, changes in mood, and electrical shock.  
 
Plan For Minimizing Risk To Subjects
: 
Normal patient handling procedures are followed to eliminate risks. The subjects 
will be able to communicate with the investigators at all times. The subject’s 
emotional state and mood will be assessed before and after stimulation; and 
physical sensation will also be monitored with a questionnaire administered before, 
during, and after the stimulation procedure (see above for details).  The subject 
can ask to stop the experiment at any time for any reason.  Likewise, the 
experimenter may stop the experiment at any time if the subject reports 
experiencing any pain or discomfort.  When stopping the stimulation, the current 
will be gradually ramped down using the safe stop mode in order to avoid any 
unpleasantness or painfulness associated with abruptly aborting stimulation.  It is 
also important to note that individuals may respond differently across tDCS 
conditions.  Therefore, we will monitor all participants closely even when they have 
completed previous visits with no adverse effects.  In the unlikely event that a 
subject experiences serious side effects or injury due to the experiment, the 
experimenter will call 911, and these details will be immediately communicated to 
the IRB. We have identified the following potential risks associated with tDCS and 
address them in turn:  
 
I. Skin Damage or Irritation: 
Nitsche et al. (2003) suggest that there may be a 
slight risk of skin damage or irritation resulting from tDCS stimulation. With the 
exception of Iyer et al. (2005) who reported transient redness at the stimulating 
electrode site in two men who had recently shaved their heads, we have 
encountered no reports of skin damage or irritation in any of the tDCS literature. 
The possibility of skin damage resulting from electrode heat has also been tested 
using stimulation parameters comparable to those outlined in this protocol.  None 
of these results have indicated skin damage due to electrode heat. Furthermore, 
we will be using saline-soaked electrodes, or we will use electrode paste, for our 
study, which minimizes the possibility of chemical reactions at the electrode-skin 

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Neuronal Mechanisms of Cognitive Control in Schizophrenia 
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Revised: September 23, 2019 
interface and resultant skin damage. The scalps of each subject will be visually 
inspected immediately before stimulation. Any identified irritation or evidence of 
recent shaving of the head will postpone or terminate that subject’s participation in 
the study. Subjects will also be asked to remove any jewelry that may come into 
contact with the electrodes. Subjects will be encouraged at the beginning of the 
tDCS procedure to report any pain or discomfort that they may encounter 
throughout the procedure. Any such reports, or evidence of redness or irritation of 
the scalp, will result in the immediate termination of stimulation. Additionally, 
subjects will be screened for latex allergies to prevent allergic reactions to the 
electrodes. If allergic reactions are noted at any time, stimulation will be ceased, 
and electrodes will be removed.  Overall, these methods for prevention of skin 
damage follow the suggestions of Loo et al. (2011, see above). 
 
To avoid burning the patient, there is a recommended limit of 0.1 mA/cm2 for DC 
current applications (per the device manual). For example, using electrodes with a 
surface area of 35 cm2 with a current of 1 mA applies a current density of 0.02857 
mA/cm2. It is possible that subjects may experience pain at lower levels of current, 
and therefore, we will closely monitor subjects’ responses on the questionnaires. 
To avoid permanent injury of tissue, current density should not be higher than 25 
mA/cm2 at any given electrode site. This limit is far above the limit for thermal 
effects of the current density. Note that the maximum current in this protocol is 2 
mA, and the surface area of the Starstim PISTIM electrodes is 3.14 cm2.  Other 
Starstim stimulating electrode options include the SPONSTIM electrodes in either 
8 cm2 or 25 cm2. Thus, the maximal current density used in this protocol will range 
from 0.080 - 0.64 mA/cm2. Therefore, the maximum current density will always be 
set below the recommended limit to avoid any skin burning or damage. 
 
II. Tissue Damage and Discomfort
: To minimize any possible tissue damage we 
have subjects fill out a tDCS sensation questionnaire form throughout the tDCS 
procedure.  This questionnaire allows us to monitor what the subjects are 
physically feeling at the electrode sites. This will be given at the following time 
points:  1 minute after start of tDCS, 5 minutes after start of tDCS, and 20 minutes 
after tDCS.  If at any time the subject reports a sensation level of 7 on a 10-point 
scale, we immediately discontinue the experiment. We will also administer a 
subjective mood questionnaire before and following experimentation. Any 
significant changes in answers provided following the experiment will result in 
further assessment every 15 minutes until subjects return to near baseline state.  
(also see above “Skin damage or irritation” for further details). 
 
III. Pain:  At very strong, focal current density can result in pain. We will be using 
large electrodes and passing weak electrical current. As previously stated, with 
protocols similar to ours, most subjects report only mild, transient tingling at the 
stimulation site. Any subject report of pain resulting from tDCS will result in 
immediate termination of stimulation.  
 
IV. Alterations in Mood or Affect:
 There is evidence that tDCS can result in 
changes in mood and concentration. While no studies have reported negative 
affect resulting from DC stimulation, several studies have reported improved mood 
after tDCS. It should be noted that, in these studies, stimulation was applied for 
significantly longer durations. Studies designed to investigate the safety aspects 
of non-invasive brain stimulation have reported no significant changes in mood as 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
Page 27 of 36 
 
Revised: September 23, 2019 
measured with the VAMS (Visual Analog Mood Scales) and no significant changes 
in measures of fatigue when comparing stimulation to sham.  Therefore, we do not 
anticipate any changes in mood or affect resulting from our study. To further 
ensure that subjects are not experiencing alterations in mood or mental state that 
could potentially debilitate them, we will administer a subjective mood 
questionnaire before and following experimentation. Any significant changes in 
answers provided following the experiment will result in further assessment every 
15 minutes until subjects return to near baseline state.  
 
V. Electrical Shock:  As with any contact between persons and electrical 
apparatuses, there is a slight possibility of electrical shock. To our knowledge, no 
studies have reported any incidents of significant electrical shock resulting from 
DC stimulation, and we do not anticipate this event occurring in our experiment. 
To help ensure the prevention of electrical shock, we will avoid conducting 
experiments near potential liquid spills. Further, we will ensure that subjects are 
not in contact with any potential conductors other than those specified in the 
experimental design. This measure greatly reduces the likelihood that electrical 
shock will result from short-circuiting or inadequate insulation. In the very unlikely 
event that the subject experiences a shocking sensation, the current will be first be 
ramped down, turned off, and then the electrodes will be removed. 
 
There is the possibility of an electrostatic discharge by touching the patient (for 
example the patient's head) or the DC-STIMULATOR PLUS. Having an 
electrostatic discharge while electrodes are attached to a subject may cause a 
discharge current to flow through the electrodes leading to a shock sensation 
similar to that experienced in everyday life. Such currents are not dangerous but 
they are unpleasant. As such, we will avoid touching the patient during stimulation. 
 
The output circuit of the constant current source of the DC-STIMULATOR PLUS is 
equipped with an electrical fuse that limits the current to 5 mA. Therefore, in any 
faulty condition and during normal operation, current will be ramped down and then 
turned off. 
 
There is a potential of a strong stimulus to be delivered if the electrodes are 
disconnected while current is flowing. Therefore, electrodes will not be 
disconnected while current is flowing. Instead, current will be ramped down until it 
is off completely before electrodes will be removed. 
 
VI. Avoiding Electrode Placements Outside the Head:
 For safety reasons, we 
will never use bipolar stimulation on any other part of the body apart from the head. 
Although not reported in any tDCS studies, it is plausible that bipolar stimulation 
setups could potentially harm the heart if electrodes are set up in a manner that 
would pass current across the heart. Similarly, we will avoid electrode setups that 
could lead to the stimulation of the brain stem and cerebellum (vagus nerve).  Care 
will always be taken during electrode placement to ensure that areas outside the 
head are not stimulated. 
 
VII. Contraindications for Subjects with Electrical Support Systems:
  
Stimulation from tDCS may interfere with pacemakers or implanted brain 
stimulators. Accordingly, subjects will be carefully screened for pacemakers or 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
Page 28 of 36 
 
Revised: September 23, 2019 
brain stimulators prior to the initiation of the study. Subjects with pacemakers or 
brain stimulators will not be allowed to participate. 
 
VIII. Availability of PIs:  With the above safeguards in place, the tDCS stimulation 
procedures described above are expected to be safe and well-tolerated. As an 
added precaution, the PI (Cameron Carter, M.D.) will be available on call during 
each session to answer any questions for research staff. A licensed physician, Dr. 
Carter will review the case details of any adverse event and determine whether 
any modifications to the protocol are needed in order to further minimize risks. If 
he deems it necessary, he will have the authority to stop a tDCS research session 
or to halt further tDCS studies.  
 
In the unlikely event that a subject experiences serious side effects or injury due 
to the experiment, these details will be immediately communicated to the IRB.  
These subjects will also be provided with the necessary medical care. Our 
personnel will call 911 upon a medical emergency, such as a seizure, while 
ensuring that the subject does not cause further harm to him or herself. 
 
Specifically, we will report serious adverse events as well as other unanticipated 
problems to the IRB within five days of becoming aware of such an event, provided 
that the event or problem occurred at UC Davis, suggests that the research places 
subjects or others at a greater risk of harm than was previously known or 
recognized, was unanticipated, and was related or possibly related to the research.  
In the report, we will either justify why no changes to the protocol or consent form 
are needed or attach proposed modifications to the report. Responses to all 
requests from the IRB for further information will be made within 10 working days 
of receipt of the request. 
 
IX. Seizure: Although risk of seizure is very low, steps will be taken to minimize 
this risk. Any subjects with a history of epilepsy or seizures will be excluded. 
Furthermore, any subjects who are currently (less than 1 month prior to enrollment) 
taking the antipsychotic clozapine will be excluded as this antipsychotic associated 
with the greatest risk for seizures (Devinsky et al., 1991)  
 
13) Potential Benefits to Subjects 
Subjects may receive some benefit from participation. Previous studies indicate 
that tDCS may produce transient improvements in cognitive performance. For 
instance, reports have demonstrated improvements in working memory 
performance in healthy adults (Fregni et al., 2005; Keeser et al., 2011) as well as 
patients with schizophrenia (Hoy et al., 2014). Improved social cognition after tDCS 
stimulation of the DLPFC has been observed in schizophrenia as well (Rassovsky 
et al., 2015). 
 
14) Sharing of Results with Subjects 
N/A 
 
15) Provisions to Protect the Privacy Interests of Subjects 
The data and/or specimens will be labeled with a code that the research team can 
link to personal identifying information when acquired. The code sheet will be 
secured and kept separate from the dataset. All data will be stored on password-

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
Page 29 of 36 
 
Revised: September 23, 2019 
protected computers and/or networks. Information regarding personal information 
will only be requested from the subject by the recruiter and experimenter. No 
personal identifiers will be attached to data. During the experiment, the 
experimenter will thoroughly explain all procedures to ensure that the subjects feel 
at ease with the procedures. 
 
16) Economic Burden to Subjects 
N/A 
 
17) Drugs or Devices 
This study uses the Starstim device. Although not approved by the FDA, this 
device is specifically designed for non-invasive stimulation and EEG research, and 
is widely used across academic institutions worldwide. This device has 
demonstrated safety, and is also CE-Certified with approval in Europe. This device 
does not involve greater than minimal risk. A brochure for this product has been 
attached. The device will be stored in a locked laboratory that is supervised by 
investigators on the protocol during working hours. All authorized investigators will 
be trained on the procedures outlined in this protocol for the proper use of this 
device on subjects. 
 
In additional to the manuals, brochures and other info re: this device are attached 
to this submission. 
 
☐ I confirm that all investigational devices will be labeled in accordance with FDA 
regulations and stored and dispensed in such a manner that they will be used only 
on subjects and be used only by authorized investigators. 
 
18) ClinicalTrials.gov Registration 
 
FDAAA 801 establishes penalties for Responsible Parties who fail to comply 
withClinicalTrials.gov registration or results submission requirements. Penalties 
include civil monetary penalties and, for federally funded studies, the 
withholding of grant funds.
 
 
Section 1:  NIH Funded Studies
 
If yes to BOTH, the study must be registered on Clinicaltrials.gov. 
Yes  
 
This study is funded by the NIH. (If this study is not funded by NIH, go to Section 
2.) 
 
One or more human subjects will be prospectively assigned to one or more 
interventions (which may include placebo or other control) to evaluate the effects 
of those interventions on health-related biomedical or behavioral outcomes. 
 
Section 2:  Studies subject to FDA jurisdiction
 
If yes to ANY the study must be registered on Clinicaltrials.gov. 
Ye
s 
 

PROTOCOL TITLE: The Effects of Transcranial Direct Current Stimulation on the 
Neuronal Mechanisms of Cognitive Control in Schizophrenia 
Page 30 of 36 
 
Revised: September 23, 2019 
 
This is a prospective clinical study of health outcomes in human subjects that 
compares an intervention with an FDA-regulated device against a control. This 
is not a small clinical trial to determine the feasibility of a device, or a clinical 
trial to test prototype devices where the primary outcome measure relates to 
feasibility and not to health outcomes. 
 
This is a pediatric postmarket surveillance of a device as required under section 
522 of the Federal Food, Drug, and Cosmetic Act. 
 
This is a controlled clinical investigation, other than a phase I clinical 
investigation, of a drug subject to section 505 of the Federal Food, Drug, and 
Cosmetic Act or to section 351 of the Public Health Service Act. 
To view a flowchart describing applicable clinical trials subject to FDA jurisdiction click 
here. 
 
Section 3: Publishing the results
 
If yes to BOTH the study must be registered on Clinicaltrials.gov. 
Yes  
 
This study prospectively assigns people or a group of people to an intervention, 
with or without concurrent comparison or control groups, to study the cause-
and-effect relationship between a health-related intervention and a health 
outcome. 
 
The PI has access to and control over all the data from the clinical trial and has 
the right to publish the results of the trial and plans to publish the results in a 
journal that follows the ICMJE recommendations.  
This requirement includes studies of behavioral interventions. 
 
Section 4: Registration on Clinicaltrials.gov is not 
required  
Yes  
 
I have read sections 1-3 above and registration on clinicaltrials.gov is not 
required for this research.  
 
 
19) References 
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2016. A Systematic Review on the Acceptability and Tolerability of Transcranial 
Direct Current Stimulation Treatment in Neuropsychiatry Trials. Brain Stimul. 
Becker, T.M., Kerns, J.G., Macdonald, A.W., 3rd, Carter, C.S., 2008. Prefrontal 
dysfunction in first-degree relatives of schizophrenia patients during a Stroop task. 
Neuropsychopharmacology 33, 2619-2625. 
Bikson, M., Grossman, P., Thomas, C., Zannou, A.L., Jiang, J., Adnan, T., 
Mourdoukoutas, A.P., Kronberg, G., Truong, D., Boggio, P., Brunoni, A.R., 
Charvet, L., Fregni, F., Fritsch, B., Gillick, B., Hamilton, R.H., Hampstead, B.M., 
Jankord, R., Kirton, A., Knotkova, H., Liebetanz, D., Liu, A., Loo, C., Nitsche, M.A., 
Reis, J., Richardson, J.D., Rotenberg, A., Turkeltaub, P.E., Woods, A.J., 2016. 
Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. 
Brain Stimul. 

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