Remediation of Auditory Recognition in Schizophrenia With Transcranial Direct Current Stimulation (tDCS)
Phase: NA
Conditions: Schizophrenia, Schizoaffective Disorder
Sponsor: New York State Psychiatric Institute

 
 
1
 
 
Official title:   Remediation of auditory recognition in schizophrenia with 
transcranial direct current stimulation (tDCS) 
 
NCT number: NCT02869334 
 
Document date: 10/27/2016

 
 
2
NATHAN KLINE INSTITUTE/ROCKLAND PSYCHIATRIC CENTER
 
INSTITUTIONAL REVIEW BOARD  
 
IRB Office Telephone: (845) 398-5493 or 398-5492 
 
 
APPLICATION FOR APPROVAL OF NEW PROTOCOL 
 
DATE:  8/29/2016 
Modifications required: 10/27/2016 
PROTOCOL TITLE:  Remediation of auditory recognition in schizophrenia with 
transcranial direct current stimulation (tDCS) 
 
DOCUMENTS SUBMITTED WITH THIS APPLICATION (Include a list of all documents submitted, 
including protocol, consent forms, advertisements, etc., with version date for each. Include all information 
required for the IRB approval letter):   
Cover memo 9/28/2016/ 
Cover memo(response to conditions/modifications required dated 10/24/2016 
Application for Approval of New Protocol 8/29/2016/modifications required version 10/24/2016 
Protocol  8/29/2016/modifications required version 10/27/2016 
Examples of Session flow charts with list of study procedures(for Auditory remediation/tDCS 
computer training conditions and for game computer training condition) 
Consent form 8/29/2016/modifications required version 10/27/2016 
Scope of Work-requested by IRB for response to conditions submission 
Progress report-included in response to conditions submission 
HIPAA addendum 8/29/2016 
Waiver of consent 8/29/2016 
Phone Screening Script 9/28/2016 
NKI Notice of Privacy Practice  
Copies of CITI training and CVs for Odeta Beggel, Constance Shope, Anastasia Stoops 
Uploaded training and credentials for Drs. Javitt, Dias, Kantrowitz, Sehatpour and for Gail Silipo 
 
PRINCIPAL INVESTIGATOR'S NAME, TITLE & TELEPHONE NUMBER: 
 
The NKI site principal investigator is Elisa Dias, Ph.D.  845-398-6541 
The overall principal investigator is Daniel Javitt, M.D., Ph.D.  845-398-6534 
  
Name and telephone number of contact person, if different: 
For details regarding the study for the IRB initial review please contact: Daniel Javitt, M.D., 
Ph.D.  845-398-6534 or Joshua Kantrowitz, M.D. at 845-398-5503 
For other IRB issues contact Gail Silipo 845-398-6536 
 
Co-Investigators (or Sponsor for research fellow or student):  
Odeta Beggel, M.A. 
Constance Shope, Ph.D. 
Anastasia Stoops, Ph.D. 
Gail Silipo, M.A. 
Joshua Kantrowitz, M.D. is the study clinician and the safety monitor 
Pejman Sehatpour, Ph.D. 
STUDY/RECRUITMENT SITES: List all sites involved in subject recruitment and/or conduct of the 
study. (If subjects will be recruited from the community, state from what community - Rockland County, 

 
 
3
Westchester County, etc.)  
Recruitment sites for patients will include inpatients from Rockland Psychiatric Center who have 
been transferred to the inpatient research unit at NKI (Clinical Research and Evaluation Facility 
(CREF).  We will also recruit outpatients through the Volunteer Recruitment Program (VRP) at 
NKI. The Volunteer Recruitment Program at NKI recruits from NYS office of Mental Health 
facilities. The VRP also recruits outpatients living on the grounds at CLUE I and II, Conway 
House(Loeb House), from Rockland County Department of Mental Health facilities and from the 
community.  We will also invite patients who have participated in IRB approved studies conducted 
by Daniel Javitt, M.D., Ph.D., to participate in this protocol (those who have agreed to be 
recontacted for other studies).   
 
 
 
FUNDING INFORMATION: 
______ No external funding 
______State 
___√___ Federal      Grant # __ R33MH099265_____   
______ Other (Name of agency/company/private sponsor)________________________________ 
 
Please indicate which institution grant is funded through:   
RFMH _√_____;  NYU ______;  Other ______  specify: __Funded to NYSPI/Columbia and NKI is a 
subcontract (subcontract to NKI in process).        
 
Is this a multicenter trial?  Yes ______    No___√____   If yes, indicate # of sites _____________ 
 
IS THIS A CLINICAL TRIAL?   __√____YES      ____NO  
CLINICAL TRIAL REGISTRATION:   Controlled clinical investigations, other than Phase 1 studies, of 
a product subject to FDA regulation must be registered on clinicaltrials.gov.   (This includes IND-exempt 
clinical trials).  Please provide   NCT #__ NCT02869334_________   Identity of Responsible Party  
Daniel Javitt, M.D., Ph.D. is the overall study PI. 
Dr. Javitt/Dr. Kantrowitz will update the information in clinical trials.gov 
Does this research require an IND or IDE?  Yes _has an abbreviated IDE___   No ____ ;  If yes, provide 
the number   CE Reg#MED30003_ and name the person/entity that holds the IND or IDE  Brainvision 
LLC. 
Note:  The study may not begin until this information is provided to the IRB office.   
 
PLEASE ANSWER IN LAY LANGUAGE WITHOUT JARGON, TECHNICAL TERMS OR 
UNDEFINED ABBREVIATIONS.  ALSO, ATTACH FULL PROTOCOL WHICH CONTAINS A 
BACKGROUND SECTION, THE AIMS AND OBJECTIVES OF THE PROJECT, A FULL 
DESCRIPTION OF THE EXPERIMENTAL DESIGN AND PROCEDURES, AND AN 
EXPLANATION OF HOW DATA WILL BE ANALYZED AND INTERPRETED. 
 
 
A.    IRB Submission Abstract 
  
All IRB submissions must be accompanied by a submission abstract. The abstract, at a minimum, 
should include the elements as per below.  Be complete yet concise; restrict your abstract to 2 pages, 
and expand on the components in the abstract in the other sections of this application as required.     
  
Outline of the IRB Submission Abstract 
1.     Brief Introduction (2-3 sentences) 
2.     Specific Aims/Hypotheses (list and explain in bulleted format) 

 
 
4
3.     Research Participants 
a.     Number 
b.     Method for Ascertainment 
c.     Inclusion/Exclusion Criteria 
d.     Relevant safety cut point (s) for dropping subject from the study 
       4.     Research Procedures 
5.     Risks 
6.     Consent Process 
7. State whether any drugs tested are approved by FDA, are under an IND (Investigational New Drug 
Application), or are marketed products being used “off-label”.   
8. State whether any devices are under an IDE or Abbreviated IDE 
9. Issues requiring special attention of the IRB 
 
1. Abstract of Protocol:    
 Schizophrenia is associated with impairments in basic auditory functions, such as the ability to 
match tones following brief delay. These impairments contribute to difficulties that patients have 
in detecting emotion based on tone of voice (auditory emotion recognition, AER) along with 
other auditory functions such as sounding out words during reading (phonological processing). 
Schizophrenia patients also have difficulty in benefiting from remediation exercises designed to 
correct these deficits. 
 
Transcranial direct current stimulation (tDCS) is a form of non-invasive brain stimulation in 
which low level electrical currents are applied to the scalp in order to manipulate brain function. 
In the present study, tDCS will be paired with auditory training to remediate deficits in basic 
auditory function in schizophrenia with the goal of assessing the tolerability and feasibility of 
this approach. 
 
Patients will receive 34 sessions of auditory remediation over approximately 12-17 weeks. A 
total of up to 60 individuals will be enrolled and of the 60, it is anticipated that 45 individuals 
with a diagnosis of DSM-IV Schizophrenia or Schizoaffective Disorder who have auditory 
sensory deficits (as reflected in a score of <65% correct on the tone matching task) will complete 
the study. Patients will be randomly assigned to one of 3 groups: 1) auditory remediation with 
active tDCS; 2) auditory remediation with sham tDCS; 3) computer video-game remediation. 
 
Behavioral measures (e.g. auditory emotion recognition) and EEG/event-related potential (ERP) 
measures (e.g. mismatch negativity; MMN) will be used to evaluate effects of the tDCS and 
training methods. 
 
2. Specific Aims and Hypotheses 
 
   The Specific Aims are: 
• 
To evaluate effects of transcranial Direct Current Stimulation (tDCS)-
enhanced auditory remediation on specific measures of auditory function. 
Patients will receive 34 sessions of auditory remediation over approximately 
3-4 months.   45 individuals with a SCID diagnosis of DSM-IV Sz or 
Schizoaffective Disorder who have auditory sensory deficits (<65% on tone 
matching task) will be enrolled (complete the study). Patients will be 
randomized to 1 of 3 program trainings: 1) auditory remediation plus active 
tDCS; 2) auditory remediation plus sham-inactive tDCS; 3) computer video 
game remediation. 
 
 

 
 
5
• 
To assess changes in auditory function after auditory remediation. This will 
be assessed using event related potentials (ERP) and electroencephalographic 
(EEG) measures pre/post completion of the tDCS program training. The ERPs 
and EEG measures will include auditory event related potential component N1 
and P3, mismatch negativity-MMN, auditory steady state response- ASSR. 
• 
To evaluate effects of tDCS-enhanced auditory remediation on 
neurocognition, functioning, social skills, reading and symptoms. These will 
be obtained before and after completion of the program training. 
1. Neurocognition measures will include: MATRICS Consensus 
Cognitive Battery (MCCB) and Processing Speed Index (PSI). 
2. Social Cognition measures will include: Auditory Emotion 
Recognition (AER), Penn Emotion Recognition Test-40 Faces 
Version (ER-40), and the Awareness of Social Inference Test 
(TASIT). 
3. Functioning measures will include: The University of California 
Performance-based Skills Assessment (UPSA), Global 
assessment of function (GAF) and the Specific Levels of 
Functioning Assessment (SLOF). 
4. Social skills measure will include: The Social Skills Performance 
Assessment (SSPA). 
5. Reading measure will include the Comprehensive Test of 
Phonological Processing-2 (CTOPP). 
6. Symptoms measure will include: Positive and Negative Syndrome 
Scale (PANSS). 
 
• To evaluate potential mediators of response of both tDCS and cognitive 
remediation efficacy using plasma D-serine and BDNF levels. These will be 
obtained at study baseline and after completion of the tDCS program training. 
 
• To assess target engagement. It will be measured using the Intrinsic Motivation 
Inventory for Schizophrenia (IMI), Perceived Competency Scale (PCS) and 
Treatment Motivation Questionnaire (TMQ) scales. 
  
The Hypotheses are: 
• 
There will be objective evidence of improvement in brain function as reflected 
by auditory ERP generation 
 
• 
There will be moderate or greater effect size improvement of active 
tDCS/auditory remediation vs sham tDCS/auditory remediation. 
 
• There will be a large or greater effect size improvement of tDCS/auditory 
training vs. (control) game training on specific cognitive measures(e.g. tone 
matching, AER, verbal learning, reading).  
 
3. Research Participants 
a. Number 
We project we will need to enroll 60 subjects to obtain the 45 completers which is the 
required number to accomplish study aims. 
 

 
 
6
b. Method for Ascertainment 
Potential candidates (patients) will be identified based upon their present diagnosis of 
schizophrenia or schizoaffective disorder based upon referral from their primary 
clinician, chart reviews or the volunteer recruitment pool.   
 
c. Inclusion/Exclusion Criteria 
 
All attempts will be made to maintain patients on stable doses of antipsychotic throughout the 
study. Subjects will be permitted to have dose changes for side effects.  In cases of worsening of 
symptoms, increases of up to 50% of dose will be permitted without removing patients from the 
study. 
 
 The following adjunctive medications are allowed: beta-blockers; mood stabilizers, 
antidepressants; and anti-anxiety agents. PRN doses of clinically determined 
benzodiazepines or antipsychotics will be permitted. Given a possible detrimental 
effect on cognition, regular use of benzodiazepines will be considered covariates in 
the analysis, and patients will be asked to not take these medications for 3 hrs prior to 
testing/training session if clinically feasible. Participants receiving adjunctive 
anticholinergic medication will be excluded. 
 
Inclusion Criteria 
Method to ascertain 
Age 18-55 
Clinical evaluation and/or medical 
history; self report 
Primary diagnosis of Schizophrenia or 
schizoaffective disorder 
Clinical evaluation and/or medical 
history 
SCID primary diagnosis of DSM-IV 
schizophrenia or schizoaffective disorder 
SCID 
 
English fluency 
Interview 
Willing/capable to provide informed consent 
Capacity to Consent 
Capacity assessment by licensed 
professional 
IQ≥75 
WRAT, Clinical evaluation, medical 
history 
Score <65% on tone matching 
Tone Matching Test 
Normal Hearing 
Audiometry testing, examination                          
corresponding to a reduction of 1.5 sd 
vs. HV 
 Receiving stable antipsychotic medication for 
>2 weeks 
medical history, medication records, 
clinical evaluation (criteria used in 
prior studies) 
 

 
 
7
 
 
 
Exclusion Criteria 
 
Method to ascertain 
Serious neurological disorder or medical 
condition/ treatment known to affect the brain. 
Neurological Disorder that affects the central 
nervous system (CNS), such as epilepsy, 
neurodegenerative disorders, movement disorders 
and sensory disorders. 
 
 
 
 
Clinical evaluation, medical 
history 
Active suicidal ideation 
Affirmative answers to items 3, 4 
or 5 of the Suicidal ideation 
section of the screening and pre 
testing Columbia Suicide Severity 
Rating Scale (CSSRS) in the 6 
months prior to screening or 
subject who represent a 
significant risk of suicide in the 
6
h
 
Current or past history (within last 6 months) of 
substance abuse or dependence 
 (excluding Nicotine) 
Clinical evaluation , medical 
history, urine toxicology, SCID 
 
Pregnancy or breastfeeding 
 
Urine Pregnancy Test, self report, 
medical records 
Taking Adjunctive anticholinergic medication (i.e. 
Cogentin, Benztropine) 
Clinical evaluation, medical 
history,  medication records, self 
report 
  Participation in study of investigational medication within 
the past 4 weeks (prior to screening) or investigational  
device within the past 4 weeks (prior to start of tDCS 
training) 
 
Self report 
                                                                      
                                                                      
                                                                      
 
 
d.     Relevant safety cut point (s) for dropping subject from the study 
 
Subjects will be withdrawn from the protocol by the study clinician, if any of the following 
should occur: 
 
-The subject experiences a clinically significant adverse event, which, in the clinical judgment of 
the investigators/study clinician, would increase the risk to the welfare of the subject and be 
inconsistent with continuation in the study. 
 
-Clinical worsening: Clinical worsening will be defined as a > 20% increase in PANSS total 
symptom score from baseline. In the event this occurs, the study clinician will speak with the 

 
 
8
patient, and his/her treating psychiatrist will be notified. The participant will be referred to their 
primary psychiatrist for re-evaluation, who will then determine if the patient requires changes to 
his/her medication regimen and if he/she should  continue in the protocol or be exited for safety 
reasons. Patients who are judged by the study clinician to require emergency intervention due to 
clinical deterioration will be referred to the local hospital emergency department for further 
evaluation. 
-Pregnancy: If any urine test is positive for pregnancy or the subject reports becoming pregnant, 
the participant cannot to continue with tDCS training sessions and she will be withdrawn from 
the study. 
 
-Withdrawal of participant consent 
 
-Subject noncompliance, defined as refusal or inability to adhere to the study schedule or 
procedures. Missing sessions will be reviewed as to the reasons why and if it is found that the 
individual is failing to adhere to study requirements a decision will be made as to whether the 
individual will remain in the study.  This will be done on a case-by-case basis. 
 
 
4.  Research Procedures 
The present study evaluates tolerability and feasibility of repeated administration of tDCS and 
auditory remediation alone and in combination. 
 
All participants will receive an eligibility screening, which includes demographics, psychiatric 
and medical history, SCID, assessment of auditory function and auditory emotion recognition, 
urine toxicology and, if applicable, pregnancy tests, and related measures (~2 hours). 
 
After consenting and establishing eligibility, each participant will be asked to participate  3 
behavioral sessions (behavioral sessions can be combine into one or 2 sessions if preferred, each 
session is  ~2 hours or ~ 6 hours total), one ERP/EEG session (~ 3 hours) and a blood draw (~ 5 
minutes).  These assessments will be repeated at the end of the study, following completion of all 
training sessions. 
 
Once the assessment sessions are completed, each participant will be assigned randomly to 1 of 
3 study arms: 1) active auditory remediation/training + active tDCS; 2) active auditory 
remediation/training + sham  tDCS; 3) computer game condition (“control” remediation). Each 
training type involves two or three sessions per week, approximately 30 minutes each, for 
approximately 12-17 weeks (34/30 minute tDCS training sessions) depending on the number of 
sessions per week the subject is able to attend 
 
1. Eligibility Screening: 
 
After the patient signs the informed consent form and the HIPAA authorization, he/she will 
undergo a diagnostic interview (SCID) and brief audiometric examination to insure adequate 
hearing ability, and will complete a simple behavioral test of auditory processing to determine 
the presence/absence of auditory sensory deficits (Tone Matching Test), and brief evaluation 
(WRAT Reading) to estimate premorbid intellectual ability. Also a screening for active suicidal 
ideation (Columbia Suicide Severity Rating Scale) will be completed 
 
Females of childbearing capacity will receive a urine pregnancy test; tDCS cannot begin unless 
a negative result is obtained. 

 
 
9
 
A brief clinical evaluation and/or medical history will determine medication history and 
presence/absence of current alcohol or drug abuse. Additionally, a urine toxicology test will be 
performed to verify substance use. The total eligibility session length will be approximately 2 
hours. 
 
2. Pre-training assessments 
2.1 Behavioral Assessment 
 
The total behavioral assessment length will be approximately 3 sessions (can be combined into 1 
or 2 sessions), 2 hour each session (6 hours total). 
 
Behavioral assessments include standardized measures of neurocognition (MATRICS Consensus 
Cognitive Battery, Processing Speed Index of the WAIS-4), social cognition (Auditory Emotion 
Recognition, Penn Emotion Recognition Task, The Awareness of Social Inference Test), 
functional (i.e. everyday life) skills (UCSD Performance-based Skills Assessment, Global 
Assessment of Function, Specific Levels of Functioning Assessment), social skills (Social Skills 
Performance Assessment), and reading ability (Comprehensive Test of Phonological 
Processing). Assessment of current psychiatric symptoms will include the Positive and Negative 
Symptom Scale and the Columbia Suicide Severity Rating Scale, The Assessment for Treatment 
Emergent Events (SAFTEE) to assess current preexisting health issues prior to the start of the 
tDCS training sessions. 
 
2.2 Electroencephalography/Event Related Potential (EEG/ERP) sessions 
 
An EEG session will be completed before the experimental procedures. Electroencephalography 
(EEG) will be used to continuously record electrical brain activity from the scalp while subjects 
complete the tasks described below. In addition, 10 minutes of resting eyes open/closed EEG will 
be obtained, leading to 1:45 hr total recording time. The total session length, including the 
application and removal of the electrode cap and any required breaks, will be approximately 3 
hours. Based upon our prior experience, we expect this session length to be tolerable even for 
cognitively impaired individuals. 
 
EEG data will be obtained from Brain Vision electrode system with 24- 64 scalp electrodes, 
digitized at 500-1000 Hz. digital recording system (Brain Product GmbH, Gilching, Germany). 
 
ERP will be obtained to synthetic FM-tones that differ in pitch, intensity or HF500. The FM-
tones were developed by measurement of acoustic cues of the Juslin and Laukka’s prosody 
stimulus set. FM-tones were synthesized (Adobe Audition) to be 500 msec in length with a 
modulation frequency of 3 Hz (1½ cycles per tone), at a nominal intensity of 75 dB sound 
pressure level (1). The “standard” tone had moderate levels of F0M and F0SD (e.g., an 
F0M/F0SD of 125/125 Hz), and was designed to be emotionally ambiguous, while the deviants 
were designed to mimic specific emotions. The six deviants were modified from the standard 
tone as follows: 
1)   F0M: increased base pitch with unchanged pitch variability (i.e. 378 Hz/125 Hz); typically 
perceived as happy. 
2)   F0SD: unchanged base pitch with decreased pitch variability (i.e. 125 Hz/20 Hz); typically 
perceived as sad. 
3) HF500: adding an overlay of HF500 noise with unchanged pitch characteristics; typically 
perceived as angry or fearful. 

 
 
10
4)   Intensity: increasing the intensity (volume) to 85 dB with unchanged pitch characteristics; 
typically perceived as angry or fearful. 
5)   Dual (F0M/F0SD): varying both base pitch and variability (378 Hz/20 Hz); leads to a 
stimulus that differs physically from the standard, but does not convey a predominant emotion 
percept 
6)   Non-FM: a simple, non-FM modulated tone (125 Hz), which is perceived primarily as 
neutral or no emotion. 
7)   Stimuli will be presented through headphones with an interstimulus interval (ISI) of 250 
msec. During MMN testing, subjects will not be informed of the emotional intent, and watch a 
silent, unrelated movie. 
 
A multidimensional, “optimized” design will be used, allowing for multiple deviants to be 
assessed simultaneously. Four 950 tone blocks will be used, with each block divided into an 
“oddball” section, followed immediately by a “repetitive N1” section. In the oddball section, 
600 tones will be presented: Standard tones (300 total/50%) alternated with one of the six 
deviants (50 of each deviant tone per block ~8.33% for each deviant). The deviant tone cannot 
be the same as one of the previous four deviants. In the repetitive N1 section, 50 repeats of each 
of the seven tones (350 total tones, 50 each) will be presented. Thus, each tone was presented 
both as a deviant against a background of the more frequent, emotionally ambiguous “standard” 
stimuli in the oddball section and repetitively in the “repetitive N1” section. 
 
All standardized assessments (behavioral and electrophysiological) and interviews will be 
conducted by a trained rater. Dr. Elisa Dias will supervise collection of assessments and 
electrophysiology. 
 
2.3 Blood Draw 
 
BDNF/D-serine levels will be obtained at study baseline and after completion, and will be 
evaluated as potential mediators of both tDCS and cognitive remediation efficacy. Any 
additional blood remaining will be kept frozen at -70°C to be used if other potential biomarkers 
are developed over the course of the study. 
 
 
3.   Computer-based Training sessions 
 
After the first and final experimental training sessions, participants will complete questionnaire-
based measures of motivation (Intrinsic Motivation Inventory, Perceived 
Competency Scale, Treatment Motivation Questionnaire) to assess engagement. 
 
Eligible participants will be randomly assigned to one of three training programs: 
1) auditory remediation plus active tDCS; 
2) auditory remediation plus sham tDCS; 
3) computer game. 
 
All programs are 2-3 sessions per week of at least 30 minutes each tDCS training session, 
conducted over approximately 12-17 week period (34 tDCS training sessions total). During the 
auditory remediation training sessions subjects will receive either active or inactive tDCS. 
During the computer game program subjects will not receive active or sham tDCS. 
 

 
 
11
Participants in the auditory remediation conditions will sit at individual computer workstations 
and respond to auditory stimuli presented through headphones. Auditory exercises will entail 
computer-based activities designed to train ability to identify and differentiate between tones that 
vary in pitch, intensity, and frequency. The exercises provide feedback to participants to 
facilitate learning of acoustic cues to improve accuracy of auditory stimulus identification and 
discrimination. Level of difficulty for stimulus identification or discrimination is programmed to 
vary based on the performance of each individual such that as performance improves, task 
difficulty increases. After each tDCS training session, discomfort with tDCS will be assessed 
using the Wong-Baker Faces Pain Rating Scale and the Brunoni Questionaire for tDCS.   At the 
conclusion of each weekly session, participants will engage in a 10-minute discussion with the 
facilitator to bridge computer-based training to everyday life. No tDCS will be given during 
weekly discussion.  Discussion for active training will include topics aimed to enhance 
motivation for the exercises by providing a personally relevant functional context for auditory 
training. Discussion will also include study progress, enjoyment of computer activities and any 
issues relating to session adherence.  Also at the conclusion of every other weekly session 
(biweekly) and at the conclusion of the last week of training, clinical and medical symptoms will 
be assessed. 
 
The computer game is the condition where participants will work on commercially available 
puzzle games to control for clinician contact and the non-specific effects of mental stimulation. 
The schedule of computer-based activity will be the same as the auditory remediation.   
Participants will engage in a once weekly discussion with the session facilitator to discuss study 
progress, enjoyment of computer activities, and any issues related to session adherence. Also at 
the conclusion of every other weekly session (biweekly) and at the conclusion of the last week of 
training, clinical and medical symptoms will be assessed. 
 
tDCS: 
 
Stimulation will be performed using a battery-driven BrainStim SYS (Brainvision LLC, 
Germany), and transferred through two 7x5 cm sponge electrodes soaked in a saline solution 
(0.9% NaCl). tDCS electrode placement will be over frontal areas and bilateral mastoids. 
Localization of electrode placement will be established using the 10-20 EEG technique. Each 
stimulation session will last~30 minutes. 
 
tDCS stimulations will be administered by trained research staff member.  
Females of childbearing capacity will receive a urine pregnancy test monthly during computer 
based training sessions. tDCS cannot continue unless a negative result is obtained. 
 
4.    Post-training testing 
 
After completion of the computer–based training sessions, participants will be scheduled to 
complete post-training assessments which include behavioral tests, one session of EEG, and a 
blood draw as described above for the pre-training testing. They will also repeat the Tone 
Matching Task and the Audiometry (hearing test) that was done at screening. 
 
 
  
5. Risks 
Transcranial Direct Current Stimulation (tDCS) procedures: Risks associated with the tDCS 
procedures for this study are similar to risks associated with other tDCS studies, which are 

 
 
12
minimal. tDCS is presently a widely used research technique, most commonly in the areas of 
motor rehabilitation and depression. 
 
The risks to human subjects directly associated with tDCS administration include: 
a) Mild tingling sensation at the site of application during administration. 
This sensation ceases after treatment is completed. 
b) Mild headache 
c) Slight epidermal irritation, redness or burns at site of application 
d) Mild temperature changes at the site of application. 
 
The dosing of tDCS proposed in this study (2 mA x 20-40 min) are within the range used in 
recent and ongoing clinical studies. For example, in a recent study of 131 healthy subjects 
undergoing 277 tDCS sessions, no serious adverse events occurred. Side effects most commonly 
reported were tingling (76%), itching (68%), burning (54%), and pain (25%). Side effect severity 
was mild, with fewer than 2% of responses indicating a severity > 3 on all questions except 
tingling (15%), itching (20%), burning (7%), pain (5%), and fatigue (3%) during stimulation. 
Symptoms resolved promptly following termination of stimulation without long-term 
consequences. In rare cases, nausea or insomnia have been reported. Although formal toxicity 
studies have not been performed, doses of tDCS used in present clinical studies are at least two 
orders of magnitude below those that have been shown to produce brain lesions in rodent. 
 
Worsening of psychiatric condition: In addition to common tDCS side effects, the risk of 
repeated tDCS exposure in Sz is presently unknown. We have performed >100 individual 
sessions in patients with Sz without observing adverse effects on symptoms. Furthermore, in 
disorders such as depression, therapeutic effects have been observed from bifrontal tDCS. 
Nevertheless, given the lack of information there is a possibility of worsening of either symptoms 
or cognitive function (PANSS). These potentials will therefore be monitored biweekly by an 
independent safety monitor, as detailed in section procedures for minimizing risks below. As with 
all trials, there is a risk for development of suicidal ideation, which will be monitored biweekly 
using the Columbia-Suicide Severity Rating Scale as well. 
 
Electrophysiological EEG procedures: These studies entail the recording of EEG from the scalp 
employing standard sensors and amplification methods. These procedures are well standardized 
and there are few known risks. These are principally due to equipment malfunction. 
The recording equipment used in these studies meet the current design criteria for subject safety, 
including isolation from potential electrical hazards. 
 
Assessment/screening procedures: There are no known physical or psychological risks involved 
in taking these tests. Subjects may find the interviews about their psychiatric condition upsetting, 
and although the test procedures are designed to be relatively simple, some subjects might 
experience some frustration during the tests. 
 
Confidentiality:   There is a risk from study participation of loss of confidentiality 
 
Describe procedures for minimizing risks 
 
tDCS: Mild headache has been reported when tDCS is administered in some cases, but has been 
known to cease with acetaminophen, ibuprofen, or aspirin. Slight epidermal irritation at sight of 
application has been reported in some instances. Mild temperature change might be felt at the 
site of application. 

 
 
13
 
During the period of administration, the participant will be closely and regularly observed and 
asked to report any adverse effects. Subjects may opt to discontinue at any point. We will also 
regularly debrief subjects following tDCS sessions to detect patterns or procedures that might be 
associated with discomfort and will modify procedures as necessary. 
 
Additionally, we will monitor discomfort using Wong-Baker Faces Pain Rating Scale (WBFPRS) 
which we feel is readily understood by patients and provides general evaluation of discomfort. 
To date, data have been collected from 37 patient sessions in which active stimulation was used 
and 15 sham session. Discomfort during the active stimulation session was generally low (mean 
WBFPRSscore = 0.51 ± .87), corresponding to between “no-hurt” and “hurts little bit”. During 
sham, the mean scores were also low but non-zero for many subjects (mean score=.33 ± .82). 
The difference between scores was not significant (p=.48). No patient scored above a 2 on the 
scale, and no patient discontinued due to discomfort. 
 
In addition, we will incorporate additional measures as suggested by Brunoni et al. (24) to 
monitor discomfort and potential objective adverse effects of tDCS (e.g. skin redness). 
 
During this study, blinded Adverse Effects Summaries (AES) will be provided to the independent 
monitor who will evaluate to insure that adequacy of protection against risk is maintained, and 
will provide feedback to the PI and the research teams. In addition, any scores of 4 or 5 on the 
WBFPRS will be brought to the immediate attention to the PI, who will then review clinical 
procedures. 
 
Headache and dizziness are also known risks of tDCS. Anyone experiencing such symptoms will 
be monitored until symptoms resolve, and will be recontacted 24-48 hrs after the event to insure 
that there were no long-term sequelae. 
 
Adverse Effects (AEs) and Serious Adverse Effects (SAEs) will be reported to the IRB as per 
standard protocol, and will lead to review of procedures to determine whether alterations in the 
protocol or monitoring procedures are required. 
 
Worsening of psychiatric condition: 
In order to detect potential worsening of symptoms, patients will be assessed with the Positive 
and Negative  Syndrome Scale (PANSS) ratings biweekly during the training program. 
PANSS ratings, including positive, negative and cognitive factors, will be reviewed in a non-
blinded fashion by the independent monitor to insure that there is no significant worsening in the 
tDCS vs. sham group. 
 
In addition, subjects showing >10 pt worsening on PANSS or > 2 pt worsening on psychosis 
items will have case reviewed to determine potential causes and, if appropriate, will have 
tDCS/AR treatments temporarily withheld for up to 2 weeks. All attempts will be made to 
maintain patients on stable doses of antipsychotic throughout the study. However, in cases of 
worsening of symptoms, increases of up to 50% of dose will be permitted without removing 
patients from the study. 
 
In addition to PANSS ratings, we will also maintain close contact with treating clinicians and 
instruct them to contact the research team should they notice worsening of symptoms during 
clinical treatment. 
 

 
 
14
Suicidality: It is expected that patients participating in this study will be clinically stable. 
Nevertheless, because tDCS may affect mood symptoms and because effects of repeated tDCS in 
Sz are unknown, patients will be rated biweekly using the Columbia-Suicide Severity Rating 
Scale (25,26). Significant suicidal ideation will be reported immediately to the PI or his 
designee, who will insure appropriate treatment intervention. 
 
General side effects: General side effects will be assessed biweekly using the Systematic 
Assessment for Treatment Emergent Events (SAFTEE) scale (27), and will be provided in a 
unblinded fashion to the independent monitor.  All significant side effects will be reported to the 
PI, and appropriate intervention will be initiated. 
 
Independent individual/safety officer:  Because of potential discomfort induced by tDCS, Dr. 
Joshua Kantrowitz will serve as an unblinded independent individual/safety officer. Dr. 
Kantrowitz is a board certified psychiatrist. Dr. Kantrowitz will have access to unblinded subject 
safety ratings biweekly, and will monitor quarterly the side effect frequency between groups. Dr. 
Kantrowitz will notify the PI should there be significant imbalance in rate of side effects between 
active and sham treatment, in which case appropriate adjustments will be made to the sham 
stimulation protocol, or if an excess of painful events occur (Wong-Baker score >3), in which 
case procedures which be reviewed. Dr. Kantrowitz will also review biweekly subject PANSS, 
suicide (CSSRS scores), and SAFTEE scores to insure that no unanticipated side effects are 
observed. 
 
Electrophysiological EEG procedures 
Regular preventative maintenance and careful attention to recording procedures further 
minimize the already insignificant risks of electrophysiological recording. Electrodes and 
materials used for affixing them in place are kept scrupulously clean and sterilized and materials 
are utilized which minimize the chance of skin and scalp irritation 
 
Patients will be instructed to clean their hair following the procedure to minimize irritation. 
 
Subjects may find it upsetting to discuss their medical or psychiatric problems, but this is not 
different from interviews conducted during routine medical care. Participants may find the EEG 
or computer tasks tiring or difficult and may experience mental fatigue and transient stress from 
the neuropsychological testing. 
 
Blood drawings: Phlebotomy will be performed by trained phlebotomist using sterile technique 
to minimize possibility of contusion or infection. 
 
Assessment/screening procedures: Frequent breaks will be given as needed. Subjects will be 
reassured that they will not have to answer questions that cause discomfort. 
 
Confidentiality: Every effort will be made to protect the participant’s confidentiality. 
 
6. Consent Process 
Subjects selected for the study will be fully informed of the nature and scope of the study.  
Research study staff who have had consent training through the Clinical research division will 
meet with interested prospective participants.  A complete description of the protocol will be 
given including potential risks and benefits and other significant elements of the consent 
(including confidentiality, voluntary nature of research).  In addition, prior to approaching 
patients, we discuss patients who meet eligibility criteria with their treatment teams. For CREF 

 
 
15
inpatients, we will be in contact with the patient’s treating psychiatrist, and for outpatients, we 
will be in contact with a member of the patient’s treatment team/patient’s doctor to discuss the 
study and the patient’s participation. The consent process involves review of the consent form 
and the HIPAA addendum, along with additional elaboration of all elements and answering any 
questions the participant may have and asking questions to assess the participant’s 
understanding of the informed consent document. When all of the participant’s questions have 
been answered and the research study staff is satisfied that the participant understands the study, 
has had an opportunity to evaluate the risks and benefits of participation and voluntarily 
consents to participate in the study, the participant and the research study staff member will sign 
the informed consent document. 
Consent to participate by CREF inpatients and RPC outpatients is documented in their 
electronic medical record in the form of a chart note and consent form. Records of informed 
consent for all participants are maintained in the subject’s research record.  The subject is given 
a copy of their consent form and a copy of the NKI Privacy Practices form. 
 
Capacity will be assessed by the Treating Psychiatrist or licensed professional who is not 
directly involved in the research. 
 
7. State whether any drugs tested are approved by FDA, are under an IND (Investigational New 
Drug Application), or are marketed products being used “off-label”.   
No drugs are tested for this study. 
 
8. State whether any devices are under an IDE or Abbreviated IDE 
 
The device, BrainStim SYS (Brainvision LLC,Germany), has an abbreviated IDE    
CE Reg#MED30003 
There is a label on the device which contains: the name of the device, the manufacturer, a 
model and serial number.  We have placed a label on the device that states: “CAUTION--
Investigational device limited by Federal (or United States) law to investigational use." 
Since the device itself is quite small, an additional label with all warnings and precautions 
will not fit on the device.  We have placed a label on the device case. 
The manual for the device is located in the device case (where we keep the device when not 
in use) and it describes all relevant warnings and precautions. We have a label on the 
device case that states: “This case contains the device manual describing all relevant 
warnings and precautions”.  
 
9. Issues requiring special attention of the IRB 
None. 
 
B.  SUBJECT POPULATION: 
Sample Size: 
We project we will need to enroll 60 patients in order to have 45 completers. 
 
Age Range (indicate whether children, subjects under age 18, will be enrolled): 
18-55 
 
Diagnostic Groups:  
Schizophrenia or Schizoaffective Disorder 

 
 
16
 
Ethnic, Race and Gender Breakdown:  
Participants will be representative of the respective population (ethnicity, race and gender) at the 
recruitment site.  No racial or ethnic group will be specifically included or excluded. 
 
  
Also, indicate below whether the sample represents the minority and gender distribution of the population or 
immediate geographic area from which the sample is drawn.  Explain if any specific groups are excluded.  
Indicate whether each gender and minority group will be represented in sufficient numbers to allow 
statistical analysis of the results for each group.  Explain if the representation will not be sufficient.  Note: 
Although every effort should be made to include sufficient numbers of women and minorities, there are 
acceptable reasons why this cannot or need not always occur such as pilot studies, condition limited to one 
gender, limited access, limited resources, or multi-center studies where total numbers will be representative.  
If gender and/or minorities are excluded, provide a clear rationale for their exclusion. 
 
No racial or ethnic group will be specifically included or excluded.  Participants will be 
representative of the respective population (ethnicity, race, and sex) at the recruitment site.   
 
 
C. 
RECRUITMENT METHODS: 
 
• 
If advertising for subjects, describe the process and attach to this form any letters to be 
sent, texts of advertisements or other material to be used in recruitment.  If not available 
now, this material must be approved by the IRB before use. 
 
We will not be advertising at this time.  If we decide to advertise, we will submit 
material to the NKI IRB for approval first. 
   
 
 
 
• 
If screening patient medical records to identify possible subjects, please so indicate below 
and complete the form “Request for HIPAA Waiver of Authorization and/or Waiver of 
Consent under 45 CFR 46.116(d)”. 
 
Screening will be done by staff in our division.  A HIPAA Waiver of Consent is 
attached and a phone screening script.   
We will use the phone screen to call outpatients that have been referred to us by 
the Volunteer Recruitment Program (VRP) at NKI. The Volunteer Recruitment 
Program at NKI recruits from NYS office of Mental Health facilities. The VRP 
recruits outpatients living on the grounds at CLUE I and II, Conway House(Loeb 
House), from Rockland County Department of Mental Health facilities and from 
the community.  We will use the phone screen to see if the outpatient is interested 
in participating in the study and to obtain any screening information specific to 
this study.  We will also use the phone screen to call outpatients who have 
participated in IRB approved studies conducted by Daniel Javitt, M.D., Ph.D., 
(those who have agreed to be recontacted for other studies) to see if they are 
interested in participating in this protocol and if they are willing to answer phone 
screening questions.  We do not have a treating relationship with these potential 
outpatients. If the outpatient meets phone screen criteria and agrees to come in and 
sign consent and the HIPAA addendum to participate in the study, prior to starting 
the intervention, we will to speak with the outpatient’s psychiatrist about the study, 

 
 
17
the outpatient’s participation in the study(whether there is any issue with the 
subject participating in the study) and whether the psychiatrist’s plans to keep the 
outpatient’s medications stable.  
 
We will also use the phone screen for outpatients who call from the community (i.e. 
saw study on Clinical trials.gov). If the outpatient is interested in participating in 
the study and in answering phone screening questions, we will obtain screening 
information. We do not have a treating relationship with these potential 
outpatients. If the outpatient meets phone screen criteria and agrees to come in and 
sign consent and the HIPAA addendum to participate in the study, prior to starting 
the intervention, we will need to speak with the outpatient’s psychiatrist about the 
study, the outpatient’s participation in the study(whether there is any issue with the 
subject participating in the study) and whether the psychiatrist plans to keep the 
outpatient’s medications stable.   
 
For CREF inpatients, we should be able to get the phone screen information from 
the medical records or the patient’s treating psychiatrist on CREF.  However, if we 
are unable to get screening information from medical records or patient’s 
psychiatrist, we may need to speak to the patient on CREF and talk to them about 
the study and their willingness to answer some study specific screening questions.   
We will also speak to the treating psychiatrist about the patient’s participation in 
this research (whether there is any issue with participating in the study and whether 
the psychiatrist plans to keep the patient’s medications stable).  
 
 
 
• 
If recruiting by other means, such as referrals from community physicians, please describe  
below. 
 
We will not be actively recruiting from community physicians, however, we will 
accept referrals from the community (physicians, friends, and family of the 
patients). 
We will use the phone screen for outpatients who call from the community (i.e. saw 
study on Clinical trials.gov). If the outpatient is interested in participating in the 
study and in answering phone screening questions, we will obtain screening 
information. We do not have a treating relationship with these potential 
outpatients. If the outpatient meets phone screen criteria and agrees to come in and 
sign consent and the HIPAA addendum to participate in the study, prior to starting 
the intervention, we will need to speak with the outpatient’s psychiatrist about the 
study, the outpatient’s participation in the study(whether there is any issue with the 
subject participating in the study) and whether the psychiatrist plans to keep the 
outpatient’s medications stable.   
 
 
D.      RISKS AND BENEFITS: 
 
1.  Describe the risks presented by study procedures and interventions, including the expected 
frequency of the risks.   Include all physical and nonphysical risks.  (e.g., emotional distress, 
economic harm, legal jeopardy, breach of confidentiality).   
 
 
Risks are described above in item 5. Risks 

 
 
18
 
2. If the research presents more than minimal risk to subjects, describe all measures designed to 
minimize the risks.  When applicable, describe inclusion, exclusion and drop-out criteria 
intended to minimize risks and describe any procedures for follow up such as when subjects are 
found to be in need of medical or psychological referral.   
 
 
Minimizing risks are described above in item 5 . Risks 
 
3.  Describe any potential for direct benefit to individual subjects as well as the benefit to society 
based on the scientific knowledge to be gained.   These two types of benefits should be clearly 
distinguished in your discussion. 
 
E. 
CONSENT PROCESS AND PATIENT CAPACITY: 
1. Indicate Who Will Obtain Consent, Assess Capacity, and Under What Circumstances:  
 
(Include name and title of these individuals)  
 
Consent for this project will be obtained by Odeta Beggel, MA, Constance Shope, Ph.D. or 
Gail Silipo, M.A.  All have had consent training through the Clinical Research Division. 
Capacity will be assessed by a Treating Psychiatrist or licensed professional who is not 
directly involved in the research. Capacity will be assessed by Drs. Fabien Tremeau, 
Russell Tobe or his designee in the Outpatient Research Division or Dr. Karen Nolan. 
 
 
 2.  Will Individuals Potentially Lacking Capacity to Consent be Considered for Inclusion As 
Subjects:   
 
No.  Patients who lack capacity will not be considered for inclusion in this study. Capacity 
will be assessed by the Treating Psychiatrist or licensed professional who is not directly 
involved in the research. 
 
 
 
If yes, list name(s) and title(s) of persons who will assess capacity (Note: The person(s) 
who assess capacity must be a psychiatrist or a licensed psychologist who is independent of 
the research.):   
 
Capacity will be assessed by Dr. Fabien Tremeau, Dr. Russell Tobe or his designee in the 
Outpatient Research Division or Dr. Karen Nolan. 
 
F. 
COMPENSATION: 
 
Will subjects receive any compensation?     Yes_√____     No_____ 
 
If yes, indicate how much and criteria for payment.  Include method of pro-rating payment, if any, 
for subjects who do not complete the study. 
 
Subjects will be paid $20 for the eligibility screening, $60 for the pre training 
behavioral assessments, and $30 ($10 per hour) for completion of the EEG 
research procedure and $5 for the blood draw. Subjects will be paid $10 per 
tDCS/training/discussion/and assessment sessions (34 sessions) for a total of 
$340 and $60 for the post behavioral assessments and $30 for completion of the 
post EEG and $5 blood draw.  Subjects who complete the study will be paid a 

 
 
19
bonus of $50. The maximum total amount for the whole study will be $600. 
Participants will be paid for the time completed. They will not receive the bonus 
if they do not complete the study. 
 
 
 
G. 
CONFIDENTIALITY:  Describe means by which privacy of both paper and electronic files will 
be protected and confidentiality maintained.  If a Certificate of Confidentiality will be obtained, 
please indicate.  
 
Note: All study data whether on paper or in encrypted electronic records or devices must be 
stored in locked files in a secured office. All electronic data containing PHI must be kept on the 
“HIPAA drive” or, when portability is required, on a hardware-encrypted device that has been 
approved by ISD. 
 
Research information obtained will not be identified with participants’ names; we will 
use a code. All paper data will be kept in locked cabinets and in locked offices. 
Electronic data will be stored in a HIPAA password protected directory.  Any behavioral 
data that is collected on laptop computer will be collected on an ISD approved laptop 
that has been encrypted and has password protections which have been put into place by 
ISD.   
 
 
 
H.     
CONFLICT OF INTEREST:   In order for the IRB to determine whether financial interests pose   
 
a potential for bias that might affect the rights and welfare of the human subjects or the credibility  
 
of the research, please briefly describe any financial relationship the principal investigator or other 
 
researchers on this project may have with the study sponsor (other than funding this project) or any  
 
financial interest in the product being tested. 
(Note:  "“No conflict of interest” or “N/A” is not responsive to the question being asked.  
The question asks about financial relationships with the sponsor or financial interests in 
the product. These interests and relationships need not be conflicts.  If no relationships or 
interests exist the answer should be “None” or a similar response.) 
None. 
 
 
I. 
OTHER ISSUES:  Does this protocol raise any other sensitive issues concerning human subjects  
which would be of concern to the IRB or NKI Administration?  If so, please elaborate. 
 
 
No. 
 
 
 
 
 
Revised 3/24/15