Improving Visual Hallucinations by Targeting the Visual Cortex With Electrical Stimulation: A Feasibility Study
Phase: NA
Conditions: Schizophrenia, Schizoaffective Disorder, Bipolar Disorder
Sponsor: Beth Israel Deaconess Medical Center

Feasibility Electrical Stimulation Study for Visual 
Hallucinations 
 
 
NCT #: NCT04870710 
 
January 2nd, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol Number:  
2019P001016 
Title: 
Feasibility Electrical Stimulation Study for Visual Hallucinations 
Design:  
Open Label, Non-randomized, Crossover Design with Baseline, Day 
5 and 1 Month follow up visits during which tES (Cathodal tDCS & 
2hz tACS) were delivered to the visual cortex from Baseline to Day 
5 each day (5 days) twice a day for 20mins. Participants first 
entered the cathodal tDCS condition first and then after a washout 
period (~2 weeks) entered the 2hz tACS condition to test the 
effectiveness and feasibility of stimulating the visual cortex using a 
novel targeting methodology consisting of a lesion network guided 
brain target near V5/MT. 
Objectives:  
 
Enrollment:  
10 Individuals 
Clinical Sites:  
Beth Israel Deaconess Medical Center, Boston, MA 
Patient Population:  
Male or female outpatients 18-50 years of age patient’s diagnosis 
with either schizophrenia, schizoaffective disorder, or psychotic 
bipolar as defined by DSM-5 or DSM-IV-TR criteria 
Primary and Secondary 
Outcomes:  
Primary Outcomes: Steady-State Visual Evoked Potentials (SSVEP); 
Positive and Negative Syndrome Scale (PANSS); Biological Motion 
Secondary Outcomes: Global Assessment of Functioning (GAF); 
Velocity Discrimination; International Affective Picture System 
(IAPS) Task; Montgomery-Asberg Depression Rating Scale (MADRS) 
Inclusion Criteria:  
1. Meet diagnostic criteria for schizophrenia, schizoaffective 
disorder, or psychotic bipolar disorder as verified by the 
Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, 4th Edition, Text Revision 
(DSM-IV TR) and consensus clinical diagnosis; 
2. had no changes to relevant anti-psychotic medications for 
a period of 1 month prior to participation; 
3. had a sufficient level of English to allow participation. 
4. 18-50 years of age 
In addition to the criteria above, participants for this stimulation 
procedure will be included if they have a history of VH or experiencing 
moderate symptoms of VH; had no changes to relevant anti-psychotic 
medications for a period of 1 month prior to participation; and do not 
have a history of moderate-to-severe visual impairment secondary to 
glaucoma, cataract or macular degeneration. Additionally, individuals 
will need to score above 20 on the Mini Mental Status Examine to be 
included in the study. 
 
Exclusion Criteria:  
1. metal implants in head. 
2. implanted electronic devices. 
3. history of neurological problems, seizure or head injury. 

4. skin sensitivity. 
5. claustrophobia. 
6. organic brain syndrome 
7. intellectual disability or other cognitive dysfunction that 
could interfere with capacity to engage in study as determine 
by the PI 
8. a history of substance or alcohol abuse or dependence 
(other than nicotine) in the last 6 months or otherwise unable 
to commit to refraining from alcohol use during the acute 
period of study participation. The acute period of study 
participation is defined as during their visit and 24 hours 
before and after their visit.  
9. Significant suicidal ideation or those who have enacted 
suicidal behaviors within 6 months prior to intake will be 
excluded from study participation and referred for appropriate 
clinical intervention.  
10. Serious medical illness or instability requiring 
hospitalization within the next year. 
11. Experience with any cardiac event. 
12. Pregnant women, lactating women, women who are 
breastfeeding and women of childbearing potential who are 
not using medically accepted forms of contraception (e.g., IUD, 
oral contraceptives, barrier devices, condoms and foam, or 
implanted progesterone rods stabilized for at least 3 months). 
Statistical 
Methodology: 
Within and Between comparisons to statistical detect differences 
in symptoms, visual tasks and electrophysiology measures before 
and after treatment conditions (cathodal tDCS and 2hz tACS). To 
determine the effectiveness and feasibility of targeting the visual 
cortex with a novel targeting methodology to engage target 
outcomes 
 
 
 

Statement: The design, conduct and reporting of this trial shall be conducted in accordance 
with the protocol, the United States 45 Code of Federal Regulations (CFR) part 46 known as 
“The Common Rule”, 45 CFR 164.502(d), and 164.514(a)-(c) known as “The Privacy Rule” of the 
Health Insurance Portability and Accountability Act (HIPAA), and the International Conference 
on Harmonization (ICH)/Good Clinical Practice (GCP). All Investigators will have documented 
training in The Collaborative Institutional Training Initiative (CITI Program) in Biomedical 
Research and GCP.  
Background: Functional neuroimaging studies have identified neural correlates of VH across 
multiple brain regions and support hypotheses that increased visual cortex activity and sensory 
cortex over-stimulation generate VH (Zmigrod et al., 2016, Manford et al., 1998, Allen et al., 
2008, Ffytche et al 2008). Using lesion network mapping, researchers found that the 
extrastriate visual cortex was causal linked to the development of (Kim et al., 2019). The 
association between extrastriate visual cortex activation and VH would suggest this region may 
be optimal for modulation via brain stimulation. While tDCS is a promising adjunctive treatment 
of auditory hallucinations and negative symptoms in schizophrenia, less is known about its role 
in treating VH. To date, two cases have been described where cathodal tDCS over the occipital 
area was applied to patients experiencing treatment refractory VH, and this resulted in 
symptomatic improvement (Shiozawa et al., 2013, Koops et al., 2017).  
 
Transcranial Electrical Stimulation (tES): tES is a non-invasive brain stimulation technique 
which modulates cortical excitability by a weak electrical current [< 4 milliamps (mA)] between 
two electrodes via direct current (DC), alternating current (AC), random noise (RN) or oscillatory 
current (OC).This study will utlize cathodal tDCS and 2hz tACS. Five day of twiice a day tES will 
be  
 
Electroencephalography (tES): EEG is a routine, non-invasive procedure to record brain acivity. 
EEG electrodes will be attached to the skin, indirectly. Most of the electrodes are mounted in 
an elastic cap, which is fitted over the head and held in place with elastic straps. Some 
additional electrodes are placed next to the eyes, on the forehead, or behind the ears, and are 
held in place with adhesive collars. Electrical contact between the skin and the electrodes is 
achieved via a water-soluble electrode gel. 
 
Study Rationale: The visual system is an important site of pathology in patients with 
schizophrenia, schizoaffective disorder, bipolar disorder, Parkinson’s disease, Lewy body 
dementia, Charles Bonnet syndrome, and brain lesions experiencing visual hallucinations. Visual 
symptoms are associated with worse poorer outcome and treatment refractoriness. A recent 
study identified a causal location in the extrastriate visual cortex with visual hallucinations (VH). 
Two case studies have found that transcranial electrical stimulation of the occipital cortex 
improved VH in treatment refractory patients with visual hallucinations. While promising it is 
unclear whether the symptom reductions resulted from activity changes in the visual cortex or 
not. Here we aim to answer the question whether high definition transcranial direct current 
stimulation when optimally targeted to a specific brain region (extrastriate visual cortex) can 
engage the target and improve behavioral symptoms. 

Study Protocol:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Day 5 
1 Month 
Cathodal HD-tDCS 
Washout 
Enrollment 
2 Sessions X  
 5 Days  
Baseline 
Day 5 
1 Month 
2hz (Delta) HD-tACS 
Crossover 
End of Study 
2 Sessions X  
 5 Days  
Study Timeline 

Study Visits and Details: 
 
Participants will complete baseline clinical, neuropsychological, visuoperceptual and neuro-
physiological assessments (day 0), short-term follow-up (day 5) and long-term follow-up (month 
1). 
 
Pre-Screening 
Subjects will be prescreened. If the subject appears to qualify for the study, they will be invited 
in for a screening and baseline visit.  
 
Screening and Baseline Procedures (approximately 3-4 hours) 
Screening and baseline procedures will be conducted in the Massachusetts Mental Health Center 
(MMHC)/ Beth Israel Deaconess Boston. The urine toxicology screen and pregnancy test will be 
completed at MMHC or within Beth Israel Deaconess Boston. 
 
• Eligibility pre-screen will include a telephone pre-screening questionnaire that will assess 
basic inclusion and exclusion criteria.  
• Eligibility screen will include a screening questionnaire that will assess more details related 
to inclusion and exclusion criteria and will be conducted in-person during the clinical 
diagnostic session (i.e., the first visit to the laboratory). 
• Informed consent will be obtained 
• Urine toxicology screen 
• Urine pregnancy testing for females of childbearing age 
Subjects will be informed that if they do not pass the urine toxicology screen (other than 
prescribed medication), they will be withdrawn from the study and will not receive 
compensation for the initial visit. This will be made clear in the pre-screening 
questionnaire.  
• tES screening questions for tES participation  
• Demographics: Subjects will be asked to provide standard demographic information (age, 
sex, race/ethnicity, level of education, cohabitation status) using forms employed in 
previous studies. 
• Psychiatric, medical, substance use history and medication review   
• Signing a release to allow for access to recent psychiatric records, if confirmation of 
medications or psychiatric history is necessary 
• If subjects have previously had a structural MRI performed through BSNIP2, they will be 
asked for permission to review these scans for use in neuronavigation. 
 
 
 
 

OBJECTIVES  
Primary Objective  
The primary objective of this study is to evaluate the effectiveness of tES (cathodal tDCS and 
2hz tACS) improving the positive symptoms and negative symptoms associated with psychosis 
along with electrophysiology outcomes and motion perception.  
Secondary Objectives  
The secondary objective of the study is to evaluate the safety and tolerability of tES as well as 
secondary clinical outcomes including depression and global functioning and other visual 
domains.  
Clinical Outcomes: Symptom ratings will be collected using the Montgomery-Asberg 
Depression Rating Scale, Global Assessment of Functioning, Positive and Negative Syndrome 
Scale 
Electrophysiology Outcomes: To probe the oscillatory capacity of the visual cortex (i.e., visual 
sensory integration), a steady state visual evoked potentials (ssVEP) task will be implemented. 
Addiotnally, participants will be asked to perform an emotional response VEP using the 
International Affective Picture System (IAPS). 
Computerized visuoperceptual tasks: The following visual perceptual functions will be 
evaluated: visuospatial working memory, velocity discrimination, biological motion 
 
 
 
 
 
 
 
 
 

Diagnostic Assessments 
 
Structured Clinical Interview for DSM-IV (SCID) 
 
This is a structured clinical diagnostic screening interview for subjects 15 and older. It is used to 
diagnose Axis I disorders including modules on depression, mania, psychosis, alcohol and 
substance use, anxiety, somatic and eating disorders.  
 
This will also be used when possible to confirm the diagnosis of schizophrenia in the first degree 
family member for the familial high risk group. Interview with a knowledgeable family member 
or copy of medical record is also acceptable to confirm the diagnosis. 
 
It is possible that a potential participant is referred to this study from one of our other studies.  
In this case, if a previous diagnostic interview was done using the SCID then the clinician should 
obtain a BIDMC Release of Medical Information between the SPARCS study and the other study 
so the original SCID can be used as long it is updated. Be sure to check with the original study 
for the authorization dates to be used on the release (from the start of their participation in 
that study until study completion) so the correct dates are added to the release of information 
form. Depending on the length of time since the original SCID modules should be updated as 
needed. If longer than a month since the original SCID then the following updates should be 
done for: 
 
1. Major depressive and manic symptoms in the past 30 days in the affective module A. 
2. Inquire if there have been other mood episodes since the last SCID and determine if 
there has now been a past “worst” episode of depression or mania; if so evaluate past 
affective episodes. 
3. Inquire if there has been a change in psychotic symptoms since the last SCID. 
4. Inquire about current alcohol and substance use and evaluate for abuse or dependence 
if needed. 
5. Inquire if there have been any changes in the anxiety, PTSD, somatic or eating disorders 
modules. 
 
Clinical Assessments 
 
Positive and Negative Symptom Scale (PANSS) 
The ratings are based on a clinical interview, conducted by trained clinical staff, covering all of 
the items in the rating scale. 
 

● This rating scale is meant to capture many different types of symptoms including 
positive, negative and general psychopathology symptoms. The ratings are based on 
a clinical interview with the participant.  
● All items are completed for the past week.  
● Always use the manual with anchor points when scoring and do not try to score 
from your memory of the anchor points or by their headings (mild, moderate or 
severe).  
 
 
Montgomery and Asberg Depression Rating Scale (MADRS) 
 
Interviewer:  
The questions in bold for each item should be asked exactly as written. Often these questions 
will elicit enough information about the severity and frequency of a symptom for you to rate the 
item with confidence. Follow-up questions are provided; however, for use when further 
exploration or additional clarification of symptoms is necessary. The specified questions should 
be asked until you have enough information to rate the item confidently. In some cases, you may 
also have to add your own follow-up questions to obtain necessary information. 
 
*Ratings should be based on the patient's condition in the past week. 
 
Referent of "usual" or "normal" condition. Several of the interview questions refer to the 
patient's usual or normal functioning. In some cases, such as when the patient has Dysthymia or 
Seasonal Affective Disorder, the referent should be to the last time they felt OK (i.e., not 
depressed or high) for at least a few weeks. 
 
*Rate the highest level of psychopathology. When in doubt, rate up and record the higher score. 
 
 
Global Assessment Functioning (GAF) 
 
Consider psychological, social, and occupational functioning on a hypothetical continuum of 
mental health-illness. Do not include impairment in functioning due to physical (or 
environmental) limitations.  
 
Indicate appropriate code for the LOWEST level of functioning during the week of POOREST 
functioning in past month. (Use intermediate level when appropriate, i.e., 45, 68, 72). 
 
 
 
 
 
 
 

 
 
 

Visual Hallucinations Montages: 
 
Ensure to mark electrodes for stimulation and that correct settings are adjusted on tES device.  
tDCS Montage:  
 
Active Stimulation: 
 
 
 
 
 
tACS Montage: 
 
Active Stimulation: tACS montage is the same montage as above. In the case of running a 
tACS participant, PO7, P6, P08 and AF7, AF8, P9, O1, P10 amps are the same. Frequency set to 
2hz. 
 
 
 
 
 
 
 
 

EEG Tasks Directions:  
 
IAPS   
 
For the next 12 minutes you will be presented with a series of 1-second photographs, which will show 
pleasant, unpleasant and neutral scenes.  Some of the pictures may make you feel uncomfortable so if 
at any point you want to stop please let me know.  There will be a red dot at the center of each picture, 
so try to keep your eyes centered on that.  
 
Visual Steady State   
 
For this last task, you will see a series of flashing red/white squares and black/white squares on the 
screen that will look like a strobe effect. They will appear in the center, left, right or both sides of the 
screen but please try to keep your eyes focused on the plus sign in the center of the screen. Every time 
you see the red/white squares, press the number 1 and you won’t press anything when you see the 
black and white squares. This will last for 16 minutes with a break in between.  
 
IAPS Survey 
 
This is a survey about the pictures that you saw earlier and we want you rate each picture on 2 scales. 
The first scale is pleasantness, 1 is happy and 9 is unhappy and the second scale is arousal, 1 is 
stimulated and 9 is bored. There are 60 pictures and please use your best judgment. Do you have any 
questions? 
 
 

Visual Assessments 
 
Three visual assessments will be undergone for all participants: visual working memory, 
biological motion and speed discrimination. These tests are run via MATLAB and Eclipse IPE, 
respectively  
 
Set-Up: 
 
1. Connect Mac Mini to eye-tracking computer 
a. Black thick wire (taped and marked “TDCS”) with Mac adaptor 
2. Move the head and chin rest to be 75 cm from the monitor (marked with tape on the 
floor) 
3. Attach keyboard to computer and place on desk 
4. Use alcohol wipe to clean: 
a. Forehead and chin rest 
b. Keyboard 
5. Open up “Visual Assessment Instructions” PowerPoint 
a. You will use this to describe the tasks to the participant 
6. Open up “Eclipse IPE” 
a. Load in “speedDiscriminationnoClut.java” and “oddOneOut.java” 
7. Open up “MATLAB” 
a. Load in “walker_nonoise_task.m” and “biomotionwalkerwithnoise.m” 
 
 

DATABASE Quality Assurance and Analysis 
The clinical database will be reviewed and checked for omissions, apparent errors, and values 
requiring further clarification using computerized and manual procedures.  
Description of Study Endpoints  
Primary Endpoint  
Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score after 1 week 
of tES. Change from baseline in SSVEP voltage after 1 week of tES. Change from baseline in 
Biological Motion task total score after 1 week of tES.  
Secondary Endpoints  
Change from baseline in GAF total score after 1 week of tES. Change from baseline in MADRS 
voltage after 1 week of tES. Change from baseline in velocity discrimination and visuospatial 
working memory task total score after 1 week of tES.  
General Statistical Considerations  
All collected study data will be collected on Redcap and processed using R and Matlab software. 
Descriptive statistics (n, mean, standard deviation, median, minimum and maximum) will be 
calculated by treatment group for continuous variables.  
Primary Analyses  
Primary Analysis of the primary, secondary, and additional efficacy endpoints:  
Mixed Model Repeated Measures analysis (MMRM)/non- parametric methods will be used to 
compare using within group differences as well as to determine the difference between the two 
treatment groups on the primary endpoint depending on the distribution of the data.