Causal Lesion Network Guided Treatment of Bipolar Mania With Transcranial Electrical Stimulation
Phase: NA
Conditions: Bipolar Disorder, Schizo Affective Disorder
Sponsor: Beth Israel Deaconess Medical Center

 
 
Causal Lesion Network Guided Treatment of Bipolar Mania 
With Transcranial Electrical Stimulation 
 
NCT #: NCT05445466 
 
June 23, 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
Protocol Number:  
2022P000295 
Title: 
Causal Lesion Network Guided Treatment of Bipolar Mania With 
Transcranial Electrical Stimulation 
Design:  
Double blind, design with baseline, day 5, 1 month and 3 month 
follow up visits during which transcranial electrical stimulation 
(tES) was delivered to the right orbital frontal cortex (rOFC) from 
baseline to day 5 each day (5 days) twice a day for 20 mins. 
Participants were randomly assigned to either cathodal transcanial 
direct current (tDCS), 10hz or personalized transcranial alternating 
current (tACS) conditions to test the effectiveness and feasibility of 
stimulating the rOFC using a novel targeting methodology 
consisting of a lesion network guided brain target linked to mania 
symptoms. 
Objectives:  
Evaluate the effectiveness and safety of transcranial electrical 
stimulation for improving the mania symptoms 
Enrollment:  
14 Individuals 
Clinical Sites:  
Beth Israel Deaconess Medical Center, Boston, MA 
Patient Population:  
Male or female outpatients 18-65 years of age patient’s diagnosis 
with either bipolar or schizoaffective disorder, or history of mania 
as defined by DSM-5 or DSM-IV-TR criteria 
Primary and Secondary 
Outcomes:  
Primary Outcomes: Young Mania Rating Scale (YMRS); Altman Self-
Rated Mania Scale (ASRM); Average Hospitalizations 
Secondary Outcomes: Balloon Analogue Risk Task (BART); The 
Go/No Go Task; Reinforcement Learning Task (RLT); Social 
Functioning Scale (SFS); Positive and Negative Syndrome Scale 
(PANSS); Global Assessment of Functioning (GAF); Barret 
Impulsiveness Scale (BIS); Resting State EEG; Brief Assessment of 
Cognition (BAC); Montgomery-Asberg Depression Rating Scale 
(MADRS) 
Inclusion Criteria:  
1. Aged 18-65 years of age 
2. Proficient in English 
3. Able to give informed consent 
4. Meet diagnostic criteria for bipolar disorder or 
schizoaffective disorder, bipolar type as verified by the 
SCID 
5. History of mania ( >1 lifetime episode) 
6. Experiencing mild to moderate symptoms of mania 
7. No changes to mood stabilizing medications for a period of 
2 weeks prior to participation 
8. Has not recently participated in tES/TMS treatments 

In addition to the criteria above, participants for this stimulation 
procedure will be included if they have a history of mania and may 
or may not be experiencing symptoms currently.  
 
Exclusion Criteria:  
1. Substance abuse or dependence (w/in past 6 months) 
2. Those who are pregnant/breastfeeding 
3. History of head injury with > 15 minutes of loss of 
consciousness/mal sequelae 
4. DSM-V intellectual disability 
5. Having a non-removable ferromagnetic metal within the 
body (particularly in the head) 
6. History of seizures 
 
Statistical 
Methodology: 
Within and between comparisons to statistically detect differences 
in symptoms, tasks and electrophysiology measures before and 
after treatment conditions (cathodal tDCS, 10hz and personalized 
tACS). To determine the effectiveness and feasibility of targeting 
the rOFC 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: Mania is a core symptom of bipolar disorder involving periods of euphoria. 
Decreased inhibitory control, increased risk-taking behaviors, and aberrant reward processing 
are some of the more recognized symptoms of bipolar disorder and are included in the 
diagnostic criteria for mania. Current drug therapies for mania are frequently intolerable, 
ineffective, and carry significant risk for side effects. Presently there are no neurobiologically 
informed therapies that treat or prevent mania. However, using a newly validated technique 
termed lesion network mapping, researchers demonstrated that focal brain lesions having a 
causal role in the development of mania in people without a psychiatric history can occur in 
different brain locations, such as the right orbitofrontal cortex (OFC), right dorsolateral 
prefrontal cortex (DLPFC), and right inferior temporal gyrus (ITG). This lesion network evidence 
converges with existing cross-sectional and longitudinal observations in bipolar mania that have 
identified specific disruptions in network communication between the amygdala and ventro-
lateral prefrontal cortex. The OFC is associated with inhibitory control, risk-taking behavior, and 
reward learning which are major components of bipolar mania. Thus, the association between 

OFC with mania symptoms, inhibitory control, risk-taking behavior, and reward processing 
suggests that this region could be targeted using non-invasive brain stimulation. 
 
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 utilize cathodal tDCS, 10hz and personalized tACS. Five days of 
twice a day (2x20min) of tES will be used during the week.  
 
Electroencephalography (tES): EEG is a routine, non-invasive procedure to record brain activity. 
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: Mania is a core symptom of bipolar disorder involving periods of euphoria, 
delusions, and overactivity. Mania occurs in multiple medical and psychiatric illnesses and can 
be refractory to existing treatments. Two recent studies using brain lesion mapping of 
psychiatrically healthy individuals presenting with mania identified causal locations in the brain, 
including the orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC), and inferior 
temporal gyrus (ITG), that were associated with new onset mania symptoms. Moreover, these 
identified brain regions have also been implicated in bipolar mania with specific disruption in 
network communication between the amygdala and ventro-lateral prefrontal cortex. The OFC is 
of particular interest because it is a brain structure that is associated with inhibitory control, 
risk-taking behavior, and reward, which are major behavioral components of mania. Thus, the 
association between OFC with mania symptoms, inhibitory control, risk-taking behavior and 
reward suggests that this region could be targeted using noninvasive brain stimulation. While 
several studies have non-invasively targeted the DLPFC for mania, no study to date has non-
invasively stimulated the OFC with either transcranial direct current stimulation (tDCS) or 
alternating current (tACS) in bipolar disorder and examined its effects on mania, inhibitory 
control, or risk-taking behavior. However, a study in healthy volunteers showed that cathodal 
stimulation to the OFC enhanced inhibitory control and decreased risk-taking behavior. 
Recently, research have showed that targeting the OFC with tACS, personalized to the 
individual's intrinsic beta-gamma frequency of the reward network, that individuals showed 
rapid, reversible, frequency-specific modulation of reward-guided choice behavior and learning. 
Here we aim to answer the question of whether noninvasive brain stimulation when optimally 
targeted and personalized to an individual's beta-gamma frequency to the OFC can improve 
emotional cognitive processing and mania symptoms compared to tDCS or sham targeting. The 
knowledge gained from this study will provide a marker for clinical response and allow 
personalized treatment for patients with bipolar disorder. 
 
Study Protocol:  
 
 

 
 
 
 
 
 
 
 
 
 
Study Visit 
Timeline 
 
 
 
Visit 1 
 
 
 
 
Visit 2 
 
 
 
 
Visit 3 
 
 
 
 
Visit 4 
 
 
 
Visit 5 
Visit 6  
(1-
month 
follow 
up) 
Visit 7 
(3-
month 
follow 
up 
Consent  
X 
 
 
 
 
 
 
Clinical Evaluation 
X 
 
 
 
X 
X 
X 
Tasks/Cognition Testing 
X 
 
 
 
X 
X 
X 
EEG  
X 
 
 
 
X 
X 
X 
tES 
X 
X 
X 
X 
X 
 
 
Sensation Questionnaire  
X 
X 
X 
X 
X 
 
 
Self-Reports 
X 
 
 
 
X 
X 
X 
Study Timeline 

Study Visits and Details: 
 
Participants will complete baseline clinical, neuropsychological, behavioral tasks and 
neurophysiological assessments (day 0), short-term follow-up (day 5) and long-term follow-up 
(1 & 3 month). 
 
Pre-Screening 
Subjects will be prescreened. If the subject appears to qualify for the study, they will be invited 
in for a screening and a 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 Medical Center (BIDMC) in Boston, MA. The urine toxicology 
screen and pregnancy test will be completed at MMHC or within BIDMC. 
 
● Eligibility pre-screen will include a telephone pre-screening questionnaire that will assess 
basic inclusion and exclusion criteria.  
● Eligibility screening 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 
 
OBJECTIVES  
Primary Objective  
The primary objective of this study is to evaluate the effectiveness of tES for improving the 
mania symptoms (YMRS, ASRM and hospitalizations). 
 
 
Secondary Objectives  

The secondary objective of the study is to evaluate the safety and tolerability of tES targeting 
the rOFC as well as secondary clinical outcomes including depression, mania, cognition, 
impulsiveness, electrophysiology outcomes, social functioning and global functioning 
 
Clinical and Cognitive Outcomes: Symptom ratings will be collected using the PANSS, ASRM, 
YMRS, MADRS, SFS, GAF, BIS and cognition with the BAC 
 
Electrophysiology Outcomes: A reinforcement learning task will be implemented probing the 
reward feedback mechanisms related to the rOFC. A resting state task will be implemented to 
measure brain dynamics at rest.  
Computerized behavioral tasks: The BART and Go/No Go task with be used to determine the 
effective targeting of the rOFC and impulsiveness behaviors. 
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.  
 
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 on 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 participants.  
● Ratings should be based on the patient's condition in 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).  
 
 
 
Altman Self-Rated Mania Scale (ASRM): 
 
The Altman Self-Rating Mania Scale (ASRM) is a brief, self-report questionnaire used to assess the 
presence and severity of manic symptoms. It is a five-item scale where individuals rate their experiences 
over the past week, with higher scores indicating greater symptom severity. Self-administered in survey 
form.  

 
 
Barret Impulsiveness Scale (BIS):  
A brief, self-report questionnaire used to assess the presence and severity of manic symptoms. 
The scale contains 30 items that measure three main domains: attention impulsivity, motor 
impulsivity, and non-planning impulsivity. 
 
 
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 the necessary information. 
 
*Ratings should be based on the patient's condition in the past week. 
 
Referent of "usual" or "normal" conditions. 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 the past month. (Use intermediate level when appropriate, i.e., 45, 68, 72). 
 
 
Young Mania Rating Scale (YMRS) 
 
General Instructions to the Clinician: 
The purpose of each item is to rate the severity of that abnormality in the patient. When several 
keys are given for a particular grade of severity, the presence of only one is required to qualify 
for that rating. 

 
The keys provided are guides. One can ignore the keys if that is necessary to indicate severity, 
although this should be an exception rather than a rule. 
 
Scoring between the points given (whole or half points) is possible and encouraged after 
experience with the scale is acquired; this is particularly useful when severity of a particular item 
in a patient does not follow the progression indicated by the keys. 
 
Social Function Scale (SFS): 
Used 
to 
measure 
the 
degree 
of 
functioning 
across 
several 
domains. 
Social 
engagement/withdrawal (amount of time to spend alone, the likelihood to initiate conversation) 
Interpersonal behavior (number of friends, engagement in a romantic relationship) Prosocial 
activities (participation in social activities e.g. visit friends, play sports). Additionally, it provides 
competency scores for items.  
 
Brief Assessment of Cognition in Schizophrenia (BACS) 
 
Instructions (Atkins et al. 2017): 
 
Verbal Memory (Verbal Memory & Learning Domain): 7 min 
Subjects hear a list of 15 words to remember. Words are presented by the App at a standard rate. 
● Outcome measure: Total number of words recalled across 5 learning trials. 
 
Digit Sequencing (Working Memory Domain): 5 min 
Subjects are presented with randomly ordered auditory clusters of numbers (i.e., 936) with 
steadily increasing trial length. Items are presented by the App at a standard rate. Subjects are 
asked to report the numbers in order, from lowest to highest. 
● Outcome measure: Number of trials with all items in the correct order. 
 
Token Motor Task (Motor Function): 3 min 
Subjects are presented with a virtual bowl and a supply of virtual tokens and asked to swipe a 
token from each side of the tablet with the index finger from each hand simultaneously and 
release them into the center container as rapidly as possible for 60 s. 
● Outcome measure: Number of tokens correctly dragged into the container. 
 
Semantic Fluency & Letter Fluency Tasks (Verbal Fluency Domain): 5 min 
During Semantic Fluency, subjects are given 60 s to generate as many words as possible within 
the category: Animals. Subjects are asked to generate as many words as possible beginning with 
a given letter. Subjects are administered two trials using letters F and S. 
● Outcome measures: Total words generated for each fluency task in addition to total 
scores from both tasks combined to produce the Verbal Fluency domain score. 
 
Symbol Coding (Speed of Processing): 3 min 

Subjects assign numbers to non-meaningful symbols with the use of a key that is provided. 
Numbers are entered on the digital keypad and appear in the location below the corresponding 
symbol. Following instructions and practice, subjects are given 90 s to complete as many items 
as possible.  
● Outcome measure: Number items completed correctly within the 90 second test period. 
 
Tower of London (Executive Functions/Reasoning and Problem Solving): 7 min 
Subjects are shown 2 images presented on opposite sides of the tablet screen. Each image shows 
a different configuration of 3 colored balls arranged on 3 pegs. The subject is required to 
accurately determine total number of times the balls in one picture would have to be moved in 
order to make the arrangement of balls identical to that of the other, opposing picture, while 
employing the standard rules employed in tower tests (balls are moved one at a time and balls 
on top of other balls must be moved first).  
● Outcome measure: Number of correct responses. 
 
Self-Report tES Sensation Questionnaire 
 
Given a participant after each tES session (2x20min), the questionnaire measures severity of 
sensations felt during the stimulation. Rated on a scale from 0 (none) to 4 (severe). In addition, 
the questionnaire has an open-ended question to allow participants to express any additional 
sensations felt during stimulation.  
  
 
tDCS Montage: 
 
Ensure to mark electrodes for stimulation and that correct settings are adjusted on tES device. 
A 30 second ramp should be set. All impedances should be checked before stimulation is 
delivered. Experimenters should remain blinded.   
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EEG Tasks Directions:  
 
Resting State   
 
For the next 5 minutes you will be asked to sit still and keep your eyes on a small white fixation cross at 
the center of the screen. Try to keep your eyes centered on that and try not to move excessively.  
 
Reinforcement Leaning Task   
 
The game is divided into 4 sessions, each comprising 90 trials and lasting 10 minutes. The first 
session will be used as a practice session before scanning. The three other sessions will be 
performed when we record the EEG. 
The word ‘ready’ will be displayed 10 seconds before the game starts. 

In each trial you have to choose between the two symbols displayed on the screen, above and 
below the central cross. Your choice will be circled in red after a 4 second delay. 
As an outcome of your choice, you may 
- get nothing 
- gain +10  
- lose -10  
The two symbols displayed on a same screen are not equivalent in terms of outcome: with one 
you are more likely to get nothing than the other. Each symbol has its own meaning, regardless 
of where and when it is displayed. 
The aim of the game is to win as much money as possible. 
 
BART and Go/No Go: 
 
These assessments will be conducted for all participants: These tests are run via ePRIME. 
 
Set-Up: 
 
BART 
1. Connect eRPIME computer  
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 “BART_2” instructions 
a. You will use this to describe the tasks to the participant 
6. Open up “BART_2” 
a. Load in program 
 
Go/No Go 
7. Connect eRPIME computer  
8. Move the head and chin rest to be 75 cm from the monitor (marked with tape on the 
floor) 
9. Attach keyboard to computer and place on desk 
10. Use alcohol wipe to clean: 
a. Forehead and chin rest 
b. Keyboard 
11. Open up “Go/No Go” instructions 
a. You will use this to describe the tasks to the participant 

12. Open up “Go/No Go” 
a. Load in program 
 
 
 

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 to day 5, 1 month and 3 month in clinical measures (PANSS, ASRM) and 
hospitalizations after 1 week of tES. 
Secondary Endpoints  
Change from baseline to day 5, 1 month and 3 month in GAF, SFS total score after 1 week of 
tES. Change from baseline to day 5 and 1 month in MADRS, PANSS, BIS after 1 week of tES. 
Change from baseline to day 5 and 1 month in voltage and peak frequency for reinforcement 
learning task measures after 1 week of tES. Change from baseline to day 5, 1 month and 3 
month in cognition scores after 1 week of tES. Change from baseline to day 5, 1 month and 3 
month in behavioral tasks (BART & Go/No Go) scores after 1 week of tES. 
Safety and Tolerability Endpoint 
A self-rated questionnaire related to sensations of tES is given to participants after each 
stimulation.  
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 and sham 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, secondary and safety endpoints depending on the distribution of the 
data.