Causal Lesion Network Guided Treatment of Bipolar Mania With Transcranial Electrical Stimulation

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.

Study Overview

• Status: Completed
• Conditions: Bipolar Disorder; Schizo Affective Disorder
• Intervention / Treatment: Device: High-Definition Transcranial Electrical-Current Stimulation; Device: High-Definition Transcranial Alternate-Current Stimulation; Device: High-Definition Personalized Beta-Gamma Electrical Stimulation

Detailed Description

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, researches 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 Type: Interventional
• Enrollment (Actual): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: HD-tDCS; HD-tDCS; Two, twenty-minute sessions of tDCS to the OFC for 5 days (10 total sessions)	Device: High-Definition Transcranial Electrical-Current Stimulation; Non-frequency dependent transcranial electrical stimulation condition for 5 days of twice a day treatment; Other Names: Soterix Medical; GTEN 200
Active Comparator: HD-tACS (alpha, 10 Hz); 10 Hz HD-tACS; Two, twenty-minute sessions of tACS to the OFC for 5 days (10 total sessions).	Device: High-Definition Transcranial Alternate-Current Stimulation; Active-control stimulation condition will target alpha (10 Hz) for 5 days of twice a day treatment; Other Names: Soterix Medical; GTEN 200
Active Comparator: Personalized Beta-Gamma HD-tACS; Personalized HD-tACS; Two, twenty-minute sessions of tACS to the OFC for 5 days (10 total sessions).	Device: High-Definition Personalized Beta-Gamma Electrical Stimulation; Personalized beta-gamma electrical stimulation for 5 days of twice a day treatment; Other Names: Soterix Medical; GTEN 200

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Young Mania Rating Scale (YMRS)	Measuring total Mania scores; 11 items used to access severity of mania (total score 0-60); higher scores represent higher severity of symptoms	Change from baseline to 5 Day follow-up
Young Mania Rating Scale (YMRS)	Measuring total Mania scores; 11 items used to access severity of mania (total score 0-60); higher scores represent higher severity of symptoms	Change from baseline to 1-month follow-up
Young Mania Rating Scale (YMRS)	Measuring total Mania scores; 11 items used to access severity of mania (total score 0-60); higher scores represent higher severity of symptoms	Change from baseline to 3-month follow-up
Altman Self-Rating Mania Scale (ASRM)	The ASRM is a 5-item self rating mania scale, assessing the presence and severity of manic symptoms. The scores for all five items are added together, resulting in a total score that can range from 0 to 20. A score of 6 or higher indicates a high probability of a manic or hypomanic condition.	Change from baseline to 5 Day follow-up
Altman Self-Rating Mania Scale (ASRM)	The ASRM is a 5-item self rating mania scale, assessing the presence and severity of manic symptoms. The scores for all five items are added together, resulting in a total score that can range from 0 to 20. A score of 6 or higher indicates a high probability of a manic or hypomanic condition.	Change from baseline to 1-month follow-up
Altman Self-Rating Mania Scale (ASRM)	The ASRM is a 5-item self rating mania scale, assessing the presence and severity of manic symptoms. The scores for all five items are added together, resulting in a total score that can range from 0 to 20. A score of 6 or higher indicates a high probability of a manic or hypomanic condition.	Change from baseline to 3-month follow-up
Psychiatric Hospitalizations for Mania Post Study Entry	Psychiatric hospitalization for mania. Count of hospitalizations from baseline to end of study period assessed at Day 5, 1 Month & 3 Month.	Cumulative count of hospitalizations for mania from baseline to end of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global Assessment of Functioning (GAF)	The GAF measures how symptoms affect individuals day-to-day life; scored from 0 to 100	Change from baseline to 5 Day follow-up
Global Assessment of Functioning (GAF)	The GAF measures how symptoms affect individuals day-to-day life; scored from 0 to 100	Change from baseline to 1-month follow-up
Global Assessment of Functioning (GAF)	The GAF measures how symptoms affect individuals day-to-day life; scored from 0 to 100	Change from baseline to 3-month follow-up
Balloon Analogue Risk Task (BART)	The BART is a computerized task the measures risk-taking behavior. Participants are tasked with inflating the virtual balloon. The number of pumps a participant chooses to make on each balloon is used as a measure of their risk-taking behavior. More pumps generally indicate a higher tolerance for risk. The balloon bursts at a given point if the participant overfills it. Number of popped balloons reported for a given trial.	Change from baseline to 5 Day follow-up
Balloon Analogue Risk Task (BART)	The BART is a computerized task the measures risk-taking behavior. Participants are tasked with inflating the virtual balloon. The number of pumps a participant chooses to make on each balloon is used as a measure of their risk-taking behavior. More pumps generally indicate a higher tolerance for risk. The balloon bursts at a given point if the participant overfills it. Number of popped balloons reported for a given trial.	Change from baseline to 1-month follow-up
Balloon Analogue Risk Task (BART)	The BART is a computerized task the measures risk-taking behavior. Participants are tasked with inflating the virtual balloon. The number of pumps a participant chooses to make on each balloon is used as a measure of their risk-taking behavior. More pumps generally indicate a higher tolerance for risk. The balloon bursts at a given point if the participant overfills it. Number of popped balloons reported for a given trial.	Change from baseline to 3-month follow-up
The Go/No Go Task	The Go/No Go Task is a computerized task that measures impulsiveness. Participants presented with Go (to respond) and no Go (when not to respond) instructions. Two trials are performed. The first trial consist of two distinct auditory stimuli (both Go stimuli) where the participant is asked to respond with a different number of mouse clicks to the stimuli respectively. The second trial, has a no Go stimuli (where the participant is suppose to withhold a response) and a go stimuli. Reaction time for correct trials only for the entire task are reported in milliseconds.	Change from baseline to 5 Day follow-up
The Go/No Go Task	The Go/No Go Task is a computerized task that measures impulsiveness. Participants presented with Go (to respond) and no Go (when not to respond) instructions. Two trials are performed. The first trial consist of two distinct auditory stimuli (both Go stimuli) where the participant is asked to respond with a different number of mouse clicks to the stimuli respectively. The second trial, has a no Go stimuli (where the participant is suppose to withhold a response) and a go stimuli. Reaction time for correct trials only for the entire task are reported in milliseconds.	Change from baseline to 1-month follow-up
The Go/No Go Task	The Go/No Go Task is a computerized task that measures impulsiveness. Participants presented with Go (to respond) and no Go (when not to respond) instructions. Two trials are performed. The first trial consist of two distinct auditory stimuli (both Go stimuli) where the participant is asked to respond with a different number of mouse clicks to the stimuli respectively. The second trial, has a no Go stimuli (where the participant is suppose to withhold a response) and a go stimuli. Reaction time for correct trials only for the entire task are reported in milliseconds.	Change from baseline to 3-month follow-up
Electroencephalography (EEG) Resting State	Measuring neural activity at rest consisting of 5 minutes of eyes-open resting-state EEG (rsEEG) was recorded. Fast Fourier transformations were conducted on data, resulting in 4 frequency bands: delta/theta, alpha, beta, and gamma.	Change from baseline to 5 Day follow-up
Electroencephalography (EEG) Resting State	Measuring neural activity at rest consisting of 5 minutes of eyes-open resting-state EEG (rsEEG) was recorded. Fast Fourier transformations were conducted on data, resulting in 4 frequency bands: delta/theta, alpha, beta, and gamma.	Change from baseline to 1-month follow-up
Electroencephalography (EEG) Resting State	Measuring neural activity at rest consisting of 5 minutes of eyes-open resting-state EEG (rsEEG) was recorded. Fast Fourier transformations were conducted on data, resulting in 4 frequency bands: delta/theta, alpha, beta, and gamma.	Change from baseline to 3-month follow-up
Reinforcement Learning Task	The reinforcement learning task is a monetary based learning tasks that included reward and punishment trails. The task presents multiple trials of stimuli where the participant chooses 1 of 2 stimuli presented at a time (one of which is associated with punishment represented by loss of monetary reward while the other is associated with gain of monetary reward). EEG is record during the task and signal is captured during the participants choose and the feedback received. Reported is the peak beta/gamma range response derived from the EEG during reward feedback. This measurement is used from the baseline assessment to inform the personalized beta-gamma range stimulation for the Personalized Beta-Gamma tACS group.	Change from baseline to 5 Day follow-up
Reinforcement Learning Task	The reinforcement learning task is a monetary based learning tasks that included reward and punishment trails. The task presents multiple trials of stimuli where the participant chooses 1 of 2 stimuli presented at a time (one of which is associated with punishment represented by loss of monetary reward while the other is associated with gain of monetary reward). EEG is record during the task and signal is captured during the participants choose and the feedback received. Reported is the peak beta/gamma range response derived from the EEG during reward feedback. This measurement is used from the baseline assessment to inform the personalized beta-gamma range stimulation for the Personalized Beta-Gamma tACS group.	Change from baseline to 1-month follow-up
Reinforcement Learning Task	The reinforcement learning task is a monetary based learning tasks that included reward and punishment trails. The task presents multiple trials of stimuli where the participant chooses 1 of 2 stimuli presented at a time (one of which is associated with punishment represented by loss of monetary reward while the other is associated with gain of monetary reward). EEG is record during the task and signal is captured during the participants choose and the feedback received. Reported is the peak beta/gamma range response derived from the EEG during reward feedback. This measurement is used from the baseline assessment to inform the personalized beta-gamma range stimulation for the Personalized Beta-Gamma tACS group.	Change from baseline to 3-month follow-up
Social Functioning Scale (SFS)	The SFS a self-report questionnaire initially designed for people diagnosed with Schizophrenia; consists of 79 items designed to reflect the social skills and performances in different areas of life. Subscores are summed together for a total score. Total score of SFS ranges between 0-223 points. Higher scores mean better social functioning.	Change from baseline to 5 Day follow-up
Social Functioning Scale (SFS)	The SFS a self-report questionnaire initially designed for people diagnosed with Schizophrenia; consists of 79 items designed to reflect the social skills and performances in different areas of life. Subscores are summed together for a total score. Total score of SFS ranges between 0-223 points. Higher scores mean better social functioning.	Change from baseline to 1-month follow-up
Social Functioning Scale (SFS)	The SFS a self-report questionnaire initially designed for people diagnosed with Schizophrenia; consists of 79 items designed to reflect the social skills and performances in different areas of life. Subscores are summed together for a total score. Total score of SFS ranges between 0-223 points. Higher scores mean better social functioning.	Change from baseline to 3-month follow-up
Positive and Negative Syndrome Scale (PANSS)	30 items included in the PANSS measuring positive, negative and general symptoms; 7 related to positive symptoms, 7 for negative symptoms, and 16 for general psychopathology Scale. Ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale. Scores summed for Total Score on scale (30 to 210). Higher scores mean worse clinical symptoms. Total score reported.	Change from baseline to 5 Day follow-up
Positive and Negative Syndrome Scale (PANSS)	30 items included in the PANSS measuring positive, negative and general symptoms; 7 related to positive symptoms, 7 for negative symptoms, and 16 for general psychopathology Scale. Ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale. Scores summed for Total Score on scale (30 to 210). Higher scores mean worse clinical symptoms. Total score reported.	Change from baseline to 1-month follow-up
Positive and Negative Syndrome Scale (PANSS)	30 items included in the PANSS measuring positive, negative and general symptoms; 7 related to positive symptoms, 7 for negative symptoms, and 16 for general psychopathology Scale. Ranges are 7 to 49 for the Positive and Negative Scales, and 16 to 112 for the General Psychopathology Scale. Scores summed for Total Score on scale (30 to 210). Higher scores mean worse clinical symptoms. Total score reported.	Change from baseline to 3-month follow-up
Montgomery-Åsberg Depression Rating Scale (MADRS)	The MADRS is designed to measure depression and severity of symptoms; 0 to 6 indicates no depression, 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, 35 and greater indicates severe depression. Total score reported (0 to 60).	Change from baseline to 5 Day follow-up
Montgomery-Åsberg Depression Rating Scale (MADRS)	The MADRS is designed to measure depression and severity of symptoms; 0 to 6 indicates no depression, 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, 35 and greater indicates severe depression. Total score reported (0 to 60).	Change from baseline to 1-month follow-up
Montgomery-Åsberg Depression Rating Scale (MADRS)	The MADRS is designed to measure depression and severity of symptoms; 0 to 6 indicates no depression, 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, 35 and greater indicates severe depression. Total score reported (0 to 60).	Change from baseline to 3-month follow-up
Barratt Impulsiveness Scale-11 (BIS-11)	The BIS-11 is designed to assess the personality/behavioral impulsiveness. The BIS-11 has 30 items and is scored appropriately. Scored to yield a total score, three second-order factors, and six first-order factors. Each question has a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). Higher scores mean more impulsive behavior. Total score reported (30-120).	Change from baseline to 5 Day follow-up
Barratt Impulsiveness Scale-11 (BIS-11)	The BIS-11 is designed to assess the personality/behavioral impulsiveness. The BIS-11 has 30 items and is scored appropriately. Scored to yield a total score, three second-order factors, and six first-order factors. Each question has a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). Higher scores mean more impulsive behavior. Total score reported (30-120).	Change from baseline to 1-month follow-up
Barratt Impulsiveness Scale-11 (BIS-11)	The BIS-11 is designed to assess the personality/behavioral impulsiveness. The BIS-11 has 30 items and is scored appropriately. Scored to yield a total score, three second-order factors, and six first-order factors. Each question has a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/always). Higher scores mean more impulsive behavior. Total score reported (30-120).	Change from baseline to 3-month follow-up
Brief Assessment of Cognition (BACS)	The BACS is designed to assess several domains of cognition; Verbal Memory; Processing Speed; Working Memory; Verbal Fluency; Motor Function; Executive Functioning. Higher scores indicate better cognitive functioning. Total score reported after being transformed into z score based on normative scoring provide by test makers.	Change from baseline to 5 Day follow-up
Brief Assessment of Cognition (BACS)	The BACS is designed to assess several domains of cognition; Verbal Memory; Processing Speed; Working Memory; Verbal Fluency; Motor Function; Executive Functioning. Higher scores indicate better cognitive functioning. Total score reported after being transformed into z score based on normative scoring provide by test makers.	Change from baseline to 1-month follow-up
Brief Assessment of Cognition (BACS)	The BACS is designed to assess several domains of cognition; Verbal Memory; Processing Speed; Working Memory; Verbal Fluency; Motor Function; Executive Functioning. Higher scores indicate better cognitive functioning. Total score reported after being transformed into z score based on normative scoring provide by test makers.	Change from baseline to 3-month follow-up

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Paulo Lizano, MD,PhD, Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): December 16, 2022
• Primary Completion (Actual): June 1, 2025
• Study Completion (Actual): June 1, 2025

Study Registration Dates

• First Submitted: June 17, 2022
• First Submitted That Met QC Criteria: June 30, 2022
• First Posted (Actual): July 6, 2022

Study Record Updates

• Last Update Posted (Estimated): November 6, 2025
• Last Update Submitted That Met QC Criteria: October 22, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: Mania; Brain Stimulation
• Additional Relevant MeSH Terms: Bipolar and Related Disorders; Neurologic Manifestations; Nervous System Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Neurobehavioral Manifestations; Mood Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Mania; Psychotic Disorders; Bipolar Disorder
• Other Study ID Numbers: 2022P000295

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No