Neuromodulation of Mood Switch Circuitry in Bipolar Disorder

Phase 4Not Yet RecruitingNCT07680153

Weill Medical College of Cornell University62 enrolled

Overview

This study is exploring a new approach to treating depression in people with bipolar disorder (BD). Investigators are testing whether a non-invasive form of brain stimulation can help us understand depressed-to-euthymic mood shifts and their related brain circuits in BD. Investigators in this study will use a technique called repetitive transcranial magnetic stimulation, or rTMS. It uses non-invasive magnetic pulses delivered to the scalp to stimulate specific areas of the brain. rTMS is already used to treat depression, and investigators are now studying whether it can be made even more effective for people with bipolar disorder by precisely targeting an individualized brain region for each participant. Participants in this study will receive two courses of rTMS, one active and one placebo (called "sham"), in a randomized order so investigators can directly compare the effects. Before treatment, investigators will use brain scans (MRI) to create a personalized map of each participant's brain activity. This lets investigators identify the exact stimulation target most likely to influence the brain circuits involved in BD mood shifts. Investigators will track mood symptoms closely throughout the study to measure what changes. Investigators believe that depression in BD is partly driven by disrupted communication between two brain regions involved in processing what feels important or rewarding. Investigators want to find out whether rTMS can restore that communication and whether doing so leads to measurable improvements in depression.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Bipolar Disorder (BD)

Interventions

MagVenture MagPro TMS systemDEVICE

TANS-guided SAL Acc iTBS approach: Targeted Functional Network Stimulation (TANS) combines precision functional mapping (PFM) with electric field (E-field) modeling to individualize circuit targeting. Active rTMS will be intermittent theta burst simulation (iTBS) delivered to the salience network (SAL) with an accelerated intervention protocol (up to 5 consecutive days of 10 hourly active rTMS sessions).

Sham StimulationDEVICE

An Active/Placebo (A/P) sham TMS coil will be used to deliver placebo stimulation. The A/P coil is a double-sided coil in which one side delivers effective magnetic stimulation, while the opposite side is configured to produce a sham condition without inducing cortical activation. Sham stimulation will also be delivered to the salience network (SAL) with an accelerated intervention protocol (up to 5 consecutive days of 10 hourly sham rTMS sessions).

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Provision of signed and dated informed consent form. 2. Adults of all genders aged 18-70 at the time of screening. 3. Diagnosis of Bipolar Disorder (by DSM-V criteria) 4. Depressive symptoms of at least moderate severity (GRID HDRS-17 score \>= 14 or as determined by expert clinician). 5. Not currently taking medications for BD OR on a stable dose of medication for at least 1 month prior to screening and plans to remain off medications OR on this stable dose for the duration of participation. 6. Access to psychiatric care before, during, and after completion of the study. 7. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation. 8. Proficiency in English sufficient to complete assessments and follow study procedure instructions. 9. Stated willingness to comply with all study procedures and availability for the duration of the study. Exclusion Criteria: 1. Imminent risk of suicide. 2. Presence of a primary DSM-5 diagnosis other than bipolar disorder (BD-I or BD-II), or a current comorbid psychiatric disorder that, in the opinion of the investigators, would confound outcome assessment or interfere with safe participation. 3. History of seizures or any condition / concurrent medication that could notably lower seizure threshold. 4. Met criteria for any significant substance use disorder (by DSM-V criteria) in the 6 months prior to screening. 5. History or presence of significant neurological disorder (e.g., traumatic brain injury, stroke, Parkinson's disease or other movement disorder, epilepsy). 6. History or presence of significant heart condition (e.g., recent myocardial infarction, congestive heart failure \> stage 2, angina pectoris, bradycardia or tachycardia at the baseline assessment, uncontrolled hypertension). 7. MRI contraindication, including presence of foreign metal bodies or implants, implanted or conductive objects in or near the head (e.g., stents, deep brain stimulators, vagus nerve stimulators, aneurysm coils, ocular implants, cochlear implants), permanent make-up. 8. Individuals who are nursing, pregnant, or contemplating pregnancy within the length of study participation. 9. Abnormal bloodwork for electrolytes, thyroid, or liver function. 10. History or presence of any disorder or medical condition that, in the opinion of the study team, may compromise, interfere, or limit the individual's ability to complete the intervention or study procedures.

Outcomes

Primary Outcomes

Change from Baseline to 1-Week Post-rTMS in Montgomery-Asberg Depression Rating Scale (MADRS) Score

Within-participant difference in change in depression, measured by score on the Montgomery-Asberg Depression Rating Scale (MADRS), in the active intervention phase vs. the sham intervention phase. The minimum MADRS score is 0 and the maximum MADRS score is 60, with higher scores indicating greater depression severity. The primary analysis uses a linear mixed-effects model with fixed effects for time (pre/post), condition (active/sham), intervention phase, and randomization sequence, with a subject-specific random intercept. The primary endpoint is the time × condition interaction, reflecting differential symptom change for active versus sham rTMS.

Time frame: Baseline to 1-week post-rTMS

Secondary Outcomes

Change in salience network functional connectivity in active vs. sham rTMS

Within-participant difference in change in salience network functional connectivity (FC) in the active intervention phase vs. the sham intervention phase. Difference will be measured as pre-to-post rTMS change in FC between ventral striatum and anterior cingulate nodes of the salience network, with higher scores indicating greater FC. The secondary analysis also uses a linear mixed-effects model with fixed effects for time (pre/post), condition (active/sham), intervention phase, and randomization sequence, with a subject-specific random intercept. The primary endpoint is the time × condition interaction, reflecting differential change in FC for active versus sham rTMS.