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Transcranial light therapy, or transcranial photobiomodulation (tPBM), is a treatment that stimulates the brain by applying near-infrared light to the forehead. Transcranial light therapy has been found to promote brain metabolism, which may help improve executive function in people with bipolar disorder. The research team proposes a novel approach to treating bipolar disorder by using transcranial light therapy.
This study involves a virtual screening visit, 7 in-office visits, and a virtual check-in call with a clinician. Participation will last approximately 3 weeks in total.
Participants will attend a baseline visit during which they will complete mood questionnaires and a gambling task. Participants will then receive five treatments of transcranial light therapy over one week. The first and last of these treatments will be administered while the participant is in an MRI scanner. At the first visit, participants will also receive a "sham" tPBM treatment, meaning that the device will simulate real treatment, but will not actually apply the near-infrared light. The check-in call will occur approximately 2-3 days after the final treatment visit. This will be a brief call with a study clinician to check-in on the participant's mental and physical health. The follow up visit will occur approximately one week after the final visit. Subjects will be asked to complete mood questionnaires and/or gambling tasks during the first and fifth treatment visits, as well as at the follow up visit.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Transcranial Phoobiomodulation (tPBM) | Device | Transcranial light therapy penetrates the skin and brain using light energy; this makes transcranial light therapy noninvasive. Transcranial light therapy may activate under-stimulated brain regions. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Test the Effect of Transcranial Photobiomodulation (tPBM) on Cerebral Blood Flow (CBF) | Compare blood-oxygenation-level-dependent (BOLD) signal during sham stimulation at Day 1 versus BOLD signal during active stimulation at Day 1. Increased BOLD signal is thought to reflect increased brain activity, and thus a positive outcome. In this specific case, higher BOLD signal during active as compared to sham treatment in the right dorsolateral prefrontal cortex (rDLPFC) is thought to reflect target engagement, that is the tPBM device which is placed on the right forehead is in fact irradiating and having an effect on brain function within the rDLPFC. | Day 1 of tPBM Treatment |
| Test Effect of tPBM on CBF | Compare BOLD signal during active stimulation at Day 1 versus active stimulation at Day 5. Greater BOLD signal at Day 5 compared to Day 1 would indicate an increase in brain activity following active treatment, supporting tPBM target engagement. | Day 1 and Day 5 |
| Measure | Description | Time Frame |
|---|---|---|
| Test the Effect of tPBM on Impaired Decision Making | Improvement in decision making will be evaluated by an increase in net gain at the Iowa Gambling Task (IGT) (higher score=better outcome, min score -3000, max score 7000), decrease in Barratt Impulsiveness Scale (BIS) score (min 30, max 120, lower score=better outcome), decrease in Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) score (min 0, max 140, lower score=better outcome), and a decrease in I-7 Impulsiveness and Venturesomeness Questionnaire score (lower score=better outcome, Impulsiveness subscale: min 0, max 19, Venturesomeness subscale: min 0, max 15). All items are evaluated at Day 5 and Follow-up visit relative to Baseline. Baseline occurred approximately 1 week prior to Day 1. Treatment Days 2-5 were scheduled for the following week, ideally once daily, however the schedule allowed for flexibility, with Day 5 occurring no later than 10 days after Day 1. Follow-up occurred approximately 1 week after Day 5, or approximately 3 weeks after Baseline. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mass General Hospital Navy Yard Building 149 | Charlestown | Massachusetts | 02129 | United States |
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Subjects underwent screening procedures to determine eligibility. A majority of subjects were excluded for not meeting the impulsivity threshold. Other subjects were excluded due to current alcohol or substance use disorder or were lost to follow up.
Recruitment took place at Massachusetts General Hospital between July 2022 and April 2024. Subjects were recruited through a variety of methods, including online advertisements and surveys, flyers, and referrals from providers and other research studies.
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| ID | Title | Description |
|---|---|---|
| FG000 | Transcranial Light Therapy | Subjects who passed screening and completed all study procedures. All subjects received a sham light therapy treatment followed by an active light therapy treatment at the first MRI session. This was a single-blind procedure. All following transcranial photobiomodulation (tPBM) sessions (Treatment Days 2, 3, 4 and MRI session on Day 5) were active and open-label. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Subjects | Subjects who passed screening and completed all study procedures. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Test the Effect of Transcranial Photobiomodulation (tPBM) on Cerebral Blood Flow (CBF) | Compare blood-oxygenation-level-dependent (BOLD) signal during sham stimulation at Day 1 versus BOLD signal during active stimulation at Day 1. Increased BOLD signal is thought to reflect increased brain activity, and thus a positive outcome. In this specific case, higher BOLD signal during active as compared to sham treatment in the right dorsolateral prefrontal cortex (rDLPFC) is thought to reflect target engagement, that is the tPBM device which is placed on the right forehead is in fact irradiating and having an effect on brain function within the rDLPFC. | Posted | Mean | Standard Deviation | A.U. | Day 1 of tPBM Treatment |
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Adverse events were collected at all visits apart from screening (Baseline, Day 1-5, Follow Up). Adverse events were also collected during a clinician check-in between Day 5 and Follow Up, approximately 2-3 days after Day 5. Baseline occurred approximately 1 week prior to Day 1. Treatment Days 2-5 were scheduled for the following week (daily); the schedule allowed for flexibility, with Day 5 occurring no later than 10 days after Day 1. Follow-up occurred approximately 1 week after Day 5.
The Adverse Events Form captures any adverse event (serious or otherwise) that the subject experiences while participating in the study. Events may occur during or outside of study procedures. Subjects or staff could report Adverse Events. The event, severity, resolution, relatedness to treatment, action taken, and expectedness were all documented along with the start and end date (course) of the Adverse Event.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Subjects | Subjects who passed screening and completed all study procedures. | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Skin Warming | Skin and subcutaneous tissue disorders | Systematic Assessment | Participant noted some slight skin warming during treatment. |
The sample size is small, limiting statistical analyses and interpretation. The results highlight the need for group-level statistical analyses in a larger sample to validate. The inter-individual variability suggests that future studies should include additional longitudinal tracking and more examination of moderating factors.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Paolo Cassano | Massachusetts General Hospital and Harvard Medical School | 617-643-9622 | pcassano@mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 18, 2023 | May 30, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D001714 | Bipolar Disorder |
| ID | Term |
|---|---|
| D000068105 | Bipolar and Related Disorders |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D028022 | Low-Level Light Therapy |
| ID | Term |
|---|---|
| D053685 | Laser Therapy |
| D013812 | Therapeutics |
| D010789 | Phototherapy |
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All participants will receive five active tPBM treatments and one sham tPBM treatment.
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During the first treatment visit within the MRI, participants will receive one active tPBM treatment and one sham tPBM treatment. Participants will be blinded as to the order in which they receive these treatments.
| Baseline to Follow-Up |
| Test the Effect of Repeated t-PBM Sessions on Mood Symptoms (MOODS-SR) in Subjects With Bipolar Disorder (BD) | Repeated t-PBM sessions on the rDLPFC will significantly decrease the total Mood Spectrum-Self Report (MOODS-SR) (min 0, max 154, lower score= better outcome) score at Day 5 and Follow-Up visit relative to Baseline. The scale was evaluated at Day 5 and Follow-up visit relative to Baseline. Baseline occurred approximately 1 week prior to Day 1. Treatment Days 2-5 were scheduled for the following week, ideally once daily, however the schedule allowed for flexibility, with Day 5 occurring no later than 10 days after Day 1. Follow-up occurred approximately 1 week after Day 5, or approximately 3 weeks after Baseline. | Baseline to Follow Up |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Barrat Impulsiveness Scale (BIS) | Measure of impulsivity. Higher scores indicate higher impulsivity (min 30, max 120, lower score=better outcome) | Mean | Standard Deviation | units on a scale |
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| Primary | Test Effect of tPBM on CBF | Compare BOLD signal during active stimulation at Day 1 versus active stimulation at Day 5. Greater BOLD signal at Day 5 compared to Day 1 would indicate an increase in brain activity following active treatment, supporting tPBM target engagement. | Posted | Mean | Standard Deviation | A.U. | Day 1 and Day 5 |
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| Secondary | Test the Effect of tPBM on Impaired Decision Making | Improvement in decision making will be evaluated by an increase in net gain at the Iowa Gambling Task (IGT) (higher score=better outcome, min score -3000, max score 7000), decrease in Barratt Impulsiveness Scale (BIS) score (min 30, max 120, lower score=better outcome), decrease in Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) score (min 0, max 140, lower score=better outcome), and a decrease in I-7 Impulsiveness and Venturesomeness Questionnaire score (lower score=better outcome, Impulsiveness subscale: min 0, max 19, Venturesomeness subscale: min 0, max 15). All items are evaluated at Day 5 and Follow-up visit relative to Baseline. Baseline occurred approximately 1 week prior to Day 1. Treatment Days 2-5 were scheduled for the following week, ideally once daily, however the schedule allowed for flexibility, with Day 5 occurring no later than 10 days after Day 1. Follow-up occurred approximately 1 week after Day 5, or approximately 3 weeks after Baseline. | Posted | Mean | Standard Deviation | units on a scale | Baseline to Follow-Up |
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| Secondary | Test the Effect of Repeated t-PBM Sessions on Mood Symptoms (MOODS-SR) in Subjects With Bipolar Disorder (BD) | Repeated t-PBM sessions on the rDLPFC will significantly decrease the total Mood Spectrum-Self Report (MOODS-SR) (min 0, max 154, lower score= better outcome) score at Day 5 and Follow-Up visit relative to Baseline. The scale was evaluated at Day 5 and Follow-up visit relative to Baseline. Baseline occurred approximately 1 week prior to Day 1. Treatment Days 2-5 were scheduled for the following week, ideally once daily, however the schedule allowed for flexibility, with Day 5 occurring no later than 10 days after Day 1. Follow-up occurred approximately 1 week after Day 5, or approximately 3 weeks after Baseline. | Posted | Mean | Standard Deviation | score on a scale | Baseline to Follow Up |
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| 4 |
| 0 |
| 4 |
| 3 |
| 4 |
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| Skin Reddening Under Diode | Skin and subcutaneous tissue disorders | Systematic Assessment | Redness under diode sites post-treatment |
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| Cold-like Virus/Common Cold | Infections and infestations | Systematic Assessment |
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| Pimple on Forehead at Diode Location | Skin and subcutaneous tissue disorders | Systematic Assessment | Pimple on forehead at the F4 diode location. Identified at the end of the tx session. Ptp reported it is uncommon for her to get pimples on her forehead. |
|
| Visual Illusion | Psychiatric disorders | Systematic Assessment | Brief visual illusion while biking to work. Participant reported she saw "a monster swiping out to get me" but then realized it was just a bike rack. Potential perception issue, visual perception or misperception. |
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The small sample size did not allow for statistical tests. Therefore, we calculated percent difference between active stimulation timepoints (Day 1 vs Day 5).
| Percent Difference |
| 4.35 |
| 2-Sided |
Difference = Day 5 Active - Day 1 Active |
| Other |
| We evaluated the effect size of the difference between active stimulation timepoints (Day 1 vs Day 5) using Cohen's d. | Cohen's d | 0.36 | 2-Sided | Other |
| Title | Measurements |
|---|---|
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| IGT Follow-Up |
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| IGT Net Gain Baseline to Day 5 |
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| BIS Baseline |
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| BIS Day 5 |
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| BIS Follow Up |
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| BIS Change Baseline to Day 5 |
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| BIS Change Baseline to Follow Up |
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| BRIEF-A Baseline |
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| BRIEF-A Day 5 |
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| BRIEF-A Follow Up |
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| BRIEF-A Change Baseline to Day 5 |
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| BRIEF-A Change Baseline to Follow Up |
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| I-7 Impulsiveness Baseline |
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| I-7 Impulsiveness Day 5 |
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| I-7 Impulsiveness Follow Up |
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| I-7 Impulsiveness Change Baseline to Day 5 |
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| I-7 Impulsiveness Change Baseline to Follow Up |
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| I-7 Venturesomeness Baseline |
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| I-7 Venturesomeness Day 5 |
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| I-7 Venturesomeness Follow Up |
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| I-7 Venturesomeness Change Baseline to Day 5 |
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| I-7 Venturesomeness Change Baseline to Follow Up |
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| Friedman test |
| 0.038 |
| Other |
The Friedman test was used to assess overall differences in IGT across Baseline, Day 1, and Day 5. |
| Friedman test | 0.043 | Other | The Friedman test was used to assess overall differences in IGT across all timepoints (Baseline, Day 1, Day 5, Follow-Up). |
| Wilcoxon signed rank test | BIS across timepoints | 0.42 | rank biserial correlation coefficient | 0.134 | 2-Sided | Other | The Wilcoxon signed-rank test was used to evaluate changes in the BIS across timepoints due to the small sample size and distributional assumptions. Effect sizes were calculated using the rank biserial correlation coefficient (r) to estimate the magnitude of change. |
| Wilcoxon signed rank test | BRIEF-A across timepoints | 0.232 | Other | The Wilcoxon signed-rank test was used to evaluate changes in the BRIEF-A across timepoints due to the small sample size and distributional assumptions. |
| Wilcoxon signed rank test | i7 Impulsivity | 0.06 | rank biserial correlation coefficient | 0.575 | 2-Sided | Other | The Wilcoxon signed-rank test was used to evaluate changes in the i7 Impulsivity across timepoints due to the small sample size and distributional assumptions. Effect sizes were calculated using the rank biserial correlation coefficient (r) to estimate the magnitude of change. |
| Wilcoxon signed rank test | 0.36 | rank biserial correlation coefficient | 0.275 | 2-Sided | Other | The Wilcoxon signed-rank test was used to evaluate changes in the i7 Venturesomeness across timepoints due to the small sample size and distributional assumptions. Effect sizes were calculated using the rank biserial correlation coefficient (r) to estimate the magnitude of change. |
| Title | Measurements |
|---|---|
|
| MOODS-SR Change Baseline to Day 5 |
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| MOODS-SR Change Baseline to Follow Up |
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| Wilcoxon signed rank test |
| 0.2 |
| Cohen's d |
| 0.24 |
| 2-Sided |
| Other |
Non-parametric tests were employed to evaluate changes across MOODS-SR Baseline to Follow Up due to the small sample size and distributional assumptions. The Wilcoxon signed-rank tests were applied for pairwise comparisons. Effect sizes were calculated using Cohen's d to estimate the magnitude of change. |