Transcranial Near Infrared Radiation and Cerebral Blood Flow in Depression

Study Overview
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Brief Summary
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This study will compare the effect of three transcranial photobiomodulation (t-PBM) doses (high, middle, and low irradiance) to sham t-PBM on PFC CBF as assessed with fMRI (BOLD) in this multi-center, phase I, double-blinded, dose-ranging, controlled, crossover study of 30 subjects with MDD. All eligible participants will undergo four sessions of t-PBM during fMRI so that they experience irradiances of 50, 300 and 700 mW/cm2 as well as sham. The order of dose administration will be randomized and t-PBM will be administered with the LightForce® EXPi Deep Tissue Laser TherapyTM System, Transcranial PhotoBioModulation-1000 (tPBM-2.0).

Detailed Description
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The purpose of this research study is to determine if application of near infrared energy to the forehead can change blood flow in the brains of people with depression. Near infrared energy is like light but is not visible to the human eye. This research study will compare near infrared exposure with a placebo or sham procedure. The sham procedure will look and feel just like the near infrared procedure but won't include near infrared exposure.

Official Title
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Transcranial Near Infrared Radiation and Cerebral Blood Flow in Depression

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Device: Transcranial Photobiomodulator
* Device: Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be able to give written informed consent and follow study procedures Participants must have major depressive disorder; all the following conditions need to be met to ensure presence of significant depression symptoms: Meeting diagnostic criteria for Major Depressive Disorder (MDD) in the past two weeks, at the DSM-5 Mini-International Neuropsychiatric Interview (MINI) Inventory for Depressive Symptomatology Clinician-rated (IDS-C) total score ≥23 at screening Depression symptoms are the primary target of treatment or treatment-seeking. Women of child-bearing potential must agree to use adequate contraception Participants taking medications or psychotherapy approved for the treatment of major depressive disorder will need to be stable for at least 8 weeks prior to screen Exclusion Criteria: Unwilling or unable to comply with study requirements Participants who are judged to be at serious and imminent suicidal (C-SSRS≥4) or homicide risk, or currently in crisis such that inpatient hospitalization or other crisis management should take priority History of any or psychotic or bipolar disorder Alcohol or substance use disorder, post-traumatic stress disorder, obsessive-compulsive disorder and eating disorders within the preceding 12 months History of dementia, traumatic brain injury (TBI), or neurological disorders affecting the brain, including any history of stroke or seizure disorders requiring treatment in the last 5 years (even if controlled with medications) Cognitive impairment significant as determined by the Montreal Cognitive Assessment (MOCA) <22 History of antisocial personality disorder, or any clinically significant personality trait that would, in the investigator's judgment, preclude safe study participation or impair ability to remain adherent with the treatment protocol. History of significant treatment non-adherence or situations where the subjects are unlikely to adhere to treatment, in the opinion of the investigator Pregnant (as confirmed by pregnancy test at screen) or nursing. Currently undergoing device-based treatment for depression or taking medications for depression other than SSRIs or SNRIs. Treatment resistance with failure to respond to more than two adequate treatments with FDA-approved antidepressant medications during current episode of major depressive disorder. History of ECT in the last 12 months; lifetime history of VNS; lifetime treatment resistance to any FDA-approved device-based treatment for major depressive disorder; device-based interventions for depression will need to be discontinued at least 8 weeks prior to screen. Serious, unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, hematologic disease; defined as any medical illness which is not well-controlled with standard-of-care medications Clinically significant abnormal findings of laboratory parameters including urine toxicology screen for drugs of abuse or at physical examination Clinical or laboratory evidence of uncontrolled hypothyroidism; if maintained on thyroid medication must be euthyroid for at least 1 month before screening. Past intolerance or hypersensivity to t-PBM. Significant skin conditions on the subject's scalp that are found in the area of the procedure sites. Any use of light-activated drugs (photodynamic therapy) within 14 days prior to study enrollment. Any type of implants in the head, whose functioning might be affected by t-PBM. Failure to meet standard MRI safety requirements as determined by the MRI Safety Checklist.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients with MDD<br>Participants will undergo 4 Transcranial Photobiomodulation (t-PBM) treatment visits and receive 1 irradiance dose per visit. The order of dose administration is randomized so patients receive each irradiance dose (50 mW/cm2; 300 mW/cm2; 770 mW/cm2), as well as a sham dose (0 mW/cm2), once over the 4 treatment visits. | Device: Transcranial Photobiomodulator<br>* Delivers laser-generated Near-Infrared Radiation (NIR) to forehead at 3 doses of irradiance - High (770 mW/cm2), Middle (300 mW/cm2), and Low (50 mW/cm2).<br>* Other names: LightForce® EXPi Deep Tissue Laser TherapyTM System, Transcranial PhotoBioModulation-1000 (tPBM-2.0);Device: Sham<br>* Transcranial Photobiomodulator delivers sham irradiance dose of 0 mW/cm2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Prefrontal Cortex (PFC) Cerebral Blood Flow (CBF) During High-Irradiance t-PBM | CBF is measured as Blood Oxygen Level Dependent (BOLD) signal on functional magnetic resonance imaging (fMRI). BOLD signal reflects changes in regional CBF that delineate regional activity. A positive BOLD signal marks an increase in regional blood flow, while a negative BOLD signal marks a decrease in regional blood flow. A positive percent change indicates that blood flow increased in the region of interest between scans, a negative percent change indicates blood flow decreased between scans. Approximately 60 minutes of fMRI data are recorded in the left and right dorsolateral prefrontal cortical regions of interest at each transcranial photobiomodulation (t-PBM) treatment visit, including: approximately 20 minutes prior to t-PBM administration, approximately 20 minutes coinciding with t-PBM administration, and approximately 20 minutes following t-PBM administration. | 20 Minutes Pre-Intervention, 20 Minutes Post-Intervention (Total duration: 60 min); Up to Week 7 | 
| Percentage Change in Prefrontal Cortex (PFC) Cerebral Blood Flow (CBF) During Middle-Irradiance t-PBM | CBF is measured as Blood Oxygen Level Dependent (BOLD) signal on functional magnetic resonance imaging (fMRI). BOLD signal reflects changes in regional CBF that delineate regional activity. A positive BOLD signal marks an increase in regional blood flow, while a negative BOLD signal marks a decrease in regional blood flow. A positive percent change indicates that blood flow increased in the region of interest between scans, a negative percent change indicates blood flow decreased between scans. Approximately 60 minutes of fMRI data are recorded in the left and right dorsolateral prefrontal cortical regions of interest at each transcranial photobiomodulation (t-PBM) treatment visit, including: approximately 20 minutes prior to t-PBM administration, approximately 20 minutes coinciding with t-PBM administration, and approximately 20 minutes following t-PBM administration. | 20 Minutes Pre-Intervention, 20 Minutes Post-Intervention (Total duration: 60 min); Up to Week 7 | 
| Percentage Change in Prefrontal Cortex (PFC) Cerebral Blood Flow (CBF) During Low-Irradiance t-PBM | CBF is measured as Blood Oxygen Level Dependent (BOLD) signal on functional magnetic resonance imaging (fMRI). BOLD signal reflects changes in regional CBF that delineate regional activity. A positive BOLD signal marks an increase in regional blood flow, while a negative BOLD signal marks a decrease in regional blood flow. A positive percent change indicates that blood flow increased in the region of interest between scans, a negative percent change indicates blood flow decreased between scans. Approximately 60 minutes of fMRI data are recorded in the left and right dorsolateral prefrontal cortical regions of interest at each transcranial photobiomodulation (t-PBM) treatment visit, including: approximately 20 minutes prior to t-PBM administration, approximately 20 minutes coinciding with t-PBM administration, and approximately 20 minutes following t-PBM administration. | 20 Minutes Pre-Intervention, 20 Minutes Post-Intervention (Total duration: 60 min); Up to Week 7 | 
| Percentage Change in Prefrontal Cortex (PFC) Cerebral Blood Flow (CBF) During Sham Treatment | CBF is measured as Blood Oxygen Level Dependent (BOLD) signal on functional magnetic resonance imaging (fMRI). BOLD signal reflects changes in regional CBF that delineate regional activity. A positive BOLD signal marks an increase in regional blood flow, while a negative BOLD signal marks a decrease in regional blood flow. A positive percent change indicates that blood flow increased in the region of interest between scans, a negative percent change indicates blood flow decreased between scans. Approximately 60 minutes of fMRI data are recorded in the left and right dorsolateral prefrontal cortical regions of interest at each transcranial photobiomodulation (t-PBM) treatment visit, including: approximately 20 minutes prior to t-PBM administration, approximately 20 minutes coinciding with t-PBM administration, and approximately 20 minutes following t-PBM administration. | 20 Minutes Pre-Intervention, 20 Minutes Post-Intervention (Total duration: 60 min); Up to Week 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Brain Temperature During High-Irradiance t-PBM | Changes computed using data recorded with magnetic resonance (MR) thermometry scans taken immediately before and after the 20-minute transcranial photobiomodulation (t-PBM) treatment administration. | Immediately Pre-Intervention, Immediately Post-Intervention; Up to Week 7 | 
| Change in Brain Temperature During Middle-Irradiance t-PBM | Changes computed using data recorded with magnetic resonance (MR) thermometry scans taken immediately before and after the 20-minute transcranial photobiomodulation (t-PBM) treatment administration. | Immediately Pre-Intervention, Immediately Post-Intervention; Up to Week 7 | 
| Change in Brain Temperature During Low-Irradiance t-PBM | Changes computed using data recorded with magnetic resonance (MR) thermometry scans taken immediately before and after the 20-minute transcranial photobiomodulation (t-PBM) treatment administration. | Immediately Pre-Intervention, Immediately Post-Intervention; Up to Week 7 | 
| Change in Brain Temperature During Sham Treatment | Changes computed using data recorded with magnetic resonance (MR) thermometry scans taken immediately before and after the 20-minute transcranial photobiomodulation (t-PBM) treatment administration. | Immediately Pre-Intervention, Immediately Post-Intervention; Up to Week 7 | 
| Change in Columbia Suicide Severity Rating Scale (C-SSRS) Suicide Ideation Score | C-SSRS systematically tracks suicidal ideation and behavior. The total score range is 0 (no ideation is present) to 5 (active suicidal ideation with specific plan and intent). The higher the score, the greater one's suicidal ideation. Any score greater than 0 is important and may indicate the need for mental health intervention. | Baseline, Follow-up (Week 8) | 
| Systematic Assessment for Treatment Emergent Events (SAFTEE) Score Prior to First Treatment | 55-item self-assessment measuring severity levels of side effects. Participants rank each item on a 4-point Likert scale ranging from 0-3, where: 0 = None; 1 = Mild; 2 = Moderate; and 3 = Severe. The total score is the sum of responses. Scores range from 0 to 165; higher scores indicate greater severity of side effects | Baseline | 
| Systematic Assessment for Treatment Emergent Events (SAFTEE) Score Following High-Irradiance t-PBM | 55-item self-assessment measuring severity levels of side effects. Participants rank each item on a 4-point Likert scale ranging from 0-3, where: 0 = None; 1 = Mild; 2 = Moderate; and 3 = Severe. The total score is the sum of responses. Scores range from 0 to 165; higher scores indicate greater severity of side effects | Immediately Post-Intervention, up to Week 7 in total | 
| Systematic Assessment for Treatment Emergent Events (SAFTEE) Score Following Middle-Irradiance t-PBM | 55-item self-assessment measuring severity levels of side effects. Participants rank each item on a 4-point Likert scale ranging from 0-3, where: 0 = None; 1 = Mild; 2 = Moderate; and 3 = Severe. The total score is the sum of responses. Scores range from 0 to 165; higher scores indicate greater severity of side effects | Immediately Post-Intervention, up to Week 7 in total | 
| Systematic Assessment for Treatment Emergent Events (SAFTEE) Score Following Low-Irradiance t-PBM | 55-item self-assessment measuring severity levels of side effects. Participants rank each item on a 4-point Likert scale ranging from 0-3, where: 0 = None; 1 = Mild; 2 = Moderate; and 3 = Severe. The total score is the sum of responses. Scores range from 0 to 165; higher scores indicate greater severity of side effects | Immediately Post-Intervention, up to Week 7 in total | 
| Systematic Assessment for Treatment Emergent Events (SAFTEE) Score Following Sham Treatment | 55-item self-assessment measuring severity levels of side effects. Participants rank each item on a 4-point Likert scale ranging from 0-3, where: 0 = None; 1 = Mild; 2 = Moderate; and 3 = Severe. The total score is the sum of responses. Scores range from 0 to 165; higher scores indicate greater severity of side effects | Immediately Post-Intervention, up to Week 7 in total | 
| t-PBM Self-Report Questionnaire (TSRQ) Score Following High-Irradiance t-PBM | 3-item self-report assessment of potential inconveniences and discomforts from the transcranial photobiomodulation (t-PBM). Participants rank each item on various Likert scales. The total score is the sum of responses. Total score ranges from 3-18; higher scores indicate greater perceived inconveniences and discomforts associated with t-PBM use. | Immediately Post-Intervention, up to Week 7 in total | 
| t-PBM Self-Report Questionnaire (TSRQ) Score Following Middle-Irradiance t-PBM | 3-item self-report assessment of potential inconveniences and discomforts from the transcranial photobiomodulation (t-PBM). Participants rank each item on various Likert scales. The total score is the sum of responses. Total score ranges from 3-18; higher scores indicate greater perceived inconveniences and discomforts associated with t-PBM use. | Immediately Post-Intervention, up to Week 7 in total | 
| t-PBM Self-Report Questionnaire (TSRQ) Score Following Low-Irradiance t-PBM | 3-item self-report assessment of potential inconveniences and discomforts from the transcranial photobiomodulation (t-PBM). Participants rank each item on various Likert scales. The total score is the sum of responses. Total score ranges from 3-18; higher scores indicate greater perceived inconveniences and discomforts associated with t-PBM use. | Immediately Post-Intervention, up to Week 7 in total | 
| t-PBM Self-Report Questionnaire (TSRQ) Score Following Sham Treatment | 3-item self-report assessment of potential inconveniences and discomforts from the transcranial photobiomodulation (t-PBM). Participants rank each item on various Likert scales. The total score is the sum of responses. Total score ranges from 3-18; higher scores indicate greater perceived inconveniences and discomforts associated with t-PBM use. | Immediately Post-Intervention, up to Week 7 in total | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDD, neuromodulation, transcranial photobiomodulation