Transcranial Near Infrared Radiation and Cerebral Blood Flow in Depression - R33

Inclusion Criteria:

• Participants must be able to give written informed consent and follow studyprocedures

• Participants must be 18-65 years of age

• Participants must have major depressive disorder; all the following conditions needto be met to ensure presence of significant depression symptoms:

1. Meeting diagnostic criteria for Major Depressive Disorder (MDD) in the past twoweeks, at the DSM-5 Mini-International Neuropsychiatric Interview (MINI)

2. Inventory for Depressive Symptomatology Clinician-rated (IDS-C) total score ≥23at screening

3. 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 majordepressive disorder will need to be stable for at least 8 weeks prior to screen.

Exclusion Criteria:

• Unwilling or unable to comply with study requirements

• Patients judged to be at serious and imminent suicidal (C-SSRS≥4) or homicide risk,or currently in crisis such that inpatient hospitalization or other crisismanagement should take priority.

• History of any or psychotic or bipolar disorder

• Met diagnostic criteria for an alcohol or substance use disorder, post-traumaticstress disorder, obsessive-compulsive disorder, anorexia nervosa, or bulimia nervosawithin the preceding 6 months

• History of dementia, traumatic brain injury (TBI), or neurological disordersaffecting the brain, including any history of stroke or seizure disorders requiringtreatment in the last 5 years

• Cognitive impairment significant as determined by the Montreal Cognitive Assessment (MOCA) <22 or MOCA-Blind <19.

• History of antisocial personality disorder, or any clinically significantpersonality trait that would, in the investigator's judgment, preclude safe studyparticipation or impair ability to remain adherent with the treatment protocol

• History of significant treatment non-adherence or situations where the subjects areunlikely 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 fordepression other than SSRIs, SNRIs, or Wellbutrin (bupropion).

• Treatment resistance with failure to respond to more than two adequate treatmentswith FDA-approved antidepressant medications during current episode of majordepressive disorder.

• History of ECT in the last 12 months; lifetime history of VNS; lifetime treatmentresistance to any FDA-approved device-based treatment for major depressive disorder (such as ECT, TMS, VNS); device-based interventions for depression will need to bediscontinued at least 8 weeks prior to screen.

• Serious, unstable medical illnesses including hepatic, renal, gastroenterologic,respiratory, cardiovascular, endocrinologic, neurologic, immunologic, hematologicdisease; defined as any medical illness which is not well-controlled withstandard-of-care v Clinically significant abnormal findings of laboratory parametersincluding urine toxicology screen for drugs of abuse or at physical examination.

• Clinical or laboratory evidence of uncontrolled hypothyroidism; if maintained onthyroid medication must be euthyroid for at least 1 month before screening.

• Past intolerance or hypersensitivity to tPBM.

• Significant skin conditions (i.e., hemangioma, scleroderma, psoriasis, rash, openwound or tattoo) on the subject's scalp that are found in the area of the proceduresites.

• Any use of light-activated drugs (photodynamic therapy) within 14 days prior tostudy enrollment.

• Any type of implants in the head, whose functioning might be affected by tPBM (e.g.,stent, clipped aneurysm, embolized AVM, implantable shunt - Hakim valve).

• Failure to meet standard MRI safety requirements (e.g., claustrophobia,non-removable piercings, implanted medical devices, other non-removable metals) asdetermined by the MRI Safety Checklist.