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

Inclusion Criteria: * Participants must be able to give written informed consent and follow study procedures * Participants must be 18-65 years of age * Participants must have major depressive disorder; all the following conditions need to be met to ensure presence of significant depression symptoms: 1. Meeting diagnostic criteria for Major Depressive Disorder (MDD) in the past two weeks, at the DSM-5 Mini-International Neuropsychiatric Interview (MINI) 2. Inventory for Depressive Symptomatology Clinician-rated (IDS-C) total score ≥23 at 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 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 * 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 crisis management should take priority. * History of any or psychotic or bipolar disorder * Met diagnostic criteria for an alcohol or substance use disorder, post-traumatic stress disorder, obsessive-compulsive disorder, anorexia nervosa, or bulimia nervosa within the preceding 6 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 * Cognitive impairment significant as determined by the Montreal Cognitive Assessment (MOCA) \<22 or MOCA-Blind \<19. * 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, SNRIs, or Wellbutrin (bupropion). * 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 (such as ECT, TMS, VNS); 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 v 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 hypersensitivity to tPBM. * Significant skin conditions (i.e., hemangioma, scleroderma, psoriasis, rash, open wound or tattoo) 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 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) as determined by the MRI Safety Checklist.