Major Depressive Disorder (MDD) has a high prevalence, is the leading cause of disability, and currently available interventions are associated with side effects and high treatment resistance. There is an urgent need for the development of novel interventions for MDD with alternate mechanisms of action. Temporal Interference (TI) stimulation is a newly emerging form of transcranial alternating current stimulation (tACS) that involves the application of two high-frequency currents at slightly different kHz frequencies. Since neurons, due to their intrinsic low-pass filtering, do not respond to high frequencies (i.e. > 100 Hz), TI relies on the 'beat' interaction leading to neuromodulation at any given location, resulting in a much smaller focus and allowing for better targeting. The subgenual cingulate cortex (SCC) appears to be critical in the pathophysiology of depression and treatment response, especially in treatment-resistant cases. Non-invasive treatments, however, are not able to accurately target SCC due to its deep location within the brain. In this trial, 30 participants meeting the diagnostic criteria for MDD will be randomized to receive 10 sessions of 130 Hz TI delivered daily for 30 minutes, or 10 sessions of sham stimulation. During the stimulation, participants will be watching emotional film clips to enhance target engagement. The investigators will collect metrics of SCC target engagement using the resting-state fMRI and EEG technologies, and determine feasibility, tolerability, safety, and therapeutic efficacy of TI stimulation in MDD. The results of this trial will inform the TI technology as a therapeutic tool for network-based psychiatric disorders, including MDD, and be vital for the design and development of a large-scale randomized-controlled trial.

Inclusion Criteria - Patients will be included if they:

1. provide written informed consent before initiation of any study-related procedures
2. are outpatients
3. meet the DSM-5 criteria for major depressive disorder (MDD) with a current major depressive episode (MDE) without psychotic features as confirmed at Screening by the Mini International Neuropsychiatric Interview (MINI)
4. are male or female, 18 to 65 years of age (inclusive) at screening
5. have a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≥ 20 (moderate to severe depression) at screening
6. have had no increase or initiation of any psychotropic medication in the 4 weeks prior to screening
7. able to adhere to the treatment schedule
8. pass the TI adult safety screening questionnaire
9. are able to understand and comply with the requirements of the study, as judged by the investigator(s)

Exclusion Criteria - Patients will be excluded if they:

1. have an acute alcohol or substance use disorder, withdrawal symptoms requiring detoxification, or went through detoxification treatment (inpatient or outpatient) within 3 months before Screening, as obtained from MINI, Module I (Alcohol Use Disorder) and Module J (Substance Use Disorder, Non-Alcohol) assessed at Screening
2. have a concomitant major unstable medical illness, active hepatitis B virus (HBV), hepatitis C virus (HPC), human immunodeficiency virus (HIV), active COVID-19 infection, cardiac pacemaker or implanted medication pump, as per medical history provided by the participant
3. have active suicidal intent, confirmed by a 'Yes' response to Question B3 AND either Question B10 or B11, obtained from the MINI Suicidality, Module B (Suicidality), OR confirmed by the MADRS item #10 score ≥ 4, both assessed at Screening
4. have a current clinical diagnosis of autism, dementia, or intellectual disability
5. take medications prohibited by the protocol. Medications will be reviewed by the responsible MD
6. are pregnant or lactating
7. have any prior or current diagnosis of bipolar I or II disorder, MDD with psychotic features, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms as obtained from MINI, Module C (Manic and Hypomanic Episodes) and Module K (Psychotic Disorders and Mood Disorders with Psychotic Features) assessed at Screening
8. have any prior or current diagnosis of obsessive-compulsive disorder, post-traumatic stress disorder (current or within the last year), confirmed by MINI and assessed by a study investigator to be primary and causing greater impairment than MDD
9. have a diagnosis of any personality disorder, and assessed by a study investigator to be primary and causing greater impairment than MDD
10. have received TI for any previous indication due to the potential compromise of subject blinding
11. have any significant neurological disorder or insult including, but not limited to: any condition likely to be associated with increased intracranial pressure, space-occupying brain lesion, any history of seizure except those therapeutically induced by ECT or a febrile seizure of infancy, cerebral aneurysm, Parkinson's disease, Huntington's chorea, multiple sclerosis, significant head trauma with loss of consciousness for greater than 5 minutes, current history of poorly controlled migraines including chronic medication for migraine prevention
12. have an intracranial implant (e.g., aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed
13. if participating in psychotherapy, have NOT been in stable treatment for at least 3 months prior to entry into the study or anticipate change in the frequency of therapeutic sessions or therapeutic focus over the duration of the study
14. have a clinically significant laboratory abnormality, in the opinion of one of the principal investigators or study physicians
15. currently take medications that potentially limit the TI efficacy
16. have a non-correctable clinically significant sensory impairment (i.e., cannot hear well enough to cooperate with an interview)
17. have a clinical finding that is unstable or that, in the opinion of the investigator(s), would be negatively affected by the study medication or that would affect the study medication (e.g., diabetes mellitus, hypertension, unstable angina)
18. have uncorrected hypothyroidism or hyperthyroidism. Subjects needing a thyroid hormone supplement to treat hypothyroidism will be excluded if they have NOT been on a stable dose of the medication for 30 days prior to enrolment
19. have any other condition that, in the opinion of the investigator(s), would adversely affect the subject's ability to complete the study or its measure
20. wear a hairstyle or headdress at the time of the stimulation that prevents electrode contact with the scalp or would interfere with the stimulation (e.g., thick or curly hair)
21. have any contraindications for receiving TI or undergoing MRI scans (e.g., hip circumference >180 cm or metal in the body)

The following roles will be blinded: i) Investigators and care providers; ii) Enrolled participants; iii) Outcome assessors; iv) MRI technician