Regulated Stimulation for Optimized Network Activity and Therapeutic Equilibrium

Inclusion Criteria: 1. Has a diagnosis of unipolar non-psychotic Major Depressive Disorder (MDD) and is currently experiencing a major depressive episode (MDE) as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-5) 2. Has a screening Montgomery-Åsberg Depression Rating Scale (MADRS) score of ≥20 3. Has not had a sustained response to 2 or more adequately dosed antidepressant treatments from at least 2 different antidepressant treatment classes in at least one episode of major depressive disorder, according to the Antidepressant Treatment History Form (ATHF) 4. Is willing and able to provide written informed consent 5. Is 22-85 years of age 6. Is willing and able to comply with the protocol, including follow-up visits 7. Has been on a stable psychiatric treatment regimen for 30 days before the study screening MADRS and is willing to maintain a stable psychiatric treatment regimen through the Week 4 follow-up visit Exclusion Criteria: 1. Has a cranial implant (with the exception of dental implants), neurostimulator, implanted medication pump, spinal cord stimulator, or pacemaker/implantable cardioverter-defibrillator 2. Has knowledge of planned magnetic resonance imaging (MRIs) in the next 12 months, after implant 3. Is unable to undergo imaging with computed tomography (CT), magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), or functional magnetic resonance imaging (fMRI) 4. In the opinion of the investigator, the implant and therapy pose an unacceptable surgical or medical risk to the patient 5. Is currently taking blood thinners and cannot be taken off blood thinners 6. Has taken ketamine or esketamine in the past 30 days or is planning on taking ketamine or esketamine before the 4-week follow-up visit 7. Has taken hallucinogenic or dissociative medications in the past 30 days or is planning on taking hallucinogenic or dissociative medications for the treatment of mood or anxiety disorders before the 4-week follow-up visit 8. Has a history of bipolar disorder 9. Has a history of schizophrenia, schizoaffective disorder, or other psychotic disorder 10. Has psychotic features in the current depressive episode 11. Has a chronic and clinically significant neurological disorder (epilepsy, dementia, delirium, amnestic disorder, brain tumor), or neuroimaging findings that would potentially impact the efficacy of treatment (e.g., extensive white matter disease, demyelinating lesions, atrophy, brain tumor) 12. Currently taking medication that would alter the seizure threshold, increasing potential seizure risks 13. Has a history of brain injury that resulted in current cognitive impairment 14. Has a history of bony disorders that impact the safe and effective use of the device as well as device implantation 15. Has a history of skin disorders that impact the safe and effective use of the device as well as device implantation 16. Has failed all attempts to achieve at least 50% reduction in depressive symptoms after completion of approved treatment courses of electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) for treatment of MDD 17. Is planning to receive any other neuromodulation therapy during the study 18. Meets the DSM-5 criteria for alcohol use disorder or other substance use disorder (not including tobacco/nicotine) within 12 months prior to study enrollment or, in the opinion of the investigator, is using illicit drugs recreationally or therapeutically which could impact the safety or effectiveness of the therapy 19. Female who is pregnant at the time of inclusion, or planning to become pregnant during the duration of the study, or not willing to use an effective method of birth control 20. Has a life expectancy less than 12 months 21. In the opinion of the investigator, is considered to be acutely suicidal (e.g., Type 4 or 5 on the Columbia-Suicide Severity Rating Scale \[C-SSRS\]) 22. In the investigator's opinion, any known comorbidity that would complicate the assessment of safety or prevent participation in follow-up visits Before implantation of the Motif Digitally Programmable Over-Brain Therapeutic (DOT) Implant, subjects must continue to meet all study eligibility criteria. Subjects must also meet the following additional criteria: 1. Psychiatric treatment regimen has remained stable 2. Has skull thickness ≥5.5 mm and ≤15.5 mm over the implant target