Inclusion Criteria:
* Age 22-70
* Meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnostic criteria for Major Depressive Disorder (MDD) without psychosis based on a Structured Clinical Interview for DSM-V (SCID) with current episode ≥ 2 years that is treatment- resistant (4 adequate trials (including ECT), 3 classes of medications, one augmentation strategy, psychotherapy) as measured by the antidepressant treatment history form (ATHF).
* Failed electroconvulsive therapy (ECT) due to inability to achieve sustained response (2 failed attempts to discontinue ECT treatment) or discontinued due to intolerable side effects.
* Has MADRS score of \> 26 at both baseline and screening visit
* The presence of variability on repeated administrations of MDD rating scales (minimum of 2-point variation on the HAMD-6 administered 3 times a day for 3 days), which is required for the identification of a neural biomarker.
* If patient is on a regimen of psychotropic medication, no changes in this regimen should be made during the 4 weeks prior to entry into and the duration of the study.
* Willing and able to undergo invasive brain recording/stimulation study
* Willing and able to attend multiple research visits and perform at-home research protocol
* Willing and able to provide informed consent
* Ability to speak and read English
Exclusion Criteria:
* Meets DSM-V criteria for a psychotic disorder, eating disorder, panic disorder, posttraumatic stress disorder, bipolar disorder, obsessive compulsive disorder, tic disorder, or another comorbid psychiatric disorder other than MDD or generalized anxiety disorder based on a SCID
* Generalized anxiety disorder is the primary DSM-V disorder during the current MDD episode
* Active suicidal ideation with intent and plan as defined by a score of 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS)
* History of suicide attempt requiring hospitalization in previous 2 years.
* Meets criteria for alcohol or substance abuse or dependence (other than caffeine) in previous 6 months, determined by the SCID
* Has a personality disorder based on the investigator's assessment that the investigator believes will adversely impact subject compliance or safety
* Fibromyalgia or chronic fatigue syndrome
* Current condition requiring chronic narcotic use
* History of traumatic brain injury, another neurological disorder, or developmental delay
* History of seizures
* MRI (done within one year of the first visit) with significant abnormalities
* Previous ablative intracranial surgery or previously implanted deep brain stimulation system or any previously implanted device treatment involving brain stimulation
* Implantable hardware not compatible with MRI or with the study
* Major medical co-morbidities increasing the risk of surgery including severe diabetes, major organ system failure, history of hemorrhagic stroke, need for chronic anticoagulation other than aspirin, active infection, intracranial space occupying lesion, increased intracranial pressure, cardiovascular accident within the last month, aneurysm/abnormality, retinal detachment, unstable cardiovascular disease (recent myocardial infarction, severe ischemia, severe or uncontrolled hypertension), immunocompromised state, or malignancy with \< 5 years life expectancy
* Inability to stop Coumadin or platelet anti-aggregation therapy for surgery and after surgery. - Patients taking these medications will need to discuss the need/risk of continuing these medications with their physicians and the PI or study personnel may contact the treating physician(s) to discuss the risks of anticoagulation/antiaggregation therapy discontinuation
* Coagulopathy. Patients will be excluded unless assessed and cleared by hematology
* Allergies or known hypersensitivity to materials in the NeuroPace RNS® System (i.e. titanium, polyurethane, silicone, polyetherimide, stainless steel)
* Subject lives alone without possibility of caregiver support post-hospital stay
* Inability to comply with study follow-up visits
* Women who are pregnant, plan to become pregnant, or breast feeding
* Inability to speak and/or read English
* Inability to give consent
* Significant cognitive impairment or dementia (MoCA \< 25)
* Likely to require ECT during the course of the study
