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Inclusion Criteria

In order to participate in this study, potential participants must meet all of the following eligibility criteria:

1. 18-65 years old
2. DSM-5 diagnosis of major depressive (at least 90%) or persistent depressive disorder (no more than 10%) as per SCID clinical interview.
3. PHQ-9 score = or \> than 10 (to maintain minimal severity of symptoms in the MDD sample)
4. Comprehension of instructions in the English language.
5. Capacity to provide informed consent and follow study procedures.
6. Availability for the duration of the study.

Exclusion Criteria

Any individual who meets any of the following criteria at the time of enrollment will be excluded from participation:

1. Implanted medical devices, metallic implants, or drug infusion pumps that are not MRI-safe (e.g., aneurysm clips, defibrillators, or cochlear implants)
2. History of significant medical events (e.g., stroke, seizures, brain scarring) or neurological/neurodevelopmental conditions (e.g., epilepsy) that are contraindications for TMS and MRI or may adversely affect brain function and data interpretation.
3. Current psychosis, mania, or substance use disorder
4. Prior failed response to full rTMS or ECT/MST trial. Any successful prior treatments are acceptable and support a prognosis that a new rTMS treatment would be worth attempting.
5. Inability to complete an MRI scan (e.g., claustrophobia, inability to remain still for extended periods).
6. Inability to tolerate TMS administration
7. Significant handicaps that would interfere with testing procedures
8. Acute systemic infection, high fever
9. Acute sleep deprivation or medication/substance intoxication or withdrawal (TMS seizure risk)
10. Current use of cyclosporine, tacrolimus, or others that can cause leukoencephalopathy.
11. Pregnancy
12. Dialysis
13. Suicide attempt in past 6 months (safety precaution); similarly, if ideation is particularly pronounced, Drs. Oathes and Sheline will decide with the patient whether the benefit of participating in a sham controlled (all patients given the option to receive active treatment eventually) study outweighs the risks. If the patient has a mental health provider and acquiesces, consultation with the provider will also be instrumental in this decision.
14. Current use of Bupropion (Wellbutrin) above 300 mg, benzodiazepines, lithium, monoamine oxidase inhibitors (MAOIs), and/or high doses of stimulant medication is exclusionary. Note: Exclusionary dosages or medications may be reduced or discontinued under the supervision of a medical provider. For detailed information please refer to section 5.3.1.
15. Transportation limits or physical limits to attending daily M-F treatment sessions.
16. Per study physician discretion medications likely to interfere with blood flow or otherwise compromise functional imaging measures.
17. Any other factor that in the investigators' judgment may affect patient safety or compliance (e.g. distance greater than 100 miles from procedure site; unlikely to be able to schedule daily treatment sessions, etc.)

Study Participation Expectations

During this study, participants will be asked to:

1. Refrain from substance use (including marijuana and illicit drugs) for the duration of the study (self-attestation alone)
2. Abstain from alcohol for 24 hours before study visits (self-attestation alone)
3. Maintain a consistent level of caffeine consumption throughout the study period and avoid any significant increases (self-attestation).
4. Not initiate, discontinue, or adjust any psychiatric medications or therapy treatments during the study period.
5. Inform the study team of any new medical treatments or prescribed medications (e.g., antibiotics) to allow for safety review and determination of continued eligibility for the study.

Participants who do not follow these considerations will be evaluated on a case-by-case basis. Principal Investigator will determine if study withdrawal is appropriate.

• Philadelphia, Pennsylvania, United States