This study will observe changes in brain imaging, behavior, and symptom measures following intervention with low intensity focused ultrasound pulsation (LIFUP) targeting reward circuitry in individuals who are depressed and anhedonic.

Participants will wear a provided Apple watch and download a study app to their personal phones in order for activity and phone use metrics to be collected. Participants will respond to weekly email surveys, daily ecological momentary assessment (EMA) surveys, complete computer-based neurocognitive assessments, undergo a baseline MRI scan with spectroscopy, receive 3 sessions of LIFUP sonication, undergo a follow up MRI with spectroscopy, then continue to be followed with surveys, neurocognitive assessment, and watch/phone data collection for 3 weeks after follow up MRI scan.

Participants will be randomized 1:1 active:sham to receive LIFUP targeting the caudate head of the brain. Conditions will be double blinded so that neither participants nor investigators or research staff know if active or sham sonication is being administered.

Inclusion Criteria:

• • Between the ages of 18 and 65

  • Fluent in English

  • Own functioning iOS smart phone (iPhone 8 or later, iOS 15 or newer) with access to reliable data plan and Wi-Fi

  • Right-handed

  • Normal or corrected to normal vision

  • Willingness to participate in the study, including wearing the provided Apple Watch, respond to remote survey prompts, complete an MRI scan, and provide a recorded interview.

  • Able to read and understand a written informed consent form

  • Reside in the Los Angeles area for the duration of the study

  • If enrolled in IRB#22-000059, have completed the majority of assessments.

  • Eligible for MRI scanning and neuromodulation

  • Willing to receive LIFUP, participate in another MRI scan, keep a study app on their personal phone, and complete 5-7 weeks of assessments.

  • PVSS <6.5 at screening

    • If screened from the general population, PVSS severity must be endorsed in self-report as having lasted for a period of at least 3 months.
    • If screened from IRB#22-000059 scores must average <6.5 at week 6, and stable through study exit. "Stable" defined as the average of all PVSS scores from week 6 through study exit is <6.5

  • PHQ scores > 10 at screening

    • If screened from the general population, PHQ severity must be endorsed in self-report as having lasted for a period of at least 3 months.
    • If screened from IRB#22-000059 scores must average >/= 10 at week 6, and stable through study exit. "Stable" defined as the average of all PHQ scores from week 6 through study exit is >/=10

Exclusion Criteria:

• Current tobacco smoker of >11 cigarettes/day or the nicotine equivalent
• Current report of alcohol or substance abuse or dependence
• Recent changes in antidepressant dosing or medication (dose and medication need to be stabilized within the last 2 weeks)
• Any diagnosis of major neurological condition impairing mobility, cognition, or language ability including multiple sclerosis, Parkinson's disease or other movement disorder, motor neuron disease, stroke, dementia
• Any other diagnosis involving chronic mobility impairment including spinal cord injuries, or severe osteoarthritis of knee or hip
• Reported diagnosis of schizophrenia or psychotic symptoms
• Participants currently taking benzodiazepines must agree to refrain from taking this medication for 12 hours before their scan, as well as refrain from any allergy or cold medication (diphenhydramine) that causes sleepiness (e.g. Benadryl).
• History of brain tumor or brain surgery
• History of stroke or seizure
• Contraindications for MRI scanning, including pregnancy, metal implants, braces, significant grip impairment and claustrophobia
• Unable to complete 3 LIFUP sessions within 1 month of completing the MRI scan for IRB#22-000059
• Unable to complete an MRI scan
• Currently taking benzodiazepines, or taken benzodiazepines in the past 8 weeks
• Any previous treatment with electroconvulsive therapy (ECT) or deep brain stimulation (DBS) due to increased risk of seizure and unclear evidence of how LIFUP will affect individuals who have received these treatments.
• Less than 6 months since any other neuromodulation treatment such as transcranial magnetic stimulation (TMS), Vagal nerve electrostimulation, or transcranial direct current stimulation(TDCS).
• Less than 6 months since prescribed ketamine infusion or other intensive, acute therapy for depressive symptoms.
• History of medical event(s) likely to result in neurological abnormalities including diagnoses of Alzheimer's, Parkinson's, neurodegenerative disorders, movement disorders, or reports of seizures or history of brain tumors.
• Unwilling or unable to refrain from making significant changes to hair style after enrollment and before LIFUP sessions are complete. (ie. full hair style to shaved head, significant change in locs, etc)

Data collected will be deidentified and shared with the team members of this MC Psych research consortium under Wellcome Trust. Shared data types will include individual participant survey responses, self-report diagnostic measures, treatment history, neurocognitive performance, interview data including de-identified face and speech summary metrics, Apple watch metrics, phone usage metrics, fMRI data, demographic data.

Data is being made available throughout the course of collection, and will remain available for study for up to 10 years.

Researchers permitted access to the deidentified data from this study must be a part of the MC Psych consortium, as designated and approved by the sponsor, Wellcome Trust. All other requests for access to data from this project will be reviewed by the principal investigator for approval.