Ultrasound Neuromodulation of Circuits and Negative Valence Systems in Treatment-Resistant Depression

Inclusion criteria

• Persons 18-65 years old, with sex and ethnicity recruitment targets including a M:F proportion of 1:2 and White:Black:Hispanic:Native American proportion as close as possible to 8:2:2:1 to reflect the regional epidemiology of TRD (63% White American; 16% African American; 14% Hispanic of any race; 5% Native American),
• DSM-5-TR diagnosis of MDD as confirmed by MINI structured interview followed by consultation with a board-certified psychiatrist,
• Evidence of treatment resistance defined as continued MDD symptoms despite any of the following:
• two or more adequate (6 week) trials of antidepressants with different mechanisms,
• evidence-based psychotherapy,
• augmentation agent (lithium, atypical antipsychotic, or T3), or
• consideration of ECT or prior ECT nonresponse or intolerance,
• at least moderate symptoms as indicated by MADRS≥20 upon screening
• stable treatments including psychotherapy and medication for at least six weeks prior to participation.
• Fluent English speaker, capable of written consent
• Consent that random observations of pathology are possible (e.g., brain abnormality seen during imaging)

Exclusion criteria

• Clinical history of at least minor neurocognitive disorder of neurodegenerative origin,
• PROMIS (Cognitive Function scale) score ≤40 (i.e., mean - 1SD), collected at baseline
• clinical history of relevant structural pathology of the central nervous system, including Parkinson's disease, multiple sclerosis, and brain malignant neoplasia,
• uncontrolled diabetes mellitus (as evidenced by a fasting glycemia ≥ 120 mg/dL or hemoglobin A1c ≥ 6.5%) or hypertension (as evidenced by two consecutive readings ≥ 140/90 mmHg) to ensure medical stability, collected at baseline
• pregnancy or lactation,
• Has positive test result(s) for alcohol or drugs of abuse (including methadone, opiates, cocaine, amphetamine/methamphetamine, and ecstasy), or substance use disorder including alcohol, stimulants, sedatives, and cannabis exceeding mild severity in the last 6 months,
• active suicidal ideation (as measured by Suicide-Risk-Assessment-C-SSRS75 "Yes" answers to items 3, 4 or 5 of Suicidal Ideation-Past 1 month section, or any "Yes" answer to any of the items of Suicidal Behavior-Past 3 months section), or any suicide attempt in the last 3 months, collected at baseline
• MRI contraindications as detected by the MRI Safety Screen, including unwillingness/unable to complete MRI scans
• medical history indicative of moderate to severe traumatic brain injury as evidenced by history of \> 5 minutes of loss of consciousness, or of skull fractures, which in theory could distort LIFU tissue propagation, and
• a current diagnosis of a psychotic disorder (e.g. schizophrenia, bipolar disorder), an eating disorder (e.g. anorexia or bulimia nervosa), learning disability, or a personality disorder that is considered by the investigator to interfere with the ability of the subject to adhere to the protocol (e.g., narcissistic personality disorder, borderline personality disorder).
• Has a history of moderate or severe substance or alcohol use disorder according to DSM-5-TR
• Use of benzodiazepines or anticonvulsants in the 7 days prior ot screening
• Medical, psychiatric, or other conditions that restrict the patient's following abilities: to interpret the study information, to give informed consent, to adhere to the rules of the protocol, or to complete the study.
• No reliable method of communication (i.e., no access to internet or phone connection)
• Prescription of a medication outside of the accepted range, as determined by best clinical practices and current research
• Unwilligness or inability to complete any of the major aspects of the study protocol
• Non-correctable vision or hearing problems