Overview
This is a double-blind, within-participant crossover, multi-site dose-finding study evaluating the safety, feasibility, and preliminary efficacy of repeated low-intensity focused ultrasound (LIFU) stimulation using the ATTN201 device across seven candidate deep-brain targets in adults with subsyndromal-to-moderate depression, anxiety, or obsessive-compulsive disorder. Every session delivers active ATTN201 stimulation; there is no sham or placebo condition. Participants and the on-site study staff who deliver stimulation and administer the clinical scales are blinded to the brain target and to the stimulation parameters assigned for each session by a constrained Bayesian optimization algorithm.
Description
Following a remote pre-screen and an in-person screening/baseline visit (Visit 0), at which informed consent is obtained, eligibility is confirmed, baseline clinical scales are administered, optional biospecimens are collected from participants who consent to them, a multi-sequence brain MRI is acquired for targeting, and monitoring devices are fitted, each participant receives between 3 and 10 ATTN201 stimulation sessions spaced approximately 7 days apart. Each stimulation visit serves as the pre-stimulation baseline for that session, the 1-week post-stimulation measurement for the prior session, and the 2-week post-stimulation measurement for the session before that. A platform-administered scale battery at day 7 after the last stimulation captures the 1-week measurement for the final session; a remote final treatment-period follow-up approximately 2 weeks after the last stimulation captures the 2-week measurement. A remote 3-month post-treatment check-in captures durability and any delayed adverse events.
The trial uses a two-stage architecture. In Stage 1, visits are allocated across all seven candidate targets. After approximately 300 visits, the Sponsor and ARPA-H convene a joint review and select 3-5 targets for continued Bayesian optimization in Stage 2.
Monitoring during enrollment includes validated clinical scales (PHQ-9, GAD-7, OCI-R) at baseline, before each stimulation visit, at the final treatment-period follow-up, and at the 3-month follow-up; transdiagnostic visual analog scales, a morning sleep diary, and brief voice recordings prompted through the Attune platform during monitoring blocks; optional nightly ambulatory EEG; and a smart watch worn from Visit 0 through device return. All scheduled platform prompts are voluntary at the individual-prompt level.
Blinding: A single on-site research associate positions the device, runs the stimulation session, and administers participant-facing assessments, and is blinded to the brain target and parameter combination; this individual occupies both the care provider and the outcomes assessor role. The stimulation condition is selected by the Bayesian optimization algorithm and pushed to the device as a sealed session. The Lead Principal Investigator and the optimization team are unblinded as required to operate the adaptive design and do not deliver stimulation or administer participant-facing assessments. The independent Medical Monitors and the Data Safety and Monitoring Board receive unblinded safety data.
Eligibility
Inclusion Criteria:
- Be between 22 and 80 years of age (inclusive) on the day of signing informed consent.
- Have at least one of the following at screening: PHQ-9 total score 5-16 (depression), GAD-7 total score 5-14 (anxiety), or OCI-R total score 14-27 (obsessive-compulsive disorder).
- If currently taking psychiatric medication, have been on the same stable dose(s) for at least 4 weeks prior to screening and be willing to maintain the regimen throughout the treatment period.
- Be able and willing to undergo a multi-sequence cranial MRI.
- Be willing to use the ATTN201 device during stimulation visits and to attempt use of monitoring devices (optional ambulatory EEG system, smart watch) during the pre- and post-stimulation monitoring blocks; use of the optional ambulatory EEG system does not affect eligibility.
- Sign the informed consent form, in accordance with local requirements, after the scope and nature of the investigation have been explained to the participant, and before any screening assessments.
- Be able to speak, read, and understand English.
- Be able to use a smartphone and the Attune platform.
- Possess the ability to respond verbally to questions, follow instructions, and complete study assessments.
- Be able to adhere to the treatment protocol and visit schedules through the 3-month post-treatment follow-up.
- Be judged by the investigator as likely to comply with study procedures and willing to participate in the entirety of the study.
- Be determined by the investigator to be medically stable at baseline as assessed by medical history and non-significant clinical results of a vital signs examination.
- Male participants must ensure a condom is used for all sexual intercourse and follow acceptable methods of contraception for their female partner for the entire duration of the study and for 90 days after the final study visit. Male participants should not father a child or donate sperm during this same period.
- Female participants who are sexually active agree to use two methods of contraception for the duration of the study and for 30 days after the final study visit, or not be of childbearing potential as indicated by natural menopause (≥12 consecutive months of spontaneous amenorrhea), hysterectomy, bilateral tubal ligation, bilateral oophorectomy (with or without hysterectomy) more than 6 weeks prior to screening, or a vasectomized partner with documented absence of sperm.
Exclusion Criteria:
- Columbia Suicide Severity Rating Scale (C-SSRS) score ≥ 3 (ideation with intent, with or without plan) at screening.
- Any suicide attempt within the past 12 months.
- Any change in psychiatric medication (start, stop, or dose change) within 4 weeks prior to screening.
- Has an unstable or severe medical or psychiatric condition that, in the investigator's judgment, would pose a safety risk to the participant or prevent completion of study procedures. Stable comorbid conditions (e.g., treated depression, anxiety, OCD, insomnia) within the protocol-specified score windows are permitted.
- Has an active, unstable substance use disorder including alcohol use disorder in the past 6 months (except for caffeine and nicotine). Participants on stable medication-assisted treatment (e.g., buprenorphine, methadone, naltrexone) for at least 6 months are eligible.
- Has a history of moderate-to-severe traumatic brain injury, or mild traumatic brain injury within the past 12 months.
- Has a history of seizure disorder or epilepsy, or any structural CNS lesion known to lower seizure threshold.
- Has any contraindications for completing a brain MRI scan (e.g., pacemaker, ferromagnetic implants).
- Body mass index (BMI) greater than 40 kg/m².
- Is pregnant, is attempting to become pregnant, or is nursing.
- Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling, or child) who is an investigational site or Sponsor staff member directly involved with this trial.
- Has a known allergy or sensitivity to ultrasound gel, silicone, or adhesive materials used in monitoring devices.
- Has an active skin condition at sensor placement sites that would prevent device wear.
- Has received an investigational drug or device in another clinical study within 30 days before screening
