Mechanisms Evaluating Striatal Systems Imaging: LIFU Effects & Outcomes (MESSI-LEO)

Mechanisms of Low-intensity Focused Ultrasound Targeting Striatal Circuits Underlying Auditory Hallucinations in Schizophrenia

Individuals with schizophrenia often experience persistent auditory hallucinations despite treatment with antipsychotic medications. Research suggests that abnormal communication between the striatum and the auditory cortex contributes to hallucinations. This first-in-human, proof-of-concept Phase 1 study will evaluate the safety, feasibility, and preliminary effects of repeated-session low-intensity focused ultrasound (LIFU), a non-invasive neuromodulation technique targeting the striatum. The study will examine whether LIFU can safely modulate brain circuits involved in hallucinations, reduce abnormal communication between the striatum and auditory cortex, and improve auditory hallucination symptoms.

Study Overview

• Status: Not yet recruiting
• Conditions: Schizophrenia; Auditory Hallucinations
• Intervention / Treatment: Device: LIFU

Detailed Description

Background:

Auditory hallucinations affect approximately 70% of individuals with schizophrenia and often persist despite antipsychotic treatment, contributing substantially to disability and reduced quality of life. Neuroimaging studies have consistently demonstrated abnormal functional connectivity between the striatum and superior temporal cortex, implicating corticostriatal circuitry in the generation and maintenance of hallucinations. Among striatal regions, the caudate has been associated with aberrant self-monitoring, abnormal predictive processing, and hallucination severity, making it a promising therapeutic target. The current study builds on these findings by evaluating whether non-invasive neuromodulation of the caudate can normalize striatal-temporal network function and improve hallucination symptoms.

Study Objective:

This first-in-human, early Phase 1 investigator-initiated clinical trial will evaluate the safety, feasibility, tolerability, target engagement, and preliminary mechanistic effects of repeated-session low-intensity focused ultrasound (LIFU) targeting the caudate, a key striatal region implicated in auditory hallucinations in schizophrenia. The study will determine whether individualized LIFU can safely modulate deep corticostriatal circuits and reduce hallucination-related functional connectivity abnormalities while improving psychotic hallucination symptoms.

Study Design:

Participants with schizophrenia and persistent clinically significant auditory hallucinations will undergo MRI-guided, neuronavigated LIFU targeting an individualized caudate target, a key striatal region implicated in hallucination-related corticostriatal circuitry. The study incorporates repeated-session stimulation with sham control to evaluate safety, feasibility, neural target engagement, and preliminary efficacy. Resting-state functional MRI will be obtained before and after treatment to quantify changes in functional connectivity between the caudate and superior temporal cortex. Clinical outcomes will include validated measures of auditory hallucination severity, psychiatric symptoms, tolerability, and adverse events.

Scientific Rationale:

LIFU provides a unique capability to non-invasively modulate deep brain structures with millimeter spatial precision that cannot be reached using conventional non-invasive brain stimulation approaches. By targeting the caudate, this study seeks to directly test the causal role of striatal circuitry in hallucination generation and determine whether modulation of corticostriatal connectivity produces measurable improvements in hallucination symptoms. The results will establish the safety and feasibility of this approach while providing mechanistic evidence to guide future randomized efficacy trials of circuit-based neuromodulation for schizophrenia.

Safety and Feasibility of LIFU This study has been designated a non-significant risk (NSR) device study by the UCSF Institutional Review Board and follows International Transcranial Ultrasonic Stimulation Safety and Standards Consortium (ITRUSST) recommendations. Individualized MRI-guided targeting and subject-specific acoustic simulations will optimize focal targeting while maintaining acoustic exposure within established safety limits. Participants will undergo continuous monitoring during treatment, structured adverse-event assessments using Common Terminology Criteria for Adverse Events (CTCAE) criteria, repeated tolerability assessments, and psychiatric safety monitoring throughout the study. Preliminary studies demonstrated that caudate-targeted LIFU was well tolerated, with no device-related adverse events beyond mild transient auditory sensations, supporting the safety and feasibility of repeated-session caudate-targeted LIFU in schizophrenia.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Karuna Subramaniam, PhD; Phone Number: 415-476-6888; Email: karuna.subramaniam@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94158
      • University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18-64 years of age, inclusive of all gender identities
2. Current DSM-5 diagnosis of schizophrenia
3. Persistent clinically-significant auditory hallucinations
4. No contraindications for MRI, confirmed via standard safety screening procedures
5. No neurological disorder
6. Clinically stable (outpatient past 12 weeks; same dose medications in 4 weeks)
7. Females will be tested for pregnancy and pregnant women will be excluded.

Exclusion Criteria:

Clinically significant neurological disorder or MRI incompatibility

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active LIFU; Active LIFU targeting teh caudate	Device: LIFU; MRI-guided, neuronavigated low-intensity focused ultrasound (LIFU) delivered to the caudate target will be compared to sham unfocused sonication delivered using the same device and procedures as the active intervention but without focal ultrasound energy to the target.; Other Names: Active LIFU targeting the caudate; Sham Unfocused Sonication
Placebo Comparator: Sham Sonication; Sham Unfocused Sonication	Device: LIFU; MRI-guided, neuronavigated low-intensity focused ultrasound (LIFU) delivered to the caudate target will be compared to sham unfocused sonication delivered using the same device and procedures as the active intervention but without focal ultrasound energy to the target.; Other Names: Active LIFU targeting the caudate; Sham Unfocused Sonication

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Auditory Hallucinations	We will compare hallucinations after LIFU to caudate with baseline and the sham unfocused sonication condition using the Visual Analog Scale (VAS) and Auditory Vocal Hallucination Rating Scales (AVHRS).	Baseline and Post-Treatment (Weekly follow-up for 8 weeks)
Caudate-superior temporal cortical (STC) connectivity	We will compare functional connectivity using Fisher r-to-z values from the CONN toolbox between the caudate and STC after LIFU compared to baseline and the sham unfocused sonication condition	Baseline and Post-Treatment ( Day 5)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Positive and Negative Symptoms	We will compare positive and negative symptoms using the Positive and Negative Syndrome Scale (PANSS) after LIFU targeting the caudate with baseline and the sham unfocused sonication condition.	Baseline and Post-Treatment (Weekly follow-up for 8 weeks)

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Attune Neurosciences Inc
• Investigators: Principal Investigator: Karuna Subramaniam, PhD, karuna.subramaniam@ucsf.edu

Publications and helpful links

General Publications

• Subramaniam K, Attalla G, Mathew M, Alvarez JL, Dadgar-Kiani E, Mahadevan R, Nagarajan S, Murphy KR. Low-intensity focused ultrasound targeting striatal circuits in schizophrenia: feasibility, safety, and effects on hallucinations and striatal-temporal functional connectivity. Brain Stimul. 2026 May-Jun;19(3):103084. doi: 10.1016/j.brs.2026.103084. Epub 2026 Mar 21. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2027
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: July 6, 2026
• First Submitted That Met QC Criteria: July 13, 2026
• First Posted (Actual): July 17, 2026

Study Record Updates

• Last Update Posted (Actual): July 27, 2026
• Last Update Submitted That Met QC Criteria: July 24, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: schizophrenia; auditory hallucinations; striatum; LIFU; caudate
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Neurobehavioral Manifestations; Perceptual Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Schizophrenia; Hallucinations
• Other Study ID Numbers: 24-42726; 1685505 (Other Grant/Funding Number: Focused Ultrasound Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No