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

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.