Abstract
BACKGROUND: Auditory hallucinations are among the most disabling symptoms in individuals with schizophrenia (SZ) and are linked to aberrant signaling within deep-striatal circuits, such as the nucleus accumbens (NAc) and caudate head (CH). However, causal tests of striatal involvement have been limited by the inaccessibility of these structures using noninvasive neuromodulatory techniques. Low-intensity focused ultrasound (LIFU) provides millimeter-scale precision capable of modulating deep-brain circuits, but its feasibility and impact on hallucinations in SZ remain unknown. METHODS: SZ participated in a within-subject cross-over feasibility trial including two active LIFU sessions (NAc, CH) and one sham control (unfocused sonication), spaced one-week apart. Resting-state fMRI and hallucination symptoms were acquired at baseline and immediately post-sonication. RESULTS: LIFU was delivered safely and well-tolerated in all patients. Acoustic simulations show consistent engagement of both striatal targets across subjects. Clinically, SZ demonstrated significant reductions in hallucination severity following active LIFU to NAc and CH, relative to baseline. Mechanistically, SZ exhibited abnormally high striatal-superior temporal cortex (STC) connectivity at baseline. Immediately after sonication, active LIFU to NAc and CH produced robust reductions in striatal-STC coupling in SZ. CONCLUSIONS: This first-in-human study demonstrates that deep striatal LIFU is safe, feasible, and produces functional-connectivity changes accompanied by hallucination severity reductions in SZ. The convergence of symptom improvement with reduced striatal-STC coupling provides mechanistic proof-of-concept evidence that this circuit provides a promising biomarker and therapeutic LIFU target in psychosis and motivates larger sham-controlled trials to test the causal role of striatal circuitry in hallucination generation in SZ.