Auditory hallucinations – or hearing voices that others do not hear – affect more than 70% of people with schizophrenia. Despite treatment with antipsychotic medications, approximately 40% continue to experience persistent hallucinations. For these patients, new treatment approaches are urgently needed.
The research team at the University of California San Francisco (UCSF), led by Karuna Subramaniam, PhD, a professor of psychiatry, has launched a first-in-human Phase 1 clinical trial (NCT07710989) to evaluate the safety and feasibility of repeated low-intensity focused ultrasound (LIFU) sessions targeting the caudate, a deep brain region within the striatum that may play a role in hallucinations. The team is using a noninvasive wearable device developed by Attune Neurosciences. Enrollment is underway to investigate whether repeated treatments can produce sustained reductions in hallucinations. The trial builds on encouraging preliminary findings published in Brain Stimulation, which demonstrated that a single session of LIFU produced significant, albeit temporary, reductions in hallucinations.
The study plans to enroll up to 12 participants. Each participant will receive five daily sessions of active LIFU targeting the caudate and five sessions of a sham control (unfocused sonication), with a washout period between conditions. The unfocused control condition delivers the same amount of ultrasound energy and is designed to preserve the sensory experience of treatment, but without focusing ultrasound energy on a specific brain target. Comparing the two conditions will help researchers evaluate whether active LIFU reduces hallucination symptoms beyond any placebo or other nonspecific treatment effects.
Resting-state functional MRI will be obtained before and after treatment to examine changes in functional connectivity between the caudate and other brain regions. Clinical outcomes will include validated measures of auditory hallucination severity, other psychiatric symptoms, and mood. The study will also evaluate treatment safety, tolerability, and potential side effects.
"For many people with schizophrenia, hearing voices remains a persistent and distressing problem despite medication," said Dr. Subramaniam. "Our goal is to determine whether LIFU can safely and noninvasively target the caudate, a deep brain region that may play a role in the emergence of hallucinations, and offer a new treatment approach to reducing these symptoms."
Initial participants in the ongoing trial have reported reductions in hallucinations following repeated LIFU. One participant described the experience by saying: "I'm so surprised the voices have gone for now. My mind is really quiet."
Another participant, who had been hearing voices constantly, described their experience before treatment: "Hours can pass, and I feel like I lose track of time when I hear the voices and they seem to originate from outside and insert thoughts in my head." After treatment, the participant remarked with laughter, "I did hear one voice saying, 'I'm still here,' but the voices are softer, more like in the distant background, and seem to be going away. I feel it's very peaceful"
These early observations are preliminary but encouraging. As enrollment continues, the study will investigate whether repeated LIFU treatments can produce more sustained reductions in hallucinations and whether similar benefits are observed in additional participants.
A similar clinical trial was just published in npj Acoustics, where researchers at NYU Langone Health used a different focused ultrasound device to target the globus pallidus region of the brain in patients with schizophrenia or schizoaffective disorder. They noted a modest but clear reduction in delusions among the participants.
The Focused Ultrasound Foundation is funding the clinical study at UCSF.
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