Transcranial focused ultrasound stimulation in schizophrenia: current evidence, mechanisms, and future directions

Schizophrenia disrupts large-scale brain networks, especially circuits linking cortical and deep subcortical structures. Transcranial focused ultrasound stimulation (tFUS) is an emerging non-invasive neuromodulation technique with the capacity to target deep brain regions with high spatial precision. However, clinical evidence for tFUS in schizophrenia remains limited.

This narrative review synthesizes available preclinical and clinical evidence, with particular attention to mechanisms, safety, stimulation targets, methodological limitations, and translational challenges.

In dizocilpine (MK-801) rodent models, tFUS has been reported to reverse cognitive deficits, prevent psychotic-like behaviors, restore parvalbumin-positive GABAergic interneuron markers in the prefrontal cortex, and upregulate NMDA receptor-related signaling. In patients with schizophrenia, early studies suggest that tFUS is feasible and generally well tolerated. Reported targets include the dorsolateral prefrontal cortex (DLPFC) for negative symptoms, the globus pallidus/globus pallidus internus for sensory gating-related circuits, and striatal circuits for auditory hallucinations. Efficacy data remain preliminary.

Key challenges include bone-conducted auditory confounds that may compromise blinding, incomplete and heterogeneous stimulation-parameter reporting, small sample sizes, short follow-up periods, and limited evidence for durable clinical benefit.

Future studies should use rigorous sham or auditory-masking procedures, adopt standardized reporting frameworks such as the ITRUSST recommendations, and move from feasibility studies toward larger, circuit-specific, hypothesis-driven trials.

Preclinical and early clinical studies suggest that tFUS may have therapeutic potential in schizophrenia, but current evidence is insufficient to support definitive clinical conclusions. Larger well-controlled studies are required.