Functional abnormalities of the globus pallidus interna (GPi) are linked to psychosis severity and treatment response in schizophrenia. Transcranial ultrasound stimulation (TUS) is a noninvasive method for precisely targeting deep brain structures. The effects of GPi-targeted TUS on psychosis had not been examined.
We conducted a random-order, sham-controlled, crossover pilot study assessing safety, tolerability, and preliminary efficacy of right GPi TUS for psychotic symptoms. Ten outpatients (mean age 37.5; 50% female) with schizophrenia or schizoaffective disorder and persistent psychosis received one TUS and one sham session, one week apart. TUS was MRI-guided, targeting right GPi with a 350 kHz transducer (100 Hz pulse repetition frequency, 5% duty cycle, in situ Ispta 400 mW/cm²).
Outcomes—delusion experience sampling assessment (DESA) and auditory hallucinations rating scale (AHRS)—were measured before, during, and immediately, 1 h, 1, and 7 days after stimulation. DESA scores decreased significantly more after TUS than sham (p = 0.002, Cohen’s d = 0.68); AHRS and cognition changes were not significant. Mild transient adverse effects occurred in both conditions; none were serious.
GPi-targeted TUS was safe, well-tolerated, and associated with a preliminary reduction in delusional severity, warranting further study in larger, randomized trials. ClinicalTrials.gov: NCT05643196, registered 21 November 2022. Neuroimaging and electrophysiological studies have implicated the cortico-striatal-pallido-thalamic (CSPT) circuit in schizophrenia1.
A key component of the CSPT circuit is the globus pallidus interna, which is the primary output structure of the dorsal striatum and conveys the dopaminergic indirect pathway linking the striatum with the thalamus. Our group studied unmedicated individuals with first-episode schizophrenia and found right anterior GPi functional hyperconnectivity compared to controls2. The right anterior GPi connectivity to the dorsal anterior cingulate gyrus was positively associated with severity of psychotic symptoms and strongly predicted treatment response after 8 weeks2, supporting the right GPi as a target for neuromodulation.
Low-intensity transcranial ultrasound stimulation (TUS) is a potentially ideal method to probe the CSPT circuit, since TUS can target deep structures with high resolution. TUS modulates neuronal excitability in animals3,4,5. In humans, TUS applied to both cortical and subcortical structures has demonstrated neuromodulatory effects without serious adverse effects6,7,8,9,10.
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