Focused and unfocused transcranial ultrasound stimulation in Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND

Transcranial ultrasound stimulation (TUS) is a non-invasive method that allows deep brain structures to be targeted, and it may benefit individuals with Alzheimer'sdisease (AD). We conducted a systematic review and meta-analysis to assess the effect of TUS on global cognitive function in mild-to-moderate AD, comparing focused transcranial pulse stimulation (TPS) with unfocused low-intensity pulsed ultrasound (LIPUS).

METHODS

We searched PubMed, Scopus, Cochrane, and Web of Science for randomized controlled trials (RCTs) comparing TUS with sham stimulation. The primary outcome was the change in global cognitive function. Secondary outcomes included functional status,depressive symptoms, and safety.

RESULTS

Three RCTs (N=84) were included. Pooled analysis showed that TUS did not significantly improve global cognition compared with sham (SMD=0.31, p=0.54). However,subgroup analysis showed a significant difference between modalities (p=0.047):unfocused LIPUS had a larger effect size (SMD=0.73) than focused TPS (SMD=0.17).Notably, significant cognitive improvement was observed in patients <70 years. Active treatment showed higher disease stabilization rates ("responders"), reduced depressive symptoms (specifically TPS, p=0.008), and improved cerebral perfusion without amyloid-related imaging abnormalities (ARIA).

CONCLUSION

While pooled analyses did not show a global cognitive benefit, the results favoured unfocused LIPUS over focused TPS; TUS had an excellent safety profile and higher disease stabilization rates; the potential benefits in younger populations and the biological effects suggest that TUS is a promising adjunct that should be further optimized for stimulation. REGISTRATION: This review was registered on PROSPERO (CRD420251276660).