Ultrasound neuromodulation as a novel dementia therapy-Investigation of possible long-term confounds

Ultrasound neuromodulation has emerged as a promising adjunctive therapy in Alzheimer's disease (AD), yet a controversial issue remains: whether its reported long-term therapeutic effects could be attributed to potential confounds rather than genuine neuromodulatory mechanisms. Although auditory confounds via air- or bone-conducted sound have been discussed for immediate effects, their relevance for enduring therapeutic outcomes-essential for clinical application-remains unknown. This exploratory study is the first to examine whether long-term cognitive and neural effects of transcranial pulse stimulation (TPS) in AD are linked to persistent auditory network activation.

A comprehensive re-analysis of task-based and resting-state functional magnetic resonance imaging (fMRI) data was conducted using data from the currently largest sham-controlled clinical ultrasound neuromodulation study (Matt et al., 2025). To isolate possible auditory contributions, we applied a contrast-based framework targeting (1) air-conducted sound, (2) combined air- and possibly bone-conducted sound, and (3) bone-conduction-specific effects. Analyses included: (a) task-based auditory cortex co-activation, (b) functional connectivity between auditory and dorsal attention networks (the latter was modulated in the original study), (c) global efficiency within the auditory network, and (d) correlations with neuropsychological test battery scores.

No significant long-term activation of auditory cortices was observed in task-based fMRI. Resting-state analyses showed no altered connectivity between auditory and attention networks, no changes in auditory network global efficiency, and no associations between auditory metrics and cognitive performance. Effect-size estimates were small, and 95% confidence intervals placed conservative upper bounds that argue against sizeable, sustained auditory confounds. These findings were consistent across all contrast conditions.

Using data from a rigorously controlled cognitive trial, we found no evidence of long-term auditory network effects following TPS. This makes it unlikely that auditory confounds are a key factor underlying the cognitive network effects observed with long-term ultrasound neuromodulation in typical verum-sham settings as investigated here.

Long-term transcranial pulse stimulation effects were evaluated for potential auditory confounds using functional magnetic resonance imaging (fMRI).Analyses included task-fMRI, resting-state functional connectivity, and auditory network efficiency.No auditory long-term effects were detected.Auditory confounds are unlikely to be the key factor for cognitive network effects.