Safety of Repeated Low-Intensity Focused Ultrasound Across Three Brain Regions Assessed With MRI

A preclinical safety study reports that repeated transcranial focused ultrasound stimulation (FUS), when combined with magnetic resonance acoustic radiation force imaging (MR-ARFI), produced no detectable tissue damage in macaque brains. The findings are significant because MR-ARFI requires higher acoustic pressures than standard neuromodulation, raising concerns about whether repeated sonication could cause microbleeds, edema, or lesions.

Researchers conducted repeated neuromodulation sessions in six macaque monkeys, targeting three distinct brain regions: the thalamic ventroposterior lateral (VPL) nucleus, the anterior cingulate cortex (ACC), and the periaqueductal gray (PAG). These sites were chosen to represent cortical, deep brain, and brainstem targets. Safety monitoring relied on susceptibility-weighted imaging (SWI) and fluid-attenuated inversion recovery (FLAIR) MRI sequences, which are sensitive to microbleeds, edema, and structural injury.

MRI signals from each target region were quantified and compared with control regions of interest with similar tissue properties. Across all sessions, signal variability remained within two standard deviations, meeting the study’s threshold for “no detectable damage.” Follow-up intervals ranged from two weeks to more than one year, allowing evaluation of both short-term and longer-term effects. Histologic analysis was also performed on one PAG target using Hematoxylin and Eosin and glial fibrillary acidic protein stains, showing evenly distributed staining without evidence of tissue damage or neuroinflammation.

Overall, the study found no imaging or histologic evidence of injury in any targeted brain region. The authors note that this includes both neuromodulation pulses delivered within current guidelines and MR-ARFI pulses that exceeded guideline limits. The results support a preliminary safety profile for repeated MR-guided FUS neuromodulation and suggest the approach may be suitable for clinical translation when similar protocols are used.