Low-intensity focused ultrasound stimulation in stroke: An intensity escalation phase I safety and feasibility study

BACKGROUNDLow-intensity focused ultrasound stimulation (LIFUS) has recently emerged as a promising neuromodulation tool for certain neuropsychiatric diseases. However, its safety and feasibility in stroke patients remains unknown. Intensity is a critical safety parameter for LIFUS. We aimed to determine the maximum safe and tolerable intensity of LIFUS in stroke patients, and to explore its effect on upper-extremity motor learning and corticospinal excitability. METHODSSubjects with first-ever stroke participated in this Phase I study. We adopted the classic 3+3 dose-escalation paradigm to sham/0, 1, 2, 4, 6, and 8 W/cm2 spatial-peak pulse-average intensity (ISPPA, estimated in-vivo transcranial value; LOW: sham/0, 1 and 2 W/cm2, HIGH: 4, 6 and 8 W/cm2). Stopping rules (dose limiting toxicities) were pre-defined: [≥]2nd-degree scalp burn, clinical seizures, [≥]20% topical apparent diffusion coefficient change, or participant discontinuation due to any reason. A 12-minute LIFUS was applied over the ipsilesional motor cortex while participants were concurrently practicing three blocks of motor sequence learning (MSL) task using the affected hand. We collected the occurrences of pre-defined adverse events, post-minus-pre improvements in MSL response time, and post-minus-pre differences in corticospinal excitability quantified by motor evoked potentials. RESULTSISPPA was escalated to 8 W/cm2 with eighteen stroke participants without meeting stopping rules. Compared to the LOW, the HIGH performed significantly better on the MSL (24.7{+/-}13.3% vs. 13.2{+/-}10.9%, p=0.01). Similarly, the HIGH also showed signs of increased corticospinal excitability (32.0{+/-}34.3% vs. 12.9{+/-}48.0%) but did not reach significance, p=0.53. CONCLUSIONSOur Phase I safety study suggests that a single session of 12-minute LIFUS up to 8 W/cm2 ISPPA is safe and feasible in stroke patients. Higher LIFUS intensities can induce greater MSL retention. The next logical step is to conduct a Phase II study to further test the efficacy of LIFUS and monitor its safety profiles in stroke patients. REGISTRATIONURL: https://www.clinicaltrials.gov; Unique identifier: NCT05016531