Effect of Low Intensity Transcranial Ultrasound Stimulation on Neuromodulation in Animals and Humans: An Updated Systematic Review.

Background: Although low-intensity transcranial ultrasound stimulation (LI-TUS) has received more recognition for its neuromodulation potential, there remains a crucial knowledge gap regarding the neuromodulatory effects of LI-TUS and its potential for translation as a therapeutic tool in humans. Objective: In this review, we summarized the findings reported by recently published studies regarding the effect of LI-TUS on neuromodulation in both animals and humans. We also aim to identify challenges and opportunities for the translation process. Methods: A literature search of PubMed, Medline, EMBASE, and Web of Science was performed from January 2019 to June 2020 with the following keywords and Boolean operators: [transcranial ultrasound OR transcranial focused ultrasound OR ultrasound stimulation] AND [neuromodulation]. The methodological quality of the animal studies was assessed by the SYRCLE's risk of bias tool, and the quality of human studies was evaluated by the PEDro score and the NIH quality assessment tool. Results: After applying the inclusion and exclusion criteria, a total of 26 manuscripts (24 animal studies and two human studies) out of 508 reports were included in this systematic review. Although both inhibitory (10 studies) and excitatory (16 studies) effects of LI-TUS were observed in animal studies, only inhibitory effects have been reported in primates (five studies) and human subjects (two studies). The ultrasonic parameters used in animal and human studies are different. The SYRCLE quality score ranged from 25 to 43%, with a majority of the low scores related to performance and detection bias. The two human studies received high PEDro scores (9/10). Conclusion: LI-TUS appears to be capable of targeting both superficial and deep cerebral structures to modulate cognitive or motor behavior in both animals and humans. Further human studies are needed to more precisely define the effective modulation parameters and thereby translate this brain modulatory tool into the clinic.

Introduction

Purpose Transcranial ultrasound stimulation

Study Objective To systematically review recent animal and human studies on low-intensity transcranial ultrasound stimulation (LI-TUS) neuromodulatory effects and identify challenges and opportunities for clinical translation.

Animal model / Human subject Multiple species (24 animal studies and 2 human studies); specific species, strain, age, and sex not specified in the provided text.

Disease model Neuromodulation (not disease-specific; includes healthy subjects and various animal models)

MRI or image guidance method Not specified in the provided text

Targeted brain region(s) Superficial And Deep Cerebral Structures

Cargo name and characteristics Low-intensity transcranial ultrasound stimulation (LI-TUS) — a non‑invasive physical neuromodulation modality using focused or unfocused ultrasound waves applied transcranially. Used experimentally to modulate neuronal activity (excitatory or inhibitory) in animals and humans; parameters varied across studies (frequency, intensity, pulse duration, duty cycle, sonication duration), capable of targeting superficial and deep brain structures.

Route of administration Not applicable (no drug/cargo delivered); intervention was noninvasive transcranial ultrasound stimulation applied through the skull

Outcomes and Safety

Summary of Outcomes Low-intensity transcranial ultrasound stimulation noninvasively modulates neural activity and functional connectivity to alter motor and cognitive behaviors—producing both excitatory and inhibitory effects in animals but predominantly inhibitory effects in primates and humans.

Duration of biological effect 0–0.5 s

Safety-related matter The authors state LI-TUS appears non-invasive and likely safe—citing no serious adverse events reported among 64 of 120 participants in prior studies—but emphasize that dedicated, systematic safety investigations are lacking and required.

Brain Region

Ultrasound Parameters

Ultrasound instrument Not specified in the provided text

FUS Frequency Not reported in the provided text

FUS Intensity Not reported

FUS Pressure Not reported in the provided text.

FUS Mode pulsed

Pulse duration Not reported in the provided text.

Duration of a single FUS session Not reported

Focal Characteristics superficial and deep cerebral structures

Treatment frequency Both single and multiple sessions

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