a-methodological-protocol-considerations-for-transcranial-ultrasonic

A Methodological Protocol and Considerations for Transcranial Ultrasonic Stimulation in Exploratory Clinical Human Studies

Transcranial ultrasonic stimulation (TUS) is emerging as a non-invasive neuromodulatory technique capable of delivering millimeter-precision stimulation ...

North Carolina State University

 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.  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.  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.  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).  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.

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

Low-intensity transcranial focused ultrasound (LI-tFUS) stimulation is a noninvasive neuromodulation tool that demonstrates high target localization accuracy and depth penetration. It has been shown to modulate activities in the primary motor and somatosensory cortex. Previous studies in animals as well as in humans, illustrated in the recently published paper in  by Braun et al. [Braun V, Blackmore J, Cleveland RO, Butler CR.  13: 1527-1534, 2020], acknowledged the possibility of indirect stimulation of the peripheral auditory pathway that could confound the somatosensory and motor responses observed with LI-tFUS stimulation. Here, we discuss the implications and interpretations of auditory confounding in the context of neuromodulation.

Implication of auditory confounding in interpreting somatosensory and motor responses in low-intensity focused transcranial ultrasound stimulation.

This paper aims to review the current state of brain-to-brain interface (B2BI) technology and its potential. B2BIs function via a brain-computer interface (BCI) to read a sender's brain activity and a computer-brain interface (CBI) to write a pattern to a receiving brain, transmitting information. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to systematically review current literature related to B2BI, resulting in 15 relevant publications. Experimental papers primarily used transcranial magnetic stimulation (tMS) for the CBI portion of their B2BI. Most targeted the visual cortex to produce phosphenes. In terms of study design, 73.3% (11) are unidirectional and 86.7% (13) use only a 1:1 collaboration model (subject to subject). Limitations are apparent, as the CBI method varied greatly between studies indicating no agreed upon neurostimulatory method for transmitting information. Furthermore, only 12.4% (2) studies are more complicated than a 1:1 model and few researchers studied direct bidirectional B2BI. These studies show B2BI can offer advances in human communication and collaboration, but more design and experiments are needed to prove potential. B2BIs may allow rehabilitation therapists to pass information mentally, activating a patient's brain to aid in stroke recovery and adding more complex bidirectionality may allow for increased behavioral synchronization between users. The field is very young, but applications of B2BI technology to neuroergonomics and human factors engineering clearly warrant more research.

Direct Communication Between Brains: A Systematic PRISMA Review of Brain-To-Brain Interface.

In the past decade, acoustics at the nanoscale (i.e., nanoacoustics) has evolved rapidly with continuous and substantial expansion of capabilities and refinement of techniques. Motivated by research innovations in the last decade, for the first time, recent advancements of acoustics-associated nanomaterials/nanostructures and nanodevices for different applications are outlined in this comprehensive review, which is written in two parts. As part I of this two part review, firstly, active and passive nanomaterials and nanostructures for acoustics are presented. Following that, representative applications of nanoacoustics including material property characterization, nanomaterial/nanostructure manipulation, and sensing, are discussed in detail. Finally, a summary is presented with point of views on the current challenges and potential solutions in this burgeoning field.

Acoustics at the nanoscale (nanoacoustics): A comprehensive literature review.: Part I: Materials, devices and selected applications.

In the past decade, acoustics at the nanoscale (i.e., nanoacoustics) has evolved rapidly with continuous and substantial expansion of capabilities and refinement of techniques. Motivated by research innovations in the last decade, for the first time, recent advancements of acoustics-associated nanomaterials/nanostructures and nanodevices for different applications are outlined in this comprehensive review, which is written in two parts. As part II of this two-part review, this paper concentrates on nanoacoustics in biomedical imaging and therapy applications, including molecular ultrasound imaging, photoacoustic imaging, ultrasound-mediated drug delivery and therapy, and photoacoustic drug delivery and therapy. Firstly, the recent developments of nanosized ultrasound and photoacoustic contrast agents as well as their various imaging applications are examined. Secondly, different types of nanomaterials/nanostructures as nanocarriers for ultrasound and photoacoustic therapies are discussed. Finally, a discussion of challenges and future research directions are provided for nanoacoustics in medical imaging and therapy.

Acoustics at the nanoscale (nanoacoustics): A comprehensive literature review.: Part II: Nanoacoustics for biomedical imaging and therapy.

Low-intensity transcranial focused ultrasound (tFUS) has gained considerable attention as a promising noninvasive neuromodulatory technique for human brains. However, the complex morphology of the skull hinders scholars from precisely predicting the acoustic energy transmitted and the region of the brain impacted during the sonication. This is due to the fact that different ultrasound frequencies and skull morphology variations greatly affect wave propagation through the skull.

Numerical and experimental evaluation of low-intensity transcranial focused ultrasound wave propagation using human skulls for brain neuromodulation.

With the rapid advancement of tracking technologies, the applications of tracking systems in ultrasound imaging have expanded across a wide range of fields. In this review article, we discuss the basic tracking principles, system components, performance analyses, as well as the main sources of error for popular tracking technologies that are utilized in ultrasound imaging. In light of the growing demand for object tracking, this article explores both the potential and challenges associated with different tracking technologies applied to various ultrasound imaging applications, including freehand 3D ultrasound imaging, ultrasound image fusion, ultrasound-guided intervention and treatment. Recent development in tracking technology has led to increased accuracy and intuitiveness of ultrasound imaging and navigation with less reliance on operator skills, thereby benefiting the medical diagnosis and treatment. Although commercially available tracking systems are capable of achieving sub-millimeter resolution for positional tracking and sub-degree resolution for orientational tracking, such systems are subject to a number of disadvantages, including high costs and time-consuming calibration procedures. While some emerging tracking technologies are still in the research stage, their potentials have been demonstrated in terms of the compactness, light weight, and easy integration with existing standard or portable ultrasound machines.

Recent Advances in Tracking Devices for Biomedical Ultrasound Imaging Applications.

Due to the rapid developments in materials science and fabrication techniques, wearable devices have recently received increased attention for biomedical applications, particularly in medical ultrasound (US) imaging, sensing, and therapy. US is ubiquitous in biomedical applications because of its noninvasive nature, nonionic radiating, high precision, and real-time capabilities. While conventional US transducers are rigid and bulky, flexible transducers can be conformed to curved body areas for continuous sensing without restricting tissue movement or transducer shifting. This article comprehensively reviews the application of flexible US transducers in the field of biomedical imaging, sensing, and therapy. First, we review the background of flexible US transducers. Following that, we discuss advanced materials and fabrication techniques for flexible US transducers and their enabling technology status. Finally, we highlight and summarize some promising preliminary data with recent applications of flexible US transducers in biomedical imaging, sensing, and therapy. We also provide technical barriers, challenges, and future perspectives for further research and development.

Flexible Ultrasonic Transducers for Wearable Biomedical Applications: A Review on Advanced Materials, Structural Designs, and Future Prospects.

 Ultrasound-induced thermal strain imaging (US-TSI) is a promising ultrasound imaging modality that has been demonstrated in preclinical studies to identify a lipid-rich necrotic core of an atherosclerotic plaque. However, human physiological motion, e.g., cardiac pulsation, poses challenges in implementing US-TSI applications, where achieving a millisecond-level temperature rise by delivering acoustic energy from a compact US-TSI probe is a key requirement. This study aims to develop a transient ultrasound heating and thermocouple monitoring technique at the millisecond level for US-TSI applications.  We designed, prototyped, and characterized a novel US-TSI probe that includes a high-power, 3.5 MHz heating transducer with symmetrical dual 1D concave array. Additionally, millisecond-level temperature monitoring was demonstrated with fast-response thermocouples in laser- and ultrasound- induced thermal tests. Subsequently, we demonstrated the prototyped US-TSI probe can produce a desired temperature rise in a millisecond-short time window  phantom and  animal tests.  The prototyped US-TSI probe delivered zero-to-peak acoustic pressure up to 6.2 MPa with a 90 V input voltage. Both laser- and ultrasound- induced thermal tests verified that the selected thermocouples can monitor temperature change within 50 ms. The fast-response thermocouple confirmed the transient heating ability of the US-TSI probe, achieving a 3.9 °C temperature rise after a 25 ms heating duration (50% duty cycle) in the gel phantom and a 2.0 °C temperature rise after a 50 ms heating duration (50% duty cycle) in a pig model.  We successfully demonstrated a millisecond-level transient heating and temperature monitoring technique utilizing the novel US-TSI probe and fast-response thermocouples. The reported transient ultrasound heating and thermocouple monitoring technique is promising for future  human subject studies in US-TSI or other ultrasound-related thermal investigations.

Millisecond-level transient heating and temperature monitoring technique for ultrasound-induced thermal strain imaging.

We aimed to determine the maximum safe spatial-peak pulse-average intensity (I) of low-intensity focused ultrasound stimulation (LIFUS) in stroke patients and explore its effect on motor learning and corticospinal excitability.

Low intensity focused ultrasound stimulation in stroke: A phase I safety & feasibility trial.

Characterization of atherosclerosis plaque (AP) is critical for diagnosing rupture-prone AP that directly causes stroke and heart attack, and for guiding in-time interventions and avoiding unnecessary surgeries for stable cases. Ultrasound thermal strain imaging (US-TSI) is known to be capable of characterizing lipids, an important feature of rupture-prone AP. However, before translating US-TSI to in vivo clinical applications, significant technical challenges must be overcome, primarily the requirements of a well-controlled heating strategy to achieve a rapid, safe and spatial-temporal-precise local tissue temperature increase.

Article	Year
Effect of Low Intensity Transcranial Ultrasound Stimulation on Neuromodulation in Animals and Humans: An Updated Systematic Review. Frontiers in neuroscience\| PubMed ID: 33935626	2021
Implication of auditory confounding in interpreting somatosensory and motor responses in low-intensity focused transcranial ultrasound stimulation. Journal of neurophysiology\| PubMed ID: 33978511	2021
Direct Communication Between Brains: A Systematic PRISMA Review of Brain-To-Brain Interface. Frontiers in neurorobotics\| PubMed ID: 34025383	2021
Acoustics at the nanoscale (nanoacoustics): A comprehensive literature review.: Part I: Materials, devices and selected applications. Sensors and actuators. A, Physical\| PubMed ID: 34937991	2021
Acoustics at the nanoscale (nanoacoustics): A comprehensive literature review.: Part II: Nanoacoustics for biomedical imaging and therapy. Sensors and actuators. A, Physical\| PubMed ID: 34937992	2021
Numerical and experimental evaluation of low-intensity transcranial focused ultrasound wave propagation using human skulls for brain neuromodulation. Medical physics\| PubMed ID: 36342303	2023
Recent Advances in Tracking Devices for Biomedical Ultrasound Imaging Applications. Micromachines\| PubMed ID: 36363876	2022
Flexible Ultrasonic Transducers for Wearable Biomedical Applications: A Review on Advanced Materials, Structural Designs, and Future Prospects. IEEE transactions on ultrasonics, ferroelectrics, and frequency control\| PubMed ID: 37971905	2024
Millisecond-level transient heating and temperature monitoring technique for ultrasound-induced thermal strain imaging. Theranostics\| PubMed ID: 39776794	2025
Low intensity focused ultrasound stimulation in stroke: A phase I safety & feasibility trial. Brain stimulation\| PubMed ID: 39842609	2025
Experimental Evaluation of an Array Transducer for Ultrasound Thermal Strain Imaging: Phantom and In Vivo Studies. Ultrasound in medicine & biology\| PubMed ID: 40484751	2025

Mengyue Chen

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