Effective Ultrasonic Stimulation in Human Peripheral Nervous System

Riis, Thomas; Kubanek, Jan

doi:10.1101/2021.04.22.440931

Cited by 5 publications

(7 citation statements)

References 70 publications

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“…PFCs have boiling points of 29 We used an ultrasonic transducer capable of operating at low (300 kHz) and high (900 kHz) frequency focused on vials containing the nanoparticle solutions. 30 We found (Fig. 2, left) that 300 kHz ultrasound triggered more drug release from the nanoparticles than 900 kHz.…”

Section: In Vitro Ultrasound-triggered Drug Releasementioning

confidence: 76%

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Targeted drug release from stable and safe ultrasound-sensitive nanocarriers

Wilson

Kubanek

2021

Preprint

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Selective delivery of medication into specified tissue targets would realize the promise of personalized medicine with minimal side effects. Such an approach could be particularly transformative for patients with brain disorders, in whom drugs could be released in the impaired brain circuits at high concentration while sparing other brain regions and organs. Focused ultrasound provides noninvasive and practical means to release drugs from nanocarriers selectively at its target. However, which nanoparticle formulations provide safe and effective release and under which ultrasound parameters has been unclear. To expedite regulatory approval, we tested release effectiveness from nanocarriers filled with perfluorocarbon cores of relatively high boiling points (up to 142°C). We confirmed the safety of these nanocarriers in non-human primates. Crucially, we found that these safe, high-boiling-point nanocarriers can be used for effective release so long as they are activated by ultrasound of frequencies lower than those used previously (300 kHz). This study informs the formulation and release parameters for safe and effective drug delivery in specific parts of the body or brain regions.Abstract FigureDrugs can be effectively released from ultrasound-sensitive nanoparticles filled with safe, high-boiling point cores so long as they are activated by low-frequency ultrasound.

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Section: In Vitro Ultrasound-triggered Drug Releasementioning

confidence: 76%

“…We used an ultrasonic transducer capable of operating at both low (300 kHz) and high (900 kHz) frequencies (Riis and Kubanek, 2021). We focused the ultrasonic beam on vials containing particular nanoparticle samples and tested the effects of specific ultrasound parameters on drug release.…”

Section: In Vitro Ultrasound-triggered Drug Releasementioning

confidence: 99%

Targeted drug release from stable and safe ultrasound-sensitive nanocarriers

Wilson

Kubanek

2021

Preprint

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“…We further tested the ability of the method to provide effective neuromodulation. We specifically focused on responses of peripheral nerves within the human thumb, which we have characterized in free field (Riis and Kubanek, 2021 ). This preparation carries three key advantages (Riis and Kubanek, 2021 ): (1) it features intact human nerves (2) there is no confound of anesthesia, and (3) there is no stimulation artifact since responses are assessed at the behavioral level.…”

Section: Resultsmentioning

confidence: 99%

“…These effects modulate neural activity or local connectivity, depending on the stimulus duration (Naor et al, 2016 ; Kubanek, 2018 ; Tyler et al, 2018 ; Blackmore et al, 2019 ). Brief stimuli, on the order of a second or less, induce transient changes in neural activity (Kubanek et al, 2020 ; Riis and Kubanek, 2021 ). For example, brief, 300 ms pulses of ultrasound delivered into specific brain regions induce trial-by-trial changes in choice behavior of non-human primates (Kubanek et al, 2020 ; Webb et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Controlled ultrasonic interventions through the human skull

Wilson,

Riis,

Kubanek

2024

Front. Hum. Neurosci.

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Transcranial focused ultrasound enables precise and non-invasive manipulations of deep brain circuits in humans, promising to provide safe and effective treatments of various neurological and mental health conditions. Ultrasound focused to deep brain targets can be used to modulate neural activity directly or localize the release of psychoactive drugs. However, these applications have been impeded by a key barrier—the human skull, which attenuates ultrasound strongly and unpredictably. To address this issue, we have developed an ultrasound-based approach that directly measures and compensates for the ultrasound attenuation by the skull. No additional skull imaging, simulations, assumptions, or free parameters are necessary; the method measures the attenuation directly by emitting a pulse of ultrasound from an array on one side of the head and measuring with an array on the opposite side. Here, we apply this emerging method to two primary future uses—neuromodulation and local drug release. Specifically, we show that the correction enables effective stimulation of peripheral nerves and effective release of propofol from nanoparticle carriers through an ex vivo human skull. Neither application was effective without the correction. Moreover, the effects show the expected dose-response relationship and targeting specificity. This article highlights the need for precise control of ultrasound intensity within the skull and provides a direct and practical approach for addressing this lingering barrier.

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“…The successful stimulation of nerves following the RTT compensation provides a physiologically-relevant validation of the method and thus serves as a proof of concept. Notably, however, the stimulation of peripheral nerves differs significantly from stimulation of neurons in the brain 60 . Therefore, these findings should be interpreted as a physiological readout of the compensated intensity rather than a direct evidence of stimulation of neurons.…”

Section: Discussionmentioning

confidence: 99%

Controlled delivery of ultrasound through the head for effective and safe therapies of the brain

Riis

Wilson

Kubanek

2022

Preprint

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Transcranial focused ultrasound provides noninvasive and reversible approaches for precise and personalized manipulations of brain circuits, with the potential to transform our understanding of brain function and treatments of brain dysfunction. However, the effectiveness and safety of these approaches have been limited by the human head, which attenuates and distorts ultrasound strongly and unpredictably. To address this lingering barrier, we have developed a Relative Through-Transmit (RTT) approach that directly measures and compensates for the attenuation and distortion of a given skull and scalp. We have implemented RTT in hardware and demonstrated that it accurately restores the operator's intended intensities inside ex-vivo human skulls. Moreover, this functionality enabled effective and intensity-dependent transcranial modulation of nerves and effective release of defined doses of propofol inside the skull. RTT was essential for these new applications of transcranial ultrasound; when not applied, there were no significant differences from sham conditions. Moreover, RTT was safely applied in humans and accounted for all intervening obstacles including hair and ultrasound coupling. This method and hardware unlock the potential of ultrasound-based approaches to provide effective, safe, and reproducible precision therapies of the brain.

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Effective Ultrasonic Stimulation in Human Peripheral Nervous System

Cited by 5 publications

References 70 publications

Targeted drug release from stable and safe ultrasound-sensitive nanocarriers

Targeted drug release from stable and safe ultrasound-sensitive nanocarriers

Controlled ultrasonic interventions through the human skull

Controlled delivery of ultrasound through the head for effective and safe therapies of the brain

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