Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation

Cotero, Victoria; Fan, Ying; Tsaava, Téa; Kressel, Adam M.; Hancu, Ileana; Fitzgerald, Peter; Wallace, Kirk; Kaanumalle, Sireesha; Graf, John; Rigby, Wayne; Kao, Tzu-Jen; Roberts, Jeannette C.; Bhushan, Chitresh; Joel, Suresh; Coleman, Thomas R.; Zanos, Stavros; Tracey, Kevin J.; Ashe, Jeffrey; Chavan, Sangeeta S.; Puleo, Chris

doi:10.1038/s41467-019-08750-9

Cited by 142 publications

(235 citation statements)

References 55 publications

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“…17 An alternative emerging approach leverages acoustic waves at ultrasound frequencies. Ultrasonic energy can be used to stimulate nervous tissue directly 18 or can be absorbed by piezoelectric transducers to power devices 19 . Though very promising, due to acoustic impedance matching requirements the ultrasound transmitter must be in intimate contact with the skin, and penetration through layers of different tissues can be a limitation of ultrasound technologies.…”

mentioning

confidence: 99%

A chronic photocapacitor implant for noninvasive neurostimulation with deep red light

Silvera-Ejneby

Jakešová

Ferrero

et al. 2020

Preprint

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AbstractImplantable clinical neuroelectronic devices are limited by a lack of reliable, safe, and minimally invasive methods to wirelessly modulate neural tissue. Here, we address this challenge by using organic electrolytic photocapacitors (OEPCs) to perform chronic peripheral nerve stimulation via transduction of tissue-penetrating deep-red light into electrical signals. The operating principle of the OEPC relies on efficient charge generation by nanoscale organic semiconductors comprising nontoxic commercial pigments. OEPCs integrated on an ultrathin cuff are implanted, and light impulses at wavelengths in the tissue transparency window are used to stimulate from outside of the body. Typical stimulation parameters involve irradiation with pulses of 50-1000 μs length (638 or 660 nm), capable of actuating the implant about 10 mm below the skin. We detail how to benchmark performance parameters of OEPCs first ex vivo, and in vivo using a rat sciatic nerve. Incorporation of a microfabricated zip-tie mechanism enabled stable, long-term nerve implantation of OEPC devices in rats, with sustained ability to non-invasively mediate neurostimulation over 100 days. OEPC devices introduce a high performance, ultralow volume (0.1 mm3), biocompatible approach to wireless neuromodulation, with potential applicability to an array of clinical bioelectronics.

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mentioning

confidence: 99%

A chronic photocapacitor implant for noninvasive neurostimulation with deep red light

Silvera-Ejneby

Jakešová

Ferrero

et al. 2020

Preprint

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“…Another alternative strategy for non-invasive nerve stimulation is the use of ultrasound. Delivery of pulsed ultrasound to the spleen stimulates components of the cholinergic anti-inflammatory pathway, and reduced kidney tissue destruction and decreased inflammation after ischemiareperfusion injury as well as reduced TNF levels in acute endotoxemia (Cotero et al 2019;Okusa et al 2017). Further research needs to be performed to assess and integrate non-invasive miniaturized stimulation interfaces in mice.…”

Section: Future Perspectives Of Experimental Bioelectronic Medicinementioning

confidence: 99%

Neural reflex control of vascular inflammation

et al. 2020

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Atherosclerosis is a multifactorial chronic inflammatory disease that underlies myocardial infarction and stroke. Efficacious treatment for hyperlipidemia and hypertension has significantly reduced morbidity and mortality in cardiovascular disease. However, atherosclerosis still confers a considerable risk of adverse cardiovascular events. In the current mechanistic understanding of the pathogenesis of atherosclerosis, inflammation is pivotal both in disease development and progression. Recent clinical data provided support for this notion and treatment targeting inflammation is currently being explored. Interestingly, neural reflexes regulate cytokine production and inflammation. Hence, new technology utilizing implantable devices to deliver electrical impulses to activate neural circuits are currently being investigated in treatment of inflammation. Hopefully, it may become possible to target vascular inflammation in cardiovascular disease using bioelectronic medicine. In this review, we discuss neural control of inflammation and the potential implications of new therapeutic strategies to treat cardiovascular disease.

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“…The focus on lower frequency ultrasound is understandable, since envisioned clinical applications involving transcranial focused ultrasound have been a primary motivation for research on ultrasound neuromodulation, and loss of ultrasound power due to attenuation in the skull limits these applications to low frequency ultrasound. For applications in which transmission through the skull does not impose limits on frequency, such as in vitro studies, neuromodulation in the peripheral nervous system (Downs et al, 2018;Cotero et al, 2019;Zachs et al, 2019), neuromodulation using subcranial implants, or neuromodulation in experimental animal model systems involving craniotomies or acoustically transparent cranial windows, high frequencies have a distinct advantage in terms of the greater spatial resolution that can be achieved. Even for in vivo applications in human subjects, however, the spatial resolutions that can be achieved with low-frequency, transcranial ultrasound neuromodulation are on the order of millimeters, making ultrasound neuromodulation superior in this respect to other, more established forms of non-invasive brain stimulation (Tyler et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Spike-frequency dependent inhibition and excitation of neural activity by high-frequency ultrasound

Prieto

Firouzi

Khuri‐Yakub

et al. 2020

Preprint

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Prieto et al. describe how ultrasound can either inhibit or potentiate action potential firing in hippocampal pyramidal neurons and demonstrate that these effects can be explained by increased potassium conductance. ABSTRACTUltrasound can modulate action potential firing in vivo and in vitro, but the mechanistic basis of this phenomenon is not well understood. To address this problem, we used patch-clamp recording to quantify the effects of focused, high-frequency (43 MHz) ultrasound on evoked action potential firing in CA1 pyramidal neurons in acute rodent hippocampal brain slices. We find that ultrasound can either inhibit or potentiate firing in a spike-frequency-dependent manner: at low (nearthreshold) input currents and low firing frequencies, ultrasound inhibits firing, while at higher input currents and higher firing frequencies, ultrasound potentiates firing. The net result of these two competing effects is that ultrasound increases the threshold current for action potential firing, the slope of frequency-input curves, and the maximum firing frequency. In addition, ultrasound slightly hyperpolarizes the resting membrane potential, decreases action potential width, and increases the depth of the afterhyperpolarization. All of these results can be explained by the hypothesis that ultrasound activates a sustained potassium conductance. According to this hypothesis, increased outward potassium currents hyperpolarize the resting membrane potential and inhibit firing at near-threshold input currents, but potentiate firing in response to higher input currents by limiting inactivation of voltage-dependent sodium channels during the action potential. This latter effect is a consequence of faster action-potential repolarization, which limits inactivation of voltage-dependent sodium channels, and deeper (more negative) afterhyperpolarization, which increases the rate of recovery from inactivation. Based on these results we propose that ultrasound activates thermosensitive and mechanosensitive, voltage-insensitive two-poredomain potassium (K2P) channels, through heating or mechanical effects of acoustic radiation force. Finite-element modelling of the effects of ultrasound on brain tissue suggests that the effects of ultrasound on firing frequency are caused by a small (less than 2°C) increase in temperature, with possible additional contributions from mechanical effects. 93force produced by reflection of the acoustic wave at the interface between the solution and the air 94 above it (Duck, 1998)). The mound of fluid was then aligned in the x-y plane to the center of a 95 reticle in one eyepiece of the dissecting microscope, and, after adding additional ACSF and the 96 tissue sample to the chamber, the center of the reticle was aligned with the region of the tissue 97 targeted for patch-clamp recording. The ultrasound intensity (50 W/cm 2 ) is the spatial peak, pulse 98 average intensity for the free field. The interval between ultrasound applications was at least 12 99 seconds. 101Electrophysiology. Current clamp re...

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Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation

Cited by 142 publications

References 55 publications

A chronic photocapacitor implant for noninvasive neurostimulation with deep red light

A chronic photocapacitor implant for noninvasive neurostimulation with deep red light

Neural reflex control of vascular inflammation

Spike-frequency dependent inhibition and excitation of neural activity by high-frequency ultrasound

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