Ultrasonic Stimuli Research Articles

A Physiological Marker for Deep Brain Ultrasonic Neuromodulation

ObjectivesTranscranial ultrasound neuromodulation (TUSN) is a noninvasive and spatially specific therapy that promises to deliver treatments tailored to the specific needs of individuals. To fulfill this promise, each treatment must be modified to adequately correct for variation across individual skulls and neural anatomy. This study examines the use of ultrasound-induced voltage potentials (measured with electroencephalography [EEG]) to guide TUSN therapies. Materials and MethodsWe measured EEG responses in two awake nonhuman primates during sonication of 12 targets surrounding two deep brain nuclei, the left and right lateral geniculate nucleus. ResultsWe report reliable ultrasound evoked potentials measured with EEG after the deep brain ultrasonic modulation in nonhuman primates. Robust responses are observed after just ten repetitions of the ultrasonic stimuli. Moreover, these potentials are only evoked for specific deep brain targets. Furthermore, a behavioral study in one subject shows a direct correspondence between the target with maximal EEG response and ultrasound-based modulation of visual choice behavior. Thus, this study provides evidence for the feasibility of EEG-based guidance for ultrasound neuromodulation therapies.

Smart Ultrasound-responsive Polymers for Drug Delivery: An Overview on Advanced Stimuli-sensitive Materials and Techniques.

In recent years, a notable advancement has occurred in the domain of drug delivery systems via the integration of intelligent polymers that respond to ultrasound. The implementation of this groundbreaking methodology has significantly revolutionised the controlled and precise delivery of therapeutic interventions. An in-depth investigation is conducted into the most recent developments in ultrasonic stimulus-responsive materials and techniques for the purpose of accomplishing precise medication administration. The investigation begins with an exhaustive synopsis of the foundational principles underlying drug delivery systems that react to ultrasonic stimuli, focusing specifically on the complex interplay between polymers and ultrasound waves. Significant attention is devoted to the development of polymers that demonstrate tailored responsiveness to ultrasound, thereby exemplifying their versatility in generating controlled drug release patterns. Numerous classifications of intelligent polymers are examined in the discussion, including those that react to variations in temperature, pH, and enzymes. When coupled with ultrasonic stimuli, these polymers offer a sophisticated framework for the precise manipulation of drug release in terms of both temporal and spatial dimensions. The present study aims to examine the synergistic effects of responsive polymers and ultrasound in overcoming biological barriers such as the blood-brain barrier and the gastrointestinal tract. By doing so, it seeks to shed light on the potential applications of these materials in intricate clinical scenarios. The issues and future prospects of intelligent ultrasound-responsive polymers in the context of drug delivery are critically analysed in this article. The objective of this study is to offer valuable perspectives on the challenges that must be overcome to enable the effective implementation of these technologies. The primary objective of this comprehensive review is to furnish researchers, clinicians, and pharmaceutical scientists with a wealth of information that will serve as a guide for forthcoming developments in the development and enhancement of intelligent drug delivery systems that employ ultrasound-responsive polymers to attain superior therapeutic outcomes.

Stem cell-derived brain organoids for controlled studies of transcranial neuromodulation

Transcranial neuromodulation methods have the potential to diagnose and treat brain disorders at their neural source in a personalized manner. However, it has been difficult to investigate the direct effects of transcranial neuromodulation on neurons in human brain tissue. Here, we show that human brain organoids provide a detailed and artifact-free window into neuromodulation-evoked electrophysiological effects. We derived human cortical organoids from induced pluripotent stem cells and implanted 32-channel electrode arrays. Each organoid was positioned in the center of the human skull and subjected to low-intensity transcranial focused ultrasound. We found that ultrasonic stimuli modulated network activity in the gamma and delta ranges of the frequency spectrum. The effects on the neural networks were a function of the ultrasound stimulation frequency. High gamma activity remained elevated for at least 20 minutes following stimulation offset. This approach is expected to provide controlled studies of the effects of ultrasound and other transcranial neuromodulation modalities on human brain tissue.

Active mass transfer for printable electrochemical sensors with ultrasonic stimuli

Active mass transfer for printable electrochemical sensors with ultrasonic stimuli

Ultrasound-driven exercise training ameliorates degeneration of ultrasonic responses in Caenorhabditis elegans

The inevitability of age-related degeneration makes research on degradation mitigation attractive to humans, while exercise is considered an effective means due to its powerful impact on life and health. Caenorhabditis elegans is a model animal with a short life cycle and is widely used in health and aging studies. In this work, ultrasonic stimuli in the form of surface acoustic waves (SAWs) were used to induce behavioral activities in worms. As the worms grew, ultrasound-elicited behavioral responses started to decrease in the early adulthood stage. However, this situation was significantly ameliorated when ultrasonic training sessions at an effective acoustic pressure of 1.1 MPa were performed four times per day for 5 or 7 days, while ultrasonic responses in trained nematodes were stronger than those in untrained ones. These results suggest that long-term ultrasonic training might positively intervene in aging-related degeneration. Besides, it was found that exercise driven by long-term ultrasonic training had insignificant effects on the lifespan of worms. A preliminary exploration of the neural mechanisms underlying the sensation of SAWs was also conducted. The results show that, apart from touch receptor neurons (TRNs), polymodal nociceptors FLP and PVD neurons may also be involved in the perception of ultrasound in C. elegans. The results of this study may inspire related studies on other animals or humans.

Piezotronic Effect Induced Schottky Barrier Decrease to Boost the Plasmonic Charge Separation of BaTiO3-Au Heterojunction for the Photocatalytic Selective Oxidation of Aminobenzyl Alcohol.

Charge carrier transfer efficiency as a crucial factor determines the performance of heterogeneous photocatalysis. Here, we demonstrate a simple nanohybrid structure of BaTiO3-Au (BTO-Au) for the efficient selective oxidization of benzyl alcohol to benzaldehyde upon piezotronic effect boosted plasmonic photocharge carrier transfer. With the aid of ultrasonic mechanical vibration, the reaction rate of the photocatalytic organic conversion would be considerably accelerated, which is about 4.2 and 6.2 times higher than those driven by sole visible light irradiation and sole ultrasonication, respectively. Photoelectrochemical tests under ultrasonic stimuli reveal the BTO-Au catalytic system is independent of the light intensity, showing a consistent photocurrent density, over a wide range of incident light brightness. The largely enhanced photocatalytic activity can be ascribed to the synergetic effect of surface plasmonic resonance (SPR)-piezotronic coupling by which a built-in electric field induced by the piezotronic effect significantly favors the oriented mobilization of energetic charge carriers generated by the SPR effect at the heterojunction. Notably, a decrease of the Schottky barrier height of ∼0.3 eV at the BTO-Au interface is verified experimentally, due to the band bending of BTO induced by the piezotronic effect, which can greatly augment the hot electron transfer efficiency. This work highlights the coupling of the piezotronic effect with SPR within the BTO-Au nanostructure as a versatile and promising route for efficient charge transfer in photocatalytic organic conversion.

C. elegans: Sensing the low-frequency profile of amplitude-modulated ultrasound

Several research groups have demonstrated that C. elegans can respond to pulsed ultrasound stimuli, and elucidating the underlying mechanisms is necessary to develop ultrasound neuromodulation. Here, amplitude-modulated (AM) ultrasound is applied to C. elegans, and its behavioral responses are investigated in detail. By loading surface acoustic waves (SAWs) onto free-moving worms on an agar surface, a carrier wave with a frequency of 8.80 MHz is selected. The signal is modulated by a rectangular or sinusoidal profile. It is demonstrated that sinusoidal modulation can produce similar responses in worms to rectangular modulation, with the strongest responses occurring at modulation frequencies of around 1.00 kHz. Meanwhile, the behavioral response is relatively weak when the ultrasonic signal is unmodulated, that is, when only the carrier wave is applied. At modulation frequencies other than 100.00 Hz to 10.00 kHz, the worms respond weakly, but when a second modulation frequency of 1.00 kHz is introduced, an improvement in response can be observed. These results suggest that C. elegans may sense the low-frequency envelope and respond to amplitude-modulated ultrasonic stimuli like an amplitude demodulator. MEC-4, an ion channel for touch sensing, is involved in the behavioral response of C. elegans to ultrasound in the present setup.

Poly(N-isopropylacrylamide) Hydrogel for Diving/Surfacing Device.

Underwater robots and vehicles have received great attention due to their potential applications in remote sensing and search and rescue. A challenge for micro aquatic robots is the lack of small motors needed for three-dimensional locomotion in water. Here, we show a simple diving and surfacing device fabricated from thermo-sensitive poly(N-isopropylacrylamide) or a poly(N-isopropylacrylamide)-containing hydrogel. The poly(N-isopropylacrylamide)-containing device exhibited fast and reversible diving/surfacing cycles in response to changing temperature. Modulation of the interaction between poly(N-isopropylacrylamide) chains and water molecules at temperatures above or below the lower critical solution temperature regulates the gel density through the swelling and de-swelling. The gel surfaced in water when heated and sank when cooled. We further showed reversible diving/surfacing cycles of the device when exposed to electrical and ultrasonic stimuli. Finally, a small electrically heated gel was incorporated into a miniature submarine and used to control the diving depth. These results suggest that the poly(N-isopropylacrylamide)-containing device has good potential for underwater remote-controlled micro aquatic robots.

Understanding ultrasound neuromodulation using a computationally efficient and interpretable model of intramembrane cavitation

Objective. Low-intensity focused ultrasound stimulation (LIFUS) emerges as an attracting technology for noninvasive modulation of neural circuits, yet the underlying action mechanisms remain unclear. The neuronal intramembrane cavitation excitation (NICE) model suggests that LIFUS excites neurons through a complex interplay between microsecond-scale mechanical oscillations of so-called sonophores in the plasma membrane and the development of a millisecond-scale electrical response. This model predicts cell-type-specific responses that correlate indirectly with experimental data, but it is computationally expensive and difficult to interpret, which hinders its potential validation. Here, we introduce a multi-scale optimized neuronal intramembrane cavitation (SONIC) model to achieve fast, accurate simulations and confer interpretability in terms of effective electrical response. Approach. The NICE system is recast in terms of smoothly evolving differential variables affected by cycle averaged internal variables that are a function of sonophore size and charge density, stimulus frequency and pressure amplitude. Problem separation allows to precompute lookup tables for these functions, which are interpolated at runtime to compute coarse-grained, electrophysiologically interpretable and spatially distributed predictions of neural responses. Main results. The SONIC model accelerates computation by more than three orders of magnitude, accurately captures millisecond-scale electrical responses of various cortical and thalamic neurons and offers an increased interpretability to the effects of ultrasonic stimuli in terms of effective membrane dynamics. Using this model, we explain how different spiking behaviors can be achieved in cortical neurons by varying LIFUS parameters, and interpret predictions of spike amplitude and firing rate in light of the effective electrical system. We demonstrate the substantial influence of sonophore size on excitation thresholds, and use a nanoscale spatially extended SONIC model to suggest that partial sonophore membrane coverage has a limited impact on neuronal excitability. Significance. By providing an electrophysiologically interpretable description, the SONIC model clarifies cell-type-specific LIFUS neuromodulation according to the intramembrane cavitation hypothesis.

Radiation Force as a Physical Mechanism for Ultrasonic Neurostimulation of the Ex Vivo Retina.

Focused ultrasound has been shown to be effective at stimulating neurons in many animal models, both in vivo and ex vivo Ultrasonic neuromodulation is the only noninvasive method of stimulation that could reach deep in the brain with high spatial-temporal resolution, and thus has potential for use in clinical applications and basic studies of the nervous system. Understanding the physical mechanism by which energy in a high acoustic frequency wave is delivered to stimulate neurons will be important to optimize this technology. We imaged the isolated salamander retina of either sex during ultrasonic stimuli that drive ganglion cell activity and observed micron scale displacements, consistent with radiation force, the nonlinear delivery of momentum by a propagating wave. We recorded ganglion cell spiking activity and changed the acoustic carrier frequency across a broad range (0.5-43 MHz), finding that increased stimulation occurs at higher acoustic frequencies, ruling out cavitation as an alternative possible mechanism. A quantitative radiation force model can explain retinal responses and could potentially explain previous in vivo results in the mouse, suggesting a new hypothesis to be tested in vivo Finally, we found that neural activity was strongly modulated by the distance between the transducer and the electrode array showing the influence of standing waves on the response. We conclude that radiation force is the dominant physical mechanism underlying ultrasonic neurostimulation in the ex vivo retina and propose that the control of standing waves is a new potential method to modulate these effects.SIGNIFICANCE STATEMENT Ultrasonic neurostimulation is a promising noninvasive technology that has potential for both basic research and clinical applications. The mechanisms of ultrasonic neurostimulation are unknown, making it difficult to optimize in any given application. We studied the physical mechanism by which ultrasound is converted into an effective energy form to cause neurostimulation in the retina and find that ultrasound acts via radiation force leading to a mechanical displacement of tissue. We further show that standing waves have a strong modulatory effect on activity. Our quantitative model by which ultrasound generates radiation force and leads to neural activity will be important in optimizing ultrasonic neurostimulation across a wide range of applications.

Sonodynamic Therapy: Advances and Challenges in Clinical Translation.

Sonodynamic therapy (SDT) consists of the synergetic interaction between ultrasound and a chemical agent. In SDT, the cytotoxicity is triggered by ultrasonic stimuli, notably through cavitation. The unique features of SDT are relevant in the clinical context more than ever: the need for efficacy, accuracy, and safety while being noninvasive and preserving the patient's quality of life. However, despite the promising results of this technique, only a few clinical reports describe the use of SDT. The objective of this article is to provide an extensive overview of the clinical and preclinical research conducted in vivo on SDT, to identify the limitations, and to detail the developed strategies to overcome them.

Somatosensory Evoked Responses Elicited by Haptic Sensations in Midair

The design of human-machine interfaces (HMIs) by virtual haptics is an emerging field of research. So far, the perception of virtual haptic feedback, e.g., generated by focused ultrasound in midair has not been objectively evaluated. This paper demonstrates the feasibility of eliciting somatosensory evoked potentials (SEPs) with ultrasonic stimuli in midair for the first time. The palm was stimulated by short ultrasonic focal points generated by an ultrasound board. The results are compared with a no stimulation condition as well as with the results of a vibro tactile stimulation. The SEPs are analyzed with the wavelet phase synchronization stability (WPSS) and the M-consecutive averaged WPSS. The results indicate a clear SEP waveform elicited by ultrasound. It can be significantly differentiated from a no stimulation condition by the M-consecutive averaged WPSS. These results could enable the possibility of developing an objective evaluation method for virtual haptic feedback in HMIs.

Graphene-Based Smart Platforms for Combined Cancer Therapy.

The extensive research of graphene and its derivatives in biomedical applications during the past few years has witnessed its significance in the field of nanomedicine. Starting from simple drug delivery systems, the application of graphene and its derivatives has been extended to a versatile platform of multiple therapeutic modalities, including photothermal therapy, photodynamic therapy, magnetic hyperthermia therapy, and sonodynamic therapy. In addition to monotherapy, graphene-based materials are widely applied in combined therapies for enhanced anticancer activity and reduced side effects. In particular, graphene-based materials are often designed and fabricated as "smart" platforms for stimuli-responsive nanocarriers, whose therapeutic effects can be activated by the tumor microenvironment, such as acidic pH and elevated glutathione (termed as "endogenous stimuli"), or light, magnetic, or ultrasonic stimuli (termed as "exogenous stimuli"). Herein, the recent advances of smart graphene platforms for combined therapy applications are presented, starting with the principle for the design of graphene-based smart platforms in combined therapy applications. Next, recent advances of combined therapies contributed by graphene-based materials, including chemotherapy-based, photothermal-therapy-based, and ultrasound-therapy-based synergistic therapy, are outlined. In addition, current challenges and future prospects regarding this promising field are discussed.

Controlled drug release from ultrasound-visualized elastic eccentric microcapsules using different resonant modes.

Ultrasound controlled drug delivery and release has attracted increased attention for targeted delivery of drug. In this report, we present a strategy for targeted drug delivery by using ultrasound to image the location of drug carriers, as well as simultaneously controlling the release rate of drug from elastic eccentric microcapsules (EEMs), based on their mode shapes (MSs) and resonant natural frequencies (NFs). We prepared a series of EEMs with various diameters of inner spherical cavities using a microfluidic chip. The EEMs could be visualized by an ultrasound imaging system within a tissue mimic (i.e. phantom). Using theoretical modeling techniques, we investigated the effects of MSs and NFs on the resonant modes of EEMs. Guided by this modelling, we applied external ultrasonic stimuli at various levels of low frequency to regulate the release rate of Rhodamine 6G (R6G, as a model drug) from EEMs. To further demonstrate the control of drug release and evaluate the efficacy of the encapsulated drugs on cancer cells, we released an anticancer drug, doxorubicin hydrochloride (DOX), from the EEMs and tested the viability of cancer cells in vitro. The results show that this novel strategy holds great promise towards development of a controlled drug release system visualized and triggered by ultrasound.

Features of the alteration of poststimulus thresholds of the pain and its subjective characteristics in patients with neuropathic pain in the process of empatho-technique

In the work there are presented results of the investigation offeatures of the alteration of thresholds of the post-stimulus pain and its subjective characteristics in patients with phantom pain syndrome and psychogenic pain in the process of empatho-technique. There was studied the role ofpsychophysiological autoregulation in the restoration of sensitivity in patients undergone to amputation of lower extremities. The use of empatho-technique was found to allow not only to significantly reduce the intensity ofphantom, and psychogenic pain, but to fully restore sensitivity to ultrasonic stimuli in the psychogenic pain and significantly eliminate cases of its disturbance in the phantom pain. It is assumed that the reducing influence of empatho-technique on the intensity of the perception ofpain can be realized by means of activation of the antinociceptive system, enhancement of its inhibitory effect on the painful stimulus, as well as decline in the activation of the nociceptive system, with a subsequent decrease in the intensity of sensations ofpain and restoration of sensitivity.

Sequential release of nanoparticle payloads from ultrasonically burstable capsules

In many biomedical contexts ranging from chemotherapy to tissue engineering, it is beneficial to sequentially present bioactive payloads. Explicit control over the timing and dose of these presentations is highly desirable. Here, we present a capsule-based delivery system capable of rapidly releasing multiple payloads in response to ultrasonic signals. In vitro, these alginate capsules exhibited excellent payload retention for up to 1 week when unstimulated and delivered their entire payloads when ultrasonically stimulated for 10–100 s. Shorter exposures (10 s) were required to trigger delivery from capsules embedded in hydrogels placed in a tissue model and did not result in tissue heating or death of encapsulated cells. Different types of capsules were tuned to rupture in response to different ultrasonic stimuli, thus permitting the sequential, on-demand delivery of nanoparticle payloads. As a proof of concept, gold nanoparticles were decorated with bone morphogenetic protein-2 to demonstrate the potential bioactivity of nanoparticle payloads. These nanoparticles were not cytotoxic and induced an osteogenic response in mouse mesenchymal stem cells. This system may enable researchers and physicians to remotely regulate the timing, dose, and sequence of drug delivery on-demand, with a wide range of clinical applications ranging from tissue engineering to cancer treatment.

Navigation of the Non-Invasive Rat Robot

A navigation system for non-invasive rat robot is described here that can control the rat navigation via ultrasonic, electrical epidermal and LED(light-emitting diode) photic stimulators.It receives commands from a remote host computer to remotely deliver ultrasonic,electrical epidermal and LED photic stimuli to the auditory,pain and visual senses of the rat respectively,and thus its motion control is accomplished.The experiments demonstrate that the appropriate coordination of the three stimuli enables the rat to proceed and make right and left turns effectively and non-invasively,what's more,the telemetry camera mounted on the rat head also achieves remote image acquisition and helps to adjust rat navigation path over a distance of 300 m.

Therapeutic Ultrasound Bypasses Canonical Syndecan-4 Signaling to Activate Rac1

The application of pulsed, low intensity ultrasound is emerging as a potent therapy for the treatment of complex bone fractures and tissue damage. Ultrasonic stimuli accelerate fracture healing by up to 40% and enhance tendon and ligament healing by promoting cell proliferation, migration, and matrix synthesis through an unresolved mechanism. Ultrasound treatment also induces closure of nonunion fractures, at a success rate (85% of cases) similar to that of surgical intervention (68-96%) while avoiding the complications associated with surgery. The regulation of cell adhesion necessary for wound healing depends on cooperative engagement of the extracellular matrix receptors, integrin and syndecan, as exemplified by the wound healing defects observed in syndecan- and integrin-knock-out mice. This report distinguishes the influence of ultrasound on signals downstream of the prototypic fibronectin receptors, alpha(5)beta(1) integrin and syndecan-4, which cooperate to regulate Rac1 and RhoA. Ultrasonic stimulation fails to activate integrins or induce cell spreading on poor, electrostatic ligands. By contrast, ultrasound treatment overcomes the necessity of engagement or expression of syndecan-4 during the process of focal adhesion formation, which normally requires simultaneous engagement of both receptors. Ultrasound exerts an influence downstream of syndecan-4 and PKCalpha to specifically activate Rac1, itself a critical regulator of tissue repair, and to a lesser extent RhoA. The ability of ultrasound to bypass syndecan-4 signaling, which is known to facilitate efficient tissue repair, explains the reduction in healing times observed in ultrasound-treated patients. By substituting for one of the key axes of adhesion-dependent signaling, ultrasound therapy has considerable potential as a clinical technique.

Ultrasonic evoked responses in rat cochlear nucleus

Numerous studies have reported auditory brainstem responses evoked by stimuli within the “normal” hearing range of rats, with maximum sensitivity peaking around 16 kHz. Yet rats also emit and respond to sounds in the ultrasonic (US) frequency range (30–100 kHz). However, very few electrophysiological studies have recorded auditory brainstem responses using US stimuli, and none have exceeded 70 kHz. We report here short-latency (1–3 ms) evoked potentials recorded in rat cochlear nucleus (CN) to US stimuli ranging from 40 to 90 kHz. Robust responses were recorded in 33 of 36 CN recording sites to stimuli ranging from 40 to 60 kHz; and twenty-eight of these sites continued to yield well-defined responses out to 90 kHz. Latencies systematically increased and overall amplitudes decreased with increasing US frequency. Amplitudes differed significantly in the three CN subnuclei, being largest in posterior-ventral (PVCN) and smallest in anterior-ventral (AVCN). The fact that well-defined responses can be recorded to stimuli as high as 90 kHz significantly extends the recorded upper frequency range of neural activity in the brainstem auditory pathway of the rat. These evoked potential results agree with the well-documented behavioral repertoire of rats in the US frequency range.

Are rats predisposed to learn 22 kHz calls as danger-predicting signals?

Alarm calls are widely used in mammals. Their biological function is to deter predators and warn relatives of danger. Despite this important function of alarm calls, the development of alarm call recognition is poorly understood. Using laboratory rats, the present study investigated in a first experiment whether alarm calls are recognized innately. In experimentally naive animals, we found significantly increased freezing if stimuli in the 22 kHz range were presented but this response was not specific to conspecific 22 kHz calls. Therefore, a second experiment addressed the hypothesis whether recognition of conspecific 22 kHz calls can be learned and whether this learning is facilitated by a preparedness to acquire defensive responses to alarm calls. Our data show that rats learned quickly to associate the 22 kHz calls with aversive stimuli. Interestingly, the animals were more reluctant to extinguish this memory, and this information retained longer in memory than in the case of other types of calls and ultrasonic stimuli. We, therefore, conclude that rats are predisposed to acquire adaptive defensive behaviour in response to alarm calls. In particular, our data indicate that better encoding of such learning in rats leads to a stable memory which better resists extinction.