-------------------------------------------------------- wipo.int patent application 2011 The acoustic frequencies used to manipulate neuronal activity range from 0.25 MHz (Tufail et al., 2010) to 7.0 MHz (Mihran et al., 1990b). While lower frequences of US have longer wavelengths and lower spatial resolutions than higher frequencies, acoustic frequencies < 1 MHz for stimulating intact brain circuits using US are a useful range. US < 0.7 MHz represents the frequency range where optimal gains between transcranial transmission and brain absorption of US have been observed (Hayner and Hynynen, 2001; White et al., 2006a, b). In mice, optimal waveforms for evoking intact brain circuit activity are composed of acoustic frequencies ranging between 0.25 and 0.50 MHz (Tufail et al., 2010). For these ranges, implementing broadband transducers, which have a center frequency between 0.2 and 0.7 MHz for UNMOD is useful. Use of immersion-type (water-matched) transducers coupled to the skin with US gel to minimize acoustic impedance mismatches when transmitting acoustic energy from a transducer into the brain is also contemplated by the present invention. Stimulation of brain activity in vivo may use other US waveforms. For example, stimulus waveforms constructed of US pulses having a low P// (< 0.1 mJ/cm^2), which were repeated at high PRFs (1.0 - 3.0 kHz) for short durations (< 0.4 sec) were effective for stimulating normal brain circuit activity in vivo (Tufail et al., 2010). These two different US pulsing strategies (high P// with a low PRF for in vitro stimulation versus a low P// with a high PRF for in vivo), indicated optimal US waveforms for triggering brain activity and have low temporal average intensity values in a range between 30 and 300 mW/cm^2. In addition to the general pulsing strategies described herein, US transmitted in a continuous wave (CW) mode is capable of influencing brain activity, and may show different effects and time courses compared to pulsed US. Short bursts of pulsed US can stimulate brief (tens of milliseconds) periods of neuronal activity and US stimuli delivered in CW-mode for 5 seconds can induce seizure activity lasting >20 seconds in normal mice, and can disrupt kainic acid-induced electrographic seizure activity in epileptic mice. Repeated short bursts of pulsed US can attenuate seizure activity in epileptic mice indicating UNMOD may be a general interference source for disrupting aberrant activity. Transmission of US from the transducer into the brain may occur at points where acoustic gel is coupling the transducer to the head. One may cover the entire face of the transducer with acoustic gel to prevent transducer face heating and damage. Alternatively, coupling the transducer to the head through small gel contact points may be a physical method for transmitting US into restricted brain regions. The spatial envelope of US transmitted into the brain may be laterally restricted by using acoustic collimators. ... An aspect of the invention comprises using air-coupled transducers to deliver transcranial pulsed ultrasound into the brain from single-element transducers or from phased arrays as described below. In aspects, gel-filled pads or other fluid filled bladders may be used for acoustically coupling transducers to the skin and or the skull in brain regulation interface designs. Although the spatial resolution for focusing US is currently limited by teh acoustics or wavelength employed, recent advances in focusing US with adaptive optics (Zhang et al., 2009) allows US to gain spatial resolutiosn below the diffraction limits, similar to that recently achieved in optical microscopy (Abbott, 2009). US may confer spatial resolutions similar to those achieved by DBS electrodes. Aspects of methods described herein contemplate use of subdiffraction methods using hyperlenses, metamaterials, and acoustic bullets with nonlinear lenses. acoustic metamaterials Li, et al. Nature Materials, DOI:10:1038, NMAT2561, p.1-4, 25 October 2009. ultrasound device Brain Regulation Interface (BRI) The intensity of the acoustic beam is given by the amount of energy that impinges on a plane perpendicular to the beam per unit time divided by the area of the beam on the plane, and is given in energy per unit tiem per unit area, i.e., the power density per unit area, e.g., Watts per square centimeter (W/cm^2). Olympus NDT/Panametrics 0.5 MHz center frequency transducers Ultran 0.5 and 0.35 MHz center frequency transducers controller/microcontrollers -- Agilent 33220A function generator ENI 240L RF amplifier transcranial pulsed ultrasound The present invention compromises methods for stimulating normal brain wave activity patterns in deep or superficial brain circuits using transcranial pulsed ultrasound. The present invention comprises modifying cognitive processes such as learning and memory using transcranial pulsed ultrasound, for example, by stimulating sharp wave ripple oscillations, or activity in any other frequency band including gamma, beta, theta, or alpha. Though not wishing to be bound by any particular theory, it is believed that sharp wave ripple oscillations underlie memory consolidation. Pulsed transcranial ultrasound methods may be used to modulate BDNF signaling and for example, other cellular cascades mediating processes underlying synaptic plasticity and learning. Due to temperature increases <0.01 Celsius in response to US stimulus waveforms, an aspect of the invention comprises predominantly nonthermal (mechanical) mechanism(s) of action. Though not wshing to be bound by any particular theory, it is thought that the nonthermal actions of US are understood in terms of cavitation - for example, radiation force, acoustic streaming, shock waves, and strain neuromodulation, where US produces fluid-mechanical effects on the cellular environments of neurons to modulate their resting membrane potentials. The direct activation of ion channels by US may also represent a mechanism of action, since many of the voltage-gated sodium, potassium, and calcium channels influencing neuronal excitability possess mechanically sensitive gating kinetics (Morris and Juranka, 2007). Pulsed US could also produce ephaptic effects or generate spatially inhomogeneous electric fields, proposed to underlie aspects of synchronous activity (Anastassiou et al., 2010; Jefferys and Haas, 1982) underlying the ability of US to stimulate intact brain circuits. For example, US stimulation of motor cortex produced short bursts of activity (<100 ms) and peripheral muscle contractions, whereas stimulation of the hippocampus with similar waveforms triggered characteristic rhythmic bursting (recurrent activity), which lasted 2-3 seconds. Using a method of transcranial US brain stimulation with an acoustic collimating tube (d = 2mm), an estimate of the volume of cortical activation maybe =~ 3 mm^3 as indicated by c-fos activity (Figure 15). The 1.5-2.0 mm lateral area of activation observed represents a more reliable measure and is approximately five times better than the =~ 1cm lateral spatial resolution offered by transcranial magnetic stimulation (TMS) (Barker, 1999). Due to the millimeter spatial resolutions conferred by US, structured US fields may be used to drive patterned activation in sparsely distributed brain circuits. Similarly, focusing with acoustic meta-materials (having a negative refractive index) enables subdiffraction spatial resolutions to be achieved for US (Zhang et al., 2009). Brain regions <1.0 mm may be accurately targeted for neurostimulation using 0.5 MHz US. Such spatial scales make transcranial US for brain stimulation amenable to a variety of research and clinical applications. The Morris Water Maze is a classic test used to assay cognition in rodents. Intact mice hippocampi were stimulated using ultrasound methods disclosed herein. If US stimulation occurred 5 minutes immediately before training the mice on the MWM task, the mice do not learn as well and additionally, the mice have worse memory of the escape location compared to sham controls. It is currently believed that the disruption of learning and memory conslidation is due to stimulating hippocamp activity in patterns absent of context, which disrupts the formations of associations amongst environmental cues, as well as alters the neuronal firing code needed for normal learning and memory to occur. Thus, by providing disruptive hippocampal stimulation with pulsed ultrasound learning can be attenuated and memory can be blocked. Methods of the present invention comprise providing ultrasound to disrupt learning and/or interfere with memory consolidation by stimulating one or more brain regions in the absence of context (for the animal stimulated). For example, if mice are stimulated for 5min per day for 7 days before training them on the MWM task (without stimulating the day of or immediately before training on any training day) then the mice receiving intact hippocampal stimulation in this chronic paradigm perform better than sham controls. They remember better and learn faster. It is believed that traditional models of plasticity explain the findings, where the synaptic strengths of hippocampal synapses are increased by stimulating across repeated days in controlled environments. Ultrasound stimulates the release of brain-derived neurotrophic factor (BDNF) and BDNF induces plasticity and mediates learning, thus, the repeated prolonged increase in BDNF signaling enhances cognitive function. Methods of the present invention comprise repeated stimulation of the hippocampus by transcranial ultrasound to improve learning and memory. Methods of the present invention comprise repeated stimulation of one or more brain regions by transcranial ultrasound to improve learning and memory. ... Methods of the present invention comprise upregulation of neurotrophic factors, including but not limited to BDNF, Nerve Growth Factor, Neurotrophin-3, Fibroblast Growth Factor, Insulin-like Growth Factor, by transcranial ultrasound for treating a disease or physiological condition where neurotrophic dysregulation or impaired neurotrophic signaling occurs. For example, increasing BDNF signaling by performing chronic repeated brain stimulation with ultrasound may encourage plasticity which can have a profound effect on diseased, faulty or impaired brain circuits. Likewise, chronic repeated brain stimulation with ultrasound may encourage plasticity to enhance learning and memory in normal brain circuits. An ultrasonic method of the present invention comprises enhancing learning or memory formation in a subject, comprising providing an effective amount of ultrasound to a brain region, wherein the brain region comprises the hippocampal formation, hippocampus proper, amygdala, thalamus, cerebellum, striatum, entorhinal cortex, perirhinal cortex, and cerebral cortex, prefrontal cortex, auditory cortex, visual cortex, somatosensory cortex, or motor cortex, afferents or efferents of the regions, or combinations thereof. Methods of the present invention comprise use of an ultrasound device to provide ultrasound to activate brain regions, which increase arousal, attention, and awareness. Methods for activation of brain regions may be employed by any subject where arousal, attention or awareness are sought. For example, ultrasound devices may be worn by operators of heavy machinery or equipment, astronauts, pilots, and combat or tactical personnel where increased attention, arousla, increased alertness and for long-term wakefulness is desirable in order to improve performance to minimize risk of injury to the user and others and/or accidents. Shift-workers or long-haul truck drivers may also benefit from such methods. There are numerous centers in the brain which are responsible for regulating attention, arousal, and alertness. Increasing activity in these brain regions can increase reaction times, enhance cognitive performance, and promote appropriate behavioral or physiological responses. Some of the neurotransmitter and neuromodulator systems involved in the regulation of arousal and alertness are acetylcholine, dopamine, histamine, hypocretin, serotonin, and norepinephrine. Brain circuits, which mediate arousal and attention include, but are not limited to the prefrontal cortex, basal forebrain, the hypothalamus, tuberomamillary nuclei, basolateral amygdala, ventral tegmental area, medial forebrain bundle, locus ceruleus, the thalamus, and the dorsal raphe nucleus. Specific thalamocortical oscillations (~ 40 Hz) are known to occur during wakefulness or alertness and can be detected using EEG and or MEG. There are other patterns of brain activity, which indicate enhanced arousal, alertness, and attention and these can also be detected using MEG and or EEG. Methods of the present invention comprise activating arousal brain regions to increase alertness, awareness, attention or long-term wakefulness in a subject by providing an effective amount of ultrasound to a brain region, wherein the brain region comprises prefrontal cortex, basal forebrain, the hypothalamus, tuberomamillary nuclei, basolateral amygdala, ventral tegmental area, medial forebrain bundle, locus ceruleus, the thalamus, and the dorsal raphe nucleus. Ultrasound may be provided by a device of the present invention. A device may provide focused and/or unfocused ultrasound ranging from 25 kHz to 50 MHz and an intensity ranging from 0.025 to 250 W/cm^2 in a treatment method to modulate brain function in a manner that alters alertness, wakefulness, and/or attention. Methods of the present invention comprise providing ultrasound to effect release of acetylcholine, dopamine, histamine, hypocretin, serotonin, and norepinephrine. For example, an ultrasound device of the present invention may provide ultrasound to a subject to activate arousal brain regions in the subjects to increase alertness, awareness, attention, and long-term wakefulness for enhanced attention and alertness during sensitive operations, such as during combat environments, while operating heavy machinery, for astronauts, or pilots. Methods of the present invention comprise activation of reward pathways in a subject by providing an effective amount of ultrasound to a brain region, wherein the brain region comprises the mesolimbic and mesocortical pathways, including connections between the medial forebrain bundle (MFB) and its connections to the nucleus accumbens (NA) where dopamine (DA) acts as a neruomodulator, the prefrontal cortex, the atnerior cingulate cortex (ACC), basolateral amygdala (BLA), or the ventral tegmental area (VTA), as well as dopaminergic, glutamtergic, serotonergic, and cholingeric systems. ... Activation of reward pathways may be used to condition and/or reinforce certain desired attributes and/or to motivate specific behavioral actions. ... For example, in rats conditioned to press a bar to receive intracranial self-stimulation (ICSS) of the VTA, MFB, and/or NA will lead to reinforcing behaviors such that the rat ignores all other environmental cues and will engage in repeated bar pressing behaviors in order to gain the reinforcing/pleasure inducing ICSS of those brain nuclei. Ultrasound stimulus waveforms may be provided from about one hour prior to the occurence of the behaviorto be reinforced to about one hour following the behavioral actions to be reinforced. Longer or shorter time ranges for ultrasound provision may be appropriate for some behaviors, or for later stages of treatment, and such ranges may be determined by those skilled in the art. Methods of the present invention comprise modulating cerebrovascular dynamics by providing ultrasound to brain regions. Ultrasound induces vasodilation or vasoconstriction in peripheral tissues by activating nitric oxide/nitric oxide synthetase. Data of the inventor showed that air-coupled ultrasound transducers induced vasodilation in the brains of rodents. Pulsed ultrasoudn remotely modulated brain hemodynamics by inducing cerebrovascular vasodilation in an intact brain. An ultrasound device of the present invention may alter brain activity by altering cerebrovascular blood flow and indirectly increase or decrease neuronal activity, altering energy utilization and metabolism, or increase oxygen to brain regions. Methods of the present invention comprise activating sensory or motor brain regions in a subject by providing an effective amount of ultrasound to a brain region, wherein the brain region comprises all or part of a vestibular system, an aural region, a visual region, an olfactory region, a proprioperceptive region, afferents or efferents of one or more regions, or combinations thereof. Ultrasound may be provided by an ultrasound device of the present invention. An aspect of the present invention comprises methods and devices that allow a human-machine interface for communications with the subject operably attached to an ultrasound device of the persent invention to activate sensory or motor brain regions of the subject to produce movement or to create synthetic brain imagery. For example, such methods and devices are used for projections of visual sounds to auditory regions of the brain, ability to generate virtual maps/images onto visual brain regions, ability to control body movement pattersn of an individual. Such brain stimulation may be effected either directly or indirectly. For example, an operator or the subject may stimulate the vestibular system to cause the subject to make a turning motion in order to guide that subject via GPS or other feedback from navigation technology, or stimulate motor areas of the subject's brain to cause the subject to make a motor action. Such methods and devices may be used for any application, including but not limited to, recreational, entertainment, and/or video gaming applications. The disclosed methods and devices achieve acoustic impedance matching between water-matched ultrasound transducers and the surface of the head of the subject. For example, one or more water-matched ultrasound transducers are coupled to ultrasound coupling pads and installed into an ultrasound device. The water-matched ultrasound transducer receives voltage pulses from at least one microcontroller of an ultrasound device. For example, the ultrasound transducer is in electrical communication with a microcontroller at one position of the transducer, and contacts an ultrasound coupling pad at a different location of the transducer. The ultrasound coupling pad is in contact with the transducer in one location and, in another location of the pad, is in contact with the surface of the head of the wearer of the device. For example, the transducer transits frm the outside of the body of the device to the inner surface of the device. At the outer surface of the body of the device, the transducer is operably connected to a microcontroller, either remotely or by an electrical means such as a wire. At the inner surface of the body of the device, the transducer is in contact with the ultrasound coupling pad. The use of ultrasound coupling pads helps provide optimal power transfer during ultrasound transmission. Ultrasound coupling pads include but are not limited to degassed water in a polymer bladder. One or more ultrasound coupling pads mounted within an ultrasound device serve to couple water-matched ultrasound transducers directly to the subject's head surface. vestibular - influence the perception of movement Immersion-type US transducers having a center frequency of 0.5 MHz (V301-Su, Olympus NDT, Waltham, MA) or 0.3 MHz (GS-300-D19, Ultran, State College, PA) were used to produce US waveforms. US pulses were generated by brief bursts of square moves (0.2 microseconds; 0.5 mV peak-to-peak) using an Agilent 33220A function generator (Agilent Technologies, Inc., Santa Clara, CA, USA). Square waves were further amplified (50 dB gain) using a 40W ENI 240L RF amplifier. Square waves were delivered between 0.25 and 0.50 MHz depending on the acoustic frequency desired. US pulses were repeated at a pulsed repetition frequency by triggering the above-referenced function generator with square waves produced using a second Agilent 33220A function generator. needle hydrophone (HNR 500, Onda Coporation, Sunnyvale, CA, USA) Agilent DSO6012A 100 MHz digital oscilloscope connected to a PC motor cortex to muscle twitch -- response latency: 23ms The baseline failure rate in obtaining US-evoked motor responses was <5% when multiple stimulus trials were repeated once every 4-10s for time periods up to 50min. ================================ DARPA? Tyler,William James * . The Development of Pulsed Ultrasound for Noninvasive Neural Interfaces. DOD-DARPA (6/16/2010 - 6/15/2011). Smith,Brian * Tyler,William James . Remote Control of Intact Mammalian Brain Circuits Using Pulsed Ultrasound. DOD-ARMY-ARO (9/1/2009 - 8/31/2012). Ebbene, la ricerca della D.A.R.P.A., nell’ambito del progetto REPAIR (acronimo di Reorganization and Plasticity to Accelerate Injury Recovery), da un lato è finalizzata a questo stesso obiettivo, attraverso lo sviluppo di impianti cerebrali che avranno il compito di “sostituirsi” alla materia grigia danneggiata. REPAIR (Reorganization and Plasticity to Accelerate Injury Recovery) In particular the project of Tyler and DARPA is listed under the heading " Development of Pulsed Ultrasound for noninvasive Neural Interfaces "and prior to joining DARPA has been funded by the U.S. Army Research, Development and Engineering Command (RDECOM) and dall'Army Research Laboratory (ARL). In its first phase, this study aimed to develop methodologies suitable for the encoding of data in sensory cortex using ultrasonic pulses. Today we have moved to a new phase in which the ultimate goal will be to develop applications of neurotechnology for American troops. DARPA is continuing to explore the possibilities allowed by the ultrasound on the conditioning of brain function. REDCOM grant W911NF-09-0431 REPAIR (Reorganization and Plasticity to Accelerate Injury Recovery) http://www.arl.army.mil/www/pages/172/docs/AROinReview_2010.pdf http://www.arl.army.mil/www/pages/172/docs/AnnualReview2010.pdf http://www.arl.army.mil/www/pages/172/docs/AnnualReview2009.pdf -------------------------------------------------- 2011-06-26 sonothrombolysis Focused ultrasound modulates region-specific brain activity We demonstrated the in vivo feasibility of using focused ultrasound (FUS) to transiently modulate (through either stimulation or suppression) the function of regional brain tissue in rabbits. FUS was delivered in a train of pulses at low acoustic energy, far below the cavitation threshold, to the animal's somatomotor and visual areas, as guided by anatomical and functional information from magnetic resonance imaging (MRI). The temporary alterations in the brain function affected by the sonication were characterized by both electrophysiological recordings and functional brain mapping achieved through the use of functional MRI (fMRI). The modulatory effects were bimodal, whereby the brain activity could either be stimulated or selectively suppressed. Histological analysis of the excised brain tissue after the sonication demonstrated that the FUS did not elicit any tissue damages. Unlike transcranial magnetic stimulation, FUS can be applied to deep structures in the brain with greater spatial precision. Transient modulation of brain function using image-guided and anatomically-targeted FUS would enable the investigation of functional connectivity between brain regions and will eventually lead to a better understanding of localized brain functions. It is anticipated that the use of this technology will have an impact on brain research and may offer novel therapeutic interventions in various neurological conditions and psychiatric disorders. - rabbit somatomotor - rabbit visual cortex Focused ultrasound modulates the level of cortical neurotransmitters: Potential as a new functional brain mapping technique Regional modulation of the level of cortical neurotransmitters in the brain would serve as a new functional brain mapping technique to interrogate the neurochemical actions of the brain. We investigated the utility of the application of low-intensity, pulsed sonication of focused ultrasound (FUS) to the brain to modulate the extracellular level of dopamine (DA) and serotonin (5-HT). FUS was delivered to the thalamic areas of rats, and extracellular DA and 5-HT were sampled from the frontal lobe using the microdialysis technique. The concentration changes of the sampled DA and 5-HT were measured through high-performance liquid chromatography. We observed a significant increase of the extracellular concentrations of DA and 5-HT in the FUS-treated group as compared with those in the unsonicated group. Our results provide the first direct evidence that FUS sonication alters the level of extracellular concentration of these monoamine neurotransmitters and has a potential modulatory effect on their local release, uptake, or degradation. Our findings suggest that the pulsed application of FUS offers new perspectives for a possible noninvasive modulation of neurotransmitters and may have diagnostic as well as therapeutic implications for DA/5-HT-mediated neurological and psychiatric disorders Human Cadaver Model for Pre-clinical Evaluation of a 1MHz Ultrasonic Brain Therapy Device J.F. Aubry FUS Vendor Profiles Moderator: M. Buntaine Profound Medical, Inc P. Chipperton FUS Instruments, Inc. R. Chopra Image Guided Therapy E. Dumont InSightec, Ltd K. Vortman Philips Healthcare F. Busse Supersonic Imagine J. Souquet Mathias Fink - Ultrasonic Brain Therapy: Monkey study - Langevin Institute, ESPCI Mickael Tanter - Ultrasonic Brain Therapy under MR monitoring - Langevin Institute, ESPCI Ernst Martin - MRgFUS for Central Lateral Thalamotomies - University of Zurich Ernst Martin - MR-guided Functional Ultrasound-Neurosurgery - University of Zurich Seung-Schik Yoo - FUS-mediated Reversible Modulation of Region-specific Brain Function - Brigham and Women’s Hospital The Effect of Focused Ultrasound Thermal Ablation on Nerve Function - Nathan McDannold, Alexandra Golby, Natalia Vykhodtseva --------------------------- Direct observations of ultrasound microbubble contrast agent interaction with the microvessel wall http://scitation.aip.org/content/asa/journal/jasa/122/2/10.1121/1.2747204 Many thousands of contrast ultrasound studies have been conducted in clinics around the world. In addition, the microbubbles employed in these examinations are being widely investigated to deliver drugs and genes. Here, for the first time, the oscillation of these microbubbles in small vessels is directly observed and shown to be substantially different than that predicted by previous models and imaged within large fluid volumes. Using pulsed ultrasound with a center frequency of 1MHz and peak rarefactional pressure of 0.8 or 2.0MPa, microbubble expansion was significantly reduced when microbubbles were constrained within small vessels in the rat cecum (p<0.05). A model for microbubble oscillation within compliant vessels is presented that accurately predicts oscillation and vessel displacement within small vessels. As a result of the decreased oscillation in small vessels, a large resting microbubble diameter resulting from agent fusion or a high mechanical index was required to bring the agent shell into contact with the endothelium. Also, contact with the endothelium was observed during asymmetrical collapse, not during expansion. These results will be used to improve the design of drug delivery techniques using microbubbles. © 2007 Acoustical Society of America ------------------------- Quantitative evaluation of focused ultrasound with a contrast agent on blood-brain barrier disruption Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium Increasing the endothelial layer permeability through ultrasound-activated microbubbles Acoustic investigation of pressure-dependent resonance and shell elasticity of lipid-coated monodisperse microbubbles -------------------------- Stimulation of hippocampal neurogenesis by transcranial focused ultrasound and microbubbles in adult mice. http://europepmc.org/abstract/med/24629831/reload=0;jsessionid=tTPKTVt2TRm76bWLFF6T.20 Transcranial focused ultrasound (FUS) and microbubble contrast agent, applied at parameters known to transiently increase blood-brain barrier permeability, were tested for the potential to stimulate hippocampal neurogenesis. In adult mice, FUS treatment significantly increased the number of proliferating cells and newborn neurons in the dentate gyrus of the dorsal hippocampus. This provides evidence that FUS with microbubbles can stimulate hippocampal neurogenesis, a process involved in learning and memory and affected in neurological disorders, such as Alzheimer's disease. ---------------------- Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles http://www.pnas.org/content/108/40/16539.short Focused ultrasound activation of systemically administered microbubbles is a noninvasive and localized drug delivery method that can increase vascular permeability to large molecular agents. Yet the range of acoustic parameters responsible for drug delivery remains unknown, and, thus, enhancing the delivery characteristics without compromising safety has proven to be difficult. We propose a new basis for ultrasonic pulse design in drug delivery through the blood–brain barrier (BBB) that uses principles of probability of occurrence and spatial distribution of cavitation in contrast to the conventionally applied magnitude of cavitation. The efficacy of using extremely short (2.3 μs) pulses was evaluated in 27 distinct acoustic parameter sets at low peak-rarefactional pressures (0.51 MPa or lower). The left hippocampus and lateral thalamus were noninvasively sonicated after administration of Definity microbubbles. Disruption of the BBB was confirmed by delivery of fluorescently tagged 3-, 10-, or 70-kDa dextrans. Under some conditions, dextrans were distributed homogeneously throughout the targeted region and accumulated at specific hippocampal landmarks and neuronal cells and axons. No histological damage was observed at the most effective parameter set. Our results have broadened the design space of parameters toward a wider safety window that may also increase vascular permeability. The study also uncovered a set of parameters that enhances the dose and distribution of molecular delivery, overcoming standard trade-offs in avoiding associated damage. Given the short pulses used similar to diagnostic ultrasound, new critical parameters were also elucidated to clearly separate therapeutic ultrasound from disruption-free diagnostic ultrasound. ---------------------- Intracerebral administration of ultrasound-induced dissolution of lipid-coated GDNF microbubbles provides neuroprotection in a rat model of Parkinson's disease http://www.sciencedirect.com/science/article/pii/S0361923014000252 Parkinson's disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Neurotrophic factors, such as glial cell derived neurotrophic factor (GDNF), have been shown to provide a neuroprotective effect in PD rats. We have previously reported that ultrasound-induced lipid-coated GDNF microspheres, which release GDNF in a sustained manner after low frequency ultrasound stimulation, can reduce hypoxic–ischemic injury in neonatal rats. In the present study, we investigated whether lipid-coated GDNF microspheres can provide a neuroprotective effect in a rat model of PD. After a rat model of PD was produced by 6-hydroxydompamine (6-OHDA) injections, lipid-coated GDNF microspheres (1.5 mg/kg) were injected into the striatum of PD rats. We found that GDNF levels were increased in the striatum of PD rats after lipid-coated GDNF microspheres administration following low frequency ultrasound stimulation (20 kHz, 5 min per day, daily for 4 weeks). Moreover, GDNF microspheres reduced apomorphine-induced rotations, and increased striatal dopamine and nigral tyrosine hydroxylase (TH) levels in PD rats. Additionally, GDNF microspheres reduced caspase-3, tumor necrosis factor-alpha, matrix metalloproteinase 9 (MMP-9) and OX-6 levels induced by 6-OHDA injections in PD rats. These data indicated that lipid-coated GDNF microspheres can provide a neuroprotective effect in PD rats. ------------------------------------ Ultrasound-induced release of GDNF from lipid coated microbubbles injected into striatum reduces hypoxic–ischemic injury in neonatal rats Adenovirus-mediated delivery of GDNF ameliorates corticospinal neuronal atrophy and motor function deficits in rats with spinal cord injury Experimental Research on Treatment of Injured Facial Nerves Induced by Hepatocyte Growth Factor Mediated by Ultrasound-Targeted Microbubble Destruction Nonthermal ablation with microbubble-enhanced focused ultrasound close to the optic tract without affecting nerve function: Laboratory investigation Applications of lipid-coated microbubble ultrasonic contrast to tumor therapy (1993) Development of inherently echogenic liposomes as an ultrasonic contrast agent (1996) Interaction of transthoracic ultrasound and intravenous microbubbles with cardiac mechanoreceptors Observation on the integrity of the blood-brain barrier after microbubble destruction by diagnostic transcranial color-coded sonography http://jultrasoundmed.org/ Intramembrane Cavitation as a Predictive Bio-Piezoelectric Mechanism for Ultrasonic Brain Stimulation http://link.aps.org/pdf/10.1103/PhysRevX.4.011004 Direct observations of ultrasound microbubble contrast agent interaction with the microvessel wall Characterization of cell membrane response to ultrasound activated microbubbles Magnetically enhanced nucleic acid delivery. Ten years of magnetofection—Progress and prospects (2011) Acoustic droplet vaporization for enhancement of thermal ablation by high intensity focused ultrasound Design of ultrasonically-activatable nanoparticles using low boiling point perfluorocarbons Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating --------------------------------------- The laser‐generated ultrasonic phased array: Analysis and experiments http://scitation.aip.org/content/asa/journal/jasa/94/4/10.1121/1.407516 Focused ultrasonicwaves have been generated in a solid by irradiating its surface with a multiple beam‐pulsed YAG laser. A set of 16 rectilinear sources is used, equivalent to a phased array of ultrasonic transducers. Longitudinal waves are focused in the sample by introducing an appropriate time delay between each laser pulse. The elastic waves are detected either by a broadband optical heterodyne probe to analyze the wide ultrasonic signal spectrum (0–20 MHz), or by a narrow‐band piezoelectric transducer to achieve the sectorial acoustic beam scanning of the sample. Neglecting heat diffusion in the solid and considering the source as a surface center of expansion, the impulse directivity patterns of laser‐generated longitudinal acoustic waves have been computed. Experiments performed on duraluminum samples in the thermoelastic regime and steel samples in the ablation regime are presented and compared with this analysis. It is shown that a high focusing and a significant improvement of the signal sensitivity for longitudinal waves can be achieved with this technique. Experimental evaluation of enhanced generation of ultrasonic waves using an array of laser sources http://www.sciencedirect.com/science/article/pii/0041624X9500090P An array of ten pulsed Nd: YAG lasers was constructed in order to study the effects of generating ultrasound with an array of laser sources. The laser system permitted the spatial and temporal control of the firing of the individual lasers in the array necessary for the production of both narrow-band ultrasonic signals and phased array single pulses. The increase in sensitivity of a laser ultrasonic system associated with the generation of narrow-band and phased array acoustic waves is discussed theoretically and verified experimentally for surface and bulk wave generation. The ultrasonic signals were generated in aluminium samples of various thicknesses and with source laser power densities consistent with generation in the thermoelastic regime, thus causing no damage to the surface of the specimens. The signals were detected using a path stabilized Michelson interferometer. In the narrow-band case, the waveforms were digitally filtered in order to take advantage of the reduced spectral range of the generated acoustic energy. A significant increase in the sensitivity of the laser ultrasonic system, consistent with theoretical predictions, was observed in both the narrow-band and phased array cases. Sensitivity of point-and line-source laser-generated acoustic wave to surface flaws http://ieeexplore.ieee.org/xpl/login.jsp?tp=&arnumber=1226549&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Farnumber%3D1226549 Laser generation and air-coupled detection were combined as a hybrid ultrasonic technique for the inspection of surface flaws in rails. Narrowband acoustic signals were generated using a formed laser source by focusing the laser light to a point and to a line on the surface of the rail. The pulse energy, and therefore the intensity of the laser source, varied such that the generated signal transitioned from the weak thermoelastic to the strong ablative regime. The detection of flaws using a laser-generated surface acoustic wave, in the presence of surface flaws, was compared between both point and line laser sources operating under different pulse energy levels. The line source was found to be more sensitive to the presence of surface flaws than a point source. The sensitivity of the laser-generated acoustic signal appeared to be independent of the severity of the flaw and, within the ablative regime, independent of the laser-pulse energy. Theoretical analysis is provided to explain the underlying cause that influences the interaction of a formed laser-generated surface acoustic wave to surface flaws and how this sensitivity may vary between the thermoelastic and ablative regimes. Skin characteristics by laser generated surface waves http://ieeexplore.ieee.org/xpl/login.jsp?tp=&arnumber=5332725&url=http%3A%2F%2Fieeexplore.ieee.org%2Fxpls%2Fabs_all.jsp%3Farnumber%3D5332725 This paper discusses a study into the suitability of using laser generated surface acoustic waves for the characterisation of skin properties without causing any damage to the skin thermally or by mechanical disruption. Using commercial Finite Element Code ANSYS, the effects of laser wavelength, laser beam radius and laser rise time on generation of laser generated ultrasonic waves in a 3-layered elastic isotropic model of human skin were studied. The FE model is an example of a sequential coupled field analysis where the thermal and mechanical analyses are treated separately. The heating of the skin model due to the short laser pulse is simulated by a dynamic thermal analysis with the laser pulse modeled as volumetric heat generation and the results from this analysis subsequently applied as a load in the mechanical analysis where the out-of-plane displacement histories are analyzed. The technique described in this paper also involves measuring the propagation velocity of SAWs, which are directly related to the material properties, and thickness of layers, this is done over a wide frequency range in order to obtain maximum information regarding the material under test. Numerical simulation of the ultrasonic waves generated by ring-shaped laser illumination patterns Finite element modeling of bulk ultrasonic waves generated by ring-shaped laser illumination in a diamond anvil cell Application of laser ultrasound for surface acoustic wave microscopy Numerical simulation of phased-array laser ultrasound and its application for defect inspection Continuous laser generation of ultrasound Transient elastic wave generation by an array of thermoelastic sources Laser-generated ultrasound with an array of melting sources A high-frequency, 2-D array element using thermoelastic expansion in PDMS High-frequency ultrasound sensors using polymer microring resonators Real-time optoacoustic monitoring of temperature in tissues Focusing and beamsteering of laser generated ultrasound Volumetric Real-Time Imaging Using a CMUT Ring Array synthetic phased array capacitive micromachined ultrasonic transducer (CMUT) array Acoustic wave manipulation by phased operation of two-dimensionally arrayed nanocrystalline silicon ultrasonic emitters Suspended metal wire array as a thermoacoustic sound source http://tikander.net/miikka/Science/Publications_files/niskanen09.pdf ----------------------------------- Graphene-on-Paper Sound Source Devices http://pubs.acs.org/doi/abs/10.1021/nn2009535 We demonstrate an interesting phenomenon that graphene can emit sound. The application of graphene can be expanded in the acoustic field. Graphene-on-paper sound source devices are made by patterning graphene on paper substrates. Three graphene sheet samples with the thickness of 100, 60, and 20 nm were fabricated. Sound emission from graphene is measured as a function of power, distance, angle, and frequency in the far-field. The theoretical model of air/graphene/paper/PCB board multilayer structure is established to analyze the sound directivity, frequency response, and efficiency. Measured sound pressure level (SPL) and efficiency are in good agreement with theoretical results. It is found that graphene has a significant flat frequency response in the wide ultrasound range 20–50 kHz. In addition, the thinner graphene sheets can produce higher SPL due to its lower heat capacity per unit area (HCPUA). The infrared thermal images reveal that a thermoacoustic effect is the working principle. We find that the sound performance mainly depends on the HCPUA of the conductor and the thermal properties of the substrate. The paper-based graphene sound source devices have highly reliable, flexible, no mechanical vibration, simple structure and high performance characteristics. It could open wide applications in multimedia, consumer electronics, biological, medical, and many other areas. Single-layer graphene sound-emitting devices: experiments and modeling Transparent, flexible, ultrathin sound source devices using Indium Tin oxide films Electrostatic graphene loudspeaker http://arxiv.org/pdf/1303.2391 Model for thermoacoustic emission from solids Hyperbolic heat equations in laser generated ultrasound models Efficient laser-ultrasound generation by using heavily absorbing films as targets Laser generated ultrasound: a thermoelastic analysis of the source Theoretical analysis of a novel ultrasound generator on an optical fiber tip An integrated optoacoustic transducer combining etalon and black PDMS structures Hybrid photoacoustic and ultrasound section imaging with optical ultrasound detection An all-optical thin-film high-frequency ultrasound transducer Micro-Opto-Mechanical technology for the fabrication of highly miniaturized fiber-optic ultrasonic detectors Optical generation of narrowband high frequency ultrasound Tailoring ultrasonic beams with optoacoustic holography Synthetic acoustic holograms realized via optoacoustic methods Optoacoustic generation of a helicoidal ultrasonic beam ------------------------------------ Focused ultrasound as a tool to input sensory information to humans (Review) http://link.springer.com/article/10.1134/S1063771012010083 This review is devoted to the analysis of studies and implementations related to the use of focused ultrasound for functional effects on neuroreceptor structures. Special attention was paid to the stimulation of neuroreceptor structures in order to input sensory information to humans. This branch of medical and physiological acoustics appeared in Russia in the early 1970s and was being efficiently developed up to the late 1980s. Then, due to lack of financial support, only individual researchers remained at this field and, as a result, we have no full- fledged theoretical research and practical implementations in this area yet. Many promising possibilities of using functional effects of focused ultrasound in medicine and physiology have remained unimplemented for a long time. However, new interesting ideas and approaches have appeared in recent years. Very recently, very questionable projects have been reported related to the use of ultrasound for targeted functional effects on the human brain performed in some laboratories. In this review, the stages of the development of scientific research devoted to the functional effects of focused ultrasound are described. By activating the neuroreceptor structures of the skin by means pulses of focused ultrasound, one can cause all the sensations perceived by human beings through the skin in everyday life, such as tactile sensations, thermal (heat and cold), tickling, itching, and various types of pain. Stimulation of the ear labyrinth of humans with normal hearing using amplitude-modulated ultrasound causes auditory sensations corresponding to an audio modulating signal (pure tones, music, speech, etc.). Activation of neuroreceptor structures by means of focused ultrasound is used for the diagnosis of various neurological and skin diseases, as well as hearing disorders. It has been shown that the activation is related to the mechanical action of ultrasound, for example, by the radiation force, as well as to the direct action of ultrasonic vibrations on nerve fibers. The action of the radiation force is promising for the realization of the possibility of blind and even deaf-and-blind people to perceive text information on a display using tactile sensations caused by ultrasound. Very different methods of using ultrasound for local stimulation of neuroreceptor structures are discussed in this review. Among them are practical methods that have been already tested in a clinic, as well as pretending to be sensational methods that are hardly feasible in the foreseeable future. ----------------------------------- Intramembrane Cavitation as a Predictive Bio-Piezoelectric Mechanism for Ultrasonic Brain Stimulation http://journals.aps.org/prx/abstract/10.1103/PhysRevX.4.011004 Low-intensity ultrasonic waves can remotely and nondestructively excite central nervous system (CNS) neurons. While diverse applications for this effect are already emerging, the biophysical transduction mechanism underlying this excitation remains unclear. Recently, we suggested that ultrasound-induced intramembrane cavitation within the bilayer membrane could underlie the biomechanics of a range of observed acoustic bioeffects. In this paper, we show that, in CNS neurons, ultrasound-induced cavitation of these nanometric bilayer sonophores can induce a complex mechanoelectrical interplay leading to excitation, primarily through the effect of currents induced by membrane capacitance changes. Our model explains the basic features of CNS acoustostimulation and predicts how the experimentally observed efficacy of mouse motor cortical ultrasonic stimulation depends on stimulation parameters. These results support the hypothesis that neuronal intramembrane piezoelectricity underlies ultrasound-induced neurostimulation, and suggest that other interactions between the nervous system and pressure waves or perturbations could be explained by this new mode of biological piezoelectric transduction. ---------------------- Increased Anatomical Specificity of Neuromodulation via Modulated Focused Ultrasound http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0086939#pone-0086939-g013 Transcranial ultrasound can alter brain function transiently and nondestructively, offering a new tool to study brain function now and inform future therapies. Previous research on neuromodulation implemented pulsed low-frequency (250–700 kHz) ultrasound with spatial peak temporal average intensities (ISPTA) of 0.1–10 W/cm2. That work used transducers that either insonified relatively large volumes of mouse brain (several mL) with relatively low-frequency ultrasound and produced bilateral motor responses, or relatively small volumes of brain (on the order of 0.06 mL) with relatively high-frequency ultrasound that produced unilateral motor responses. This study seeks to increase anatomical specificity to neuromodulation with modulated focused ultrasound (mFU). Here, ‘modulated’ means modifying a focused 2-MHz carrier signal dynamically with a 500-kHz signal as in vibro-acoustography, thereby creating a low-frequency but small volume (approximately 0.015 mL) source of neuromodulation. Application of transcranial mFU to lightly anesthetized mice produced various motor movements with high spatial selectivity (on the order of 1 mm) that scaled with the temporal average ultrasound intensity. Alone, mFU and focused ultrasound (FUS) each induced motor activity, including unilateral motions, though anatomical location and type of motion varied. Future work should include larger animal models to determine the relative efficacy of mFU versus FUS. Other studies should determine the biophysical processes through which they act. Also of interest is exploration of the potential research and clinical applications for targeted, transcranial neuromodulation created by modulated focused ultrasound, especially mFU’s ability to produce compact sources of ultrasound at the very low frequencies (10–100s of Hertz) that are commensurate with the natural frequencies of the brain. -------------------------------- Cytomechanical Perturbations during Low-Intensity Ultrasound Pulsing http://www.sciencedirect.com/science/article/pii/S030156291400012X To establish the therapeutic potential of low-intensity ultrasound, it is important to characterize its biophysical interactions with living cells. Here, through a series of single-cell direct observations, we show that low-intensity ultrasound pulsing would give rise to a dynamic course of cytomechanical perturbations at both the membrane and nucleus levels. Our investigation was conducted using a composite platform that coupled a 1-MHz ultrasound exposure hardware to a confocal microscopy system. Short ultrasound pulses (5 cycles, 2-kHz pulse repetition frequency) with a spatial-peak time-averaged intensity of 0.24 W/cm2 (0.85-MPa peak positive acoustic pressure) were delivered over a 10-min period to adherent Neuro-2a neuroblastoma cells, and live imaging of cellular dynamics was performed before, during and after the exposure period. Bright-field imaging results revealed progressive shrinkage of cellular cross-sectional area (25%–45%, N = 7) during low-intensity ultrasound pulsing; the initial rate of size decrease was estimated to be 8%–14% per minute. This shrinkage was found to be transient, as the sonicated cells had recovered (at a rate of size increase of 0.4%–0.9% per minute) to their pre-exposure size within 30 min after the end of exposure. Three-dimensional confocal imaging results further revealed that (i) ultrasound-induced membrane contraction was volumetric in nature (21%–45% reduction), and (ii) a concomitant decrease in nucleus volume was evident (12%–25% reduction). Together, these findings indicate that low-intensity ultrasound pulsing, if applied on the order of minutes, would reversibly perturb the physical and subcellular structures of living cells. ---------------------- Focused ultrasound modulates the level of cortical neurotransmitters: Potential as a new functional brain mapping technique http://www.researchgate.net/publication/229943674_Focused_ultrasound_modulates_the_level_of_cortical_neurotransmitters_Potential_as_a_new_functional_brain_mapping_technique/file/79e41512c962b6fa9b.pdf Regional modulation of the level of cortical neurotransmitters in the brain would serve as a new functional brain mapping technique to interrogate the neurochemical actions of the brain. We investigated the utility of the application of low-intensity, pulsed sonication of focused ultrasound (FUS) to the brain to modulate the extracellular level of dopamine (DA) and serotonin (5-HT). FUS was delivered to the thalamic areas of rats, and extracellular DA and 5-HT were sampled from the frontal lobe using the microdialysis technique. The concentration changes of the sampled DA and 5-HT were measured through high-performance liquid chromatography. We observed a significant increase of the extracellular concentrations of DA and 5-HT in the FUS-treated group as compared with those in the unsonicated group. Our results provide the first direct evidence that FUS sonication alters the level of extracellular concentration of these monoamine neurotransmitters and has a potential modulatory effect on their local release, uptake, or degradation. Our findings suggest that the pulsed application of FUS offers new perspectives for a possible noninvasive modulation of neurotransmitters and may have diagnostic as well as therapeutic implications for DA/5-HT-mediated neurological and psychiatric disorders. © 2011 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 21, 232–240, 2011 Transcranial focused ultrasound to the thalamus is associated with reduced extracellular GABA levels in rats Transcranial focused ultrasound to the thalamus alters anesthesia time in rats Image‐guided navigation of single‐element focused ultrasound transducer Generation of individualized thalamus target maps by using statistical shape models and thalamocortical tractography Histological findings in the brain after focused ultrasound ablation combined with definity using parameters suited for transcranial application Creating brain lesions with low-intensity focused ultrasound with microbubbles: a rat study at half a megahertz Ultrasound Targeted Microbubble Destruction Promotes Angiogenesis and Heart Function by Inducing Myocardial Microenvironment Change Optimization of operating frequency of acoustic transducers for obtaining maximum temperature in HIFU based therapeutic ablation Three-dimensional image sensing in air by thermally induced ultrasonic emitter based on nanocrystalline porous silicon Model for thermoacoustic emission from solids Acoustic wave manipulation by phased operation of two-dimensionally arrayed nanocrystalline silicon ultrasonic emitters Tunable output directivity of thermally induced ultrasound generator based on nanocrystalline porous silicon Development of efficient broadband digital acoustic device based on nanocrystalline silicon ultrasound emitter Reproduction of mouse-pup ultrasonic vocalizations by nanocrystalline silicon thermoacoustic emitter Phased array operation of nanocrystalline porous silicon ultrasonic emitters A thermoacoustic device for sound reproduction New operating mode of nanocrystalline silicon ultrasonic emitters for use as audio speakers ------------------------- Acoustic characteristics of a flexible sound generator based on thermoacoustic effect A flexible sound generator based on the thermoacoustic effect was proposed for use with thin and flexible devices. The proposed sound generator was composed of three thin films made of aluminum, polyimide, and graphite for effective interaction between acoustic energy and heat. The aluminum functions as an electrode for heat radiation into the air, polyimide as a heat insulator, and graphite as a heat sink. The shape of the electrode was a rectangle. Relationship between sound pressure, applied voltage and temperature change of the electrode was modeled. Radiated sound pressure was analytically described as a function of the input signal's frequency. Experimental measurements were carried out and they showed the validity of the model in terms of radiated sound pressure estimation from the proposed structure with selected materials. Surface vibration was also observed, and it was confirmed that the proposed sound generator is vibration-free. ---------------------- Experiments on thermoacoustic arrays with laser excitation A recent theoretical formulation by Westervelt and Larson predicts the development of highly directive sound beams in water through the thermalization of modulated laser light. The present paper reports the experimental validation of this theory with measurements carried out in a fresh water lake. Additional theory pertinent to practical implementation is also presented and verified. The experimental apparatus includes an optically pumped laser system operating in the conventional mode at wavelengths in either the red or infrared regions of the optical spectrum. Modulation of the stochastic light burst is provided by a half‐wave Pockels cell. The acoustic measurements began with an existence test which confirmed that an acoustic signal is produced by thermo‐optic demodulation of laser light in the water. The sound pulse was generated in a beam with a width and source level that are in reasonable agreement with theory. Acoustic diffraction effects associated with laser beams of finite size were also examined, as were the nearfield effects of this type of array. The relation of laser technology to further work in the blue–green spectrum is analyzed. ------------------------ A high-frequency, 2-D array element using thermoelastic expansion in PDMS Optical generation of ultrasound is a promising alternative to piezoelectricity for high-frequency arrays. An array element is defined by the size and location of a laser beam focused on a suitable surface. Optical generation using the thermoelastic effect has traditionally suffered from low conversion efficiency. We previously demonstrated an increase in conversion efficiency of nearly 20 dB with an optical absorbing layer consisting of a mixture of polydimethylsiloxane (PDMS) and carbon black spin coated onto a glass microscope slide. Radiation pattern measurements with an 85 MHz spherically focused transducer indicated an array element size of 20 /spl mu/m. These measurements lacked the spatial resolution required to reveal fine details in the radiated acoustic field. Here we report radiation pattern measurements with a 5-/spl mu/m spatial sampling, showing that the radiated acoustic field is degraded by leaky Rayleigh waves launched from the PDMS/glass interface. We demonstrate that replacing the glass with a clear PDMS substrate eliminates the leaky Rayleigh waves, producing a broad and smooth radiation pattern suitable for a two-dimensional (2-D) phased array operating at frequencies greater than 50 MHz.