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/cm2), 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/cm2.

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/cm2).

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 mm3 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 stimulatino (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/cm2 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)



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