Transcranial ultrasound stimulation device

Abstract

The present invention is in the field of an apparatus for generating mechanical vibrations of ultrasound frequency, in particular an improved wearable ultrasound device, configured for ultra-sound therapy, in particular for transcranial stimulation, a kit of parts comprising said device, and a corresponding method, using said device in therapy.

Description

[0001] TRANSCRANIAL ULTRASOUND STIMULATION DEVICE

[0002] FIELD OF THE INVENTION

[0003] The present invention is in the field of an apparatus for generating mechanical vibrations of ultrasound frequency, in particular an improved wearable ultrasound device, configured for ultrasound therapy, in particular for transcranial stimulation, a kit of parts comprising said device, and a corresponding method, using said device in therapy.

[0004] BACKGROUND OF THE INVENTION

[0005] Ultrasound is an oscillating sound pressure wave with a frequency greater than the upper limit of the human hearing range (hence ultra-sound). Ultrasound devices may operate with frequencies from 20 kHz up to several gigahertz. Ultrasound may be used in many different fields. Ultrasonic devices are used to detect objects and measure distances. Ultrasonic imaging (sonography) is used in both veterinary medicine and human medicine. In the non-destructive testing of products and structures, ultrasound is used to detect invisible flaws. Ultrasonic imaging typically uses frequencies of 2 megahertz and higher. The power density is generally limited, e.g. less than 1 watt / cm2to avoid heating and cavitation effects in the object under examination. High and ultra high ultrasound frequency waves can be used in acoustic microscopy, with frequencies up to 4 gigahertz. Ultrasonic imaging applications include industrial non-destructive testing, quality control and medical uses. Industrially, ultrasound is used for cleaning and for mixing, and to accelerate chemical processes. At higher power levels, ultrasound may be useful for medical treatment or for changing the chemical properties of substances.

[0006] Currently, a significant percentage of the size and power of an ultrasound system is devoted to the beamformer, which is responsible for directing and / or focusing the ultrasound beam. A standard transducer array with beamformer, which consists of multiple, e.g. 64 to 128, trans- mit / receive channels, is straightforward to implement if design constraints such as size and power are relaxed.

[0007] Ultrasound can be used in therapy. It relates to use of ultrasound to transmit acoustic energy into the body, potentially for therapeutic benefit. For some ultrasound applications dedicated hand-held devices are used. These dedicated devices suffer from various drawbacks, amongst others a need of a wire between transducer and monitor, handheld use of the device; hence they are not suited for long-term monitoring. Some prior art devices may require a trained professional to handle the transducer and to evaluate what is seen or what is to be achieved in terms of therapy.

[0008] Potential effects of ultrasound may be considered, including modulation of blood flow, reduction of swelling and oedema, and gentle massage of cells, in muscle tendons and / or ligaments, and the modulation of cell activity and plasticity in the peripheral and central nervous systems These effects are achieved by two main effects of therapeutic ultrasound. The two types of effects are thermal and mechanical effects. Thermal effects are due to the absorption of the sound waves. Mechanical effects are from particle displacement, radiation force, cavitation, and streaming. Examples of ultrasound therapy relate to physiotherapy, lithotripsy, High Intensity Focused Ultrasound (HIFU), targeted ultrasound drug delivery, trans-dermal ultrasound drug delivery, ultrasound haemostasis, cancer therapy, transcranial application, and ultrasound assisted thrombolysis. It may use focused ultrasound (FUS) or unfocused ultrasound. In the above applications, the ultrasound passes through human tissue where it is the main source of the observed biological effect. HIFU generally uses lower frequencies than medical diagnostic ultrasound (250-2000 kHz), but significantly higher time-averaged intensities. The treatment is often guided by Magnetic Resonance Imaging (MRI); the combination is then referred to as Magnetic resonance-guided focused ultrasound (MRgFUS). Transcranial ultrasound may be for used in aiding tissue plasminogen activator treatment, for instance in stroke patients, in a procedure called ultra- sound-enhanced systemic thrombolysis. The transcranial technology is currently being used in ongoing research. Typical issues therein relate to a lack of stability and usability.

[0009] Transcranial ultrasonic stimulation (TUS) is a relatively novel technique that can be used to influence brain activity non-invasively. It employs ultrasonic waves that travel through the skin and skull and interact with ongoing neural activity. This technique has benefits over existing methods of neuromodulation that are currently in wide use. Namely, TUS can be targeted at deeper brain circuits as compared to electrical or magnetic brain-stimulation techniques. Additionally, stimulation can be applied more precisely. This means TUS has potential in treatment of multiple neurological or neuro-psychological disorders that are caused by aberrations of deep neural activity. Further, it can be (and is currently) used in cognitive neuroscience experiments to probe the causal influences of deep-brain circuits that, prior to the introduction of TUS, could not be reached without opening the skull.

[0010] To be effective, TUS needs to be applied using a transducer (a stimulator emitting focused sound waves) that is coupled to the scalp of a human being with no air in between the transducer and scalp. This is important because air will block sound waves at least to some extent. Currently, ultrasound gel and gel-pads are used to ultrasonically couple a device to the skull, but this is challenging, as gel-only coupling only allows direct placement of the transducer flat on the scalp, gel-pads do not allow flexible placement of the transducer and can slide, and ultrasonic coupling is easily lost, leading to failed stimulation. This practical problem makes application of TUS difficult in both research and clinical settings.

[0011] Incidentally reference can be made to CN 111 888 671 A, US 2011 / 028867 Al, and US 2008 / 033297 Al. CN 111 888 671 A recites an ultrasonic transducer coupling device for transcranial ultrasonic stimulation of a human body. The ultrasonic transducer coupling device comprises an automatic pitch adjusting mechanism, an ultrasonic transducer and a water bag structure, wherein the automatic pitch adjusting mechanism is connected with distal and proximal ends of the ultrasonic transducer and is used for adjusting an axial distance between the ultrasonic transducer and scalp of a tester; the ultrasonic transducer is used for generating focused ultrasonic waves required for the transcranial ultrasonic stimulation; the water bag structure is used for storing a liquid couplant and comprises a liquid couplant internal cavity and a liquid couplant external cavity, and a sound-transmitting film in contact with the human body is arranged at the distal end of the liquid couplant internal cavity of the water bag structure; and the liquid couplant internal cavity communicates with the liquid couplant external cavity, and the liquid couplant internal cavity and the liquid couplant external cavity store a liquid couplant which is used for conducting ultrasonic waves to the scalp of the tester. The ultrasonic transducer coupling device has the advantages that the depth of stimulation can be adjusted, the use method is simple, accurate positioning can be achieved, the safety is good, and the like. US 2011 / 028867 Al recites an apparatus for non-invasive delivery of focused ultrasound to a targeted area of a biological tissue, and a method thereof. The apparatus comprises an ultrasound wave generator to provide an amplified modulated waveform, a resonance circuit for tuning the waveform to have a predetermined frequency, an ultrasound transducer for generating a focused beam of the tuned waveform, an applicator supporting the ultrasound transducer, and an ultrasound-tissue coupling bag detachably mounted to the ultrasound transducer. US 2008 / 033297 Al recites a system for the diagnostic or therapeutic treatment of a patient's neural tissues. The system includes at least a means to directly or indirectly acoustically expose or acoustically displace at least a first tissue portion. The system further includes a means to impose, directly or indirectly, an electromagnetic, electrical, magnetic or optical field on at least a second neural tissue portion. The combined or cooperative action of the acoustic exposure / displacement and the field, whether sequentially or simultaneously applied, causes at least one diagnostically or therapeutically useful mechanism. The two tissue portions may be the same portion or different portions

[0012] Therefore, there still is a need for an improved transcranial ultrasound device, which overcomes one or more of the above disadvantages, without jeopardizing essential functionality and advantages.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention relates in a first aspect to a transcranial ultrasonic stimulation (TUS) device, in particular a wearable device (100) for stimulating brain activity, that is for modulating brain activity, or even altering neural processing, by providing ultrasound to the brain or neurons. Inventors have provided a typically balloon shaped coupler, that can be attached to the TUS transducers, such as by using a 3d printed holder. This balloon may be filled with water, which allows the ultrasound to pass through the balloon unimpeded, and undistorted, whilst ultrasonic coupling is easier. The balloon can be created in multiple sizes to fit to a corresponding transducer. In an exemplary embodiment, it can be made thicker, and shallower, by adding or releasing liquid (water), such as depending on the needs of the researcher / clinician. Moreover, its shape allows for adjustments of the angle in which the transducer is placed in relation to the skull. It is attached to the transducer, which assures it stays in place. Its property of being fixed, yet flexible is what makes it so successful. It is considered important, for the efficacy of the present TUS, that some materials can absorb the sound waves, at least to some extent, thereby reducing the effective amplitude of modulation applied. In the present coupler this is not the case, as been extensively tested. Thereto an elastic material is used. Ultrasound is allowed to pass through unimpeded. This use has led to significant further improvements in its design, such as to increase stability and usability. Inventors have measured the effectiveness of the invention both in tightly controlled environments and in settings reflecting its intended use, ensuring, amongst others, that the device does not reduce the output of the TUS transducers (see explanation below). The present balloon is typically fixed in place, and allows for movement of the transducer without risking the loss of coupling. In an alternative embodiment the ultrasonic wave coupler comprises at least one elastic receptacle (21), the receptacle comprising a fluid (22), in particular a liquid, that is, enclosing the fluid between the ultrasound transmitter 10 and the receptacle, such as wherein the elastic receptacle effectively only has one layer of elastic material, or elastic layers attached to one and another, further comprising an opening (23) configured to let ultrasound wave through, and a restrictor (24) configured for attaching the ultrasonic wave coupler into the ultrasound transmitter. In physics and materials science, elasticity is the ability of a body to resist a distorting influence and to return to its original size and shape when that influence or force is removed. Solid objects will deform when adequate loads are applied to them; if the material is elastic, the object will return to its initial shape and size after removal. This is in contrast to plasticity, in which the object fails to do so and instead remains in its deformed state. Examples of such materials are elastomers, being polymers with viscoelasticity, i.e. both viscosity and elasticity.

[0015] In a further aspect the present invention relates to a method for use of the present device in therapy or the like, such as in Transcranial ultrasonic stimulation (TUS); neuro-modulation; coupling solutions; psychiatry; neurology, and cognitive neuroscience. TUS is a novel brain stimulation technique that has the potential to revolutionize cognitive neuroscience, neurology, and psychiatry. Improving its usability is important for the facilitation of widespread use.

[0016] In a first aspect the present invention therefore relates to a transcranial ultrasonic modulation (TUS) device, in particular a wearable device 100 for non-invasive modulation of brain activity, in particular of brain cells, comprising an ultrasound transmitter 10 comprising at least one transducer 110 for providing ultrasonic waves, and a transmitter body 11 for incorporating the at least one transducer, an ultrasonic wave coupler 20 for transmitting sound waves in ultrasonic wave contact with the a least one transducer and configured to provide ultrasonic wave contact to a human scalp, wherein the ultrasonic wave coupler comprises at least one elastic receptacle 21, the receptacle comprising a fluid 22, in particular a liquid, an opening 23 configured to let ultrasound wave through, and a restrictor 24 configured for attaching the coupler to the ultrasound transmitter, that is, for keeping the receptacle in place relative to the coupler. The ultrasonic wave coupler is configured as is detailed to couple ultrasound.

[0017] In a second aspect the present invention relates to a kit of parts comprising the ultrasonic wave coupler 20 according to the invention and optionally the ultrasound transmitter 10.

[0018] In a third aspects the present invention relates to a method of Transcranial ultrasonic stimulation (TUS), comprising the steps of providing the present device, bringing the device to a person’s head, and providing ultrasonic waves to the head. Thereby the present invention provides a solution to one or more of the problems of the prior art.

[0019] Advantages of the present description are detailed throughout the description.

[0020] DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention relates in a first aspect to a device according to the invention.

[0022] In an exemplary embodiment of the present device the elastic material is selected from elastomers, from polymers, from copolymers, such as from natural rubbers, from synthetic rubbers, in particular from poly siloxanes, such as polydimethylsiloxanes (PDMS), such as natural and synthetic polymers, in particular natural and synthetic rubbers, such as diene-comprising polymers, in particular polyisoprene, polybutadiene, fluoro-elastomers, and polychloroprene, non-diene-comprising polymers, in particular butyl rubber polyisobutylene, polysiloxanes, polyurethane, thermoplastic polymers, in particular SIS and SBS block copolymers, and urethanes.

[0023] In an exemplary embodiment of the present device the elastic material has a bulk modulus of 0.5 -10 GPa, such as 1-5 GPa (ISO 9110-1 : 1990 EN). In physics and materials science, elasticity is considered the ability of a body to resist a distorting influence and to return to its original size and shape when that influence or force is removed. Solid objects may deform when adequate loads are applied to them; if the material is elastic, the object will return to its initial shape and size after removal. Typically these materials of the wall have an elastic modulus of 0.5 MPa- 2GPa, such as 10-100 MPa. However, nowadays also suitable materials with higher moduli could be used, such as up to lOOOGPa (ASTM El 11).

[0024] In an exemplary embodiment of the present device the elastic material has a density p of 0.8-3 kg / dm3in particular according to ISO 12154:2014(en), preferably a material with a Poisson’s ratio of 0.48-0.50 in particular according to ASTM D638, ISO 527, in particular about or exactly 0.50.

[0025] In an exemplary embodiment of the present device the elastic material has a shore A hardness (ASTM D 2240; ISO 7619-1) of 10-100, in particular 15-25, and / or self-bleeding, and / or a shrinkage of < 1%, in particular < 0.2%.

[0026] In an exemplary embodiment of the present device the elastic material has a self-bleeding.

[0027] In an exemplary embodiment of the present device the elastic material has a shrinkage of < 1%, in particular < 0.2%, in particular < 0.1%.

[0028] In an exemplary embodiment of the present device the elastic material has a tensile strength of 1-10 N / mm2, in particular 3-8 N / mm2, more in particular 5-7 N / mm2.

[0029] In an exemplary embodiment of the present device the elastic material has a viscosity of 1-10 Pa s, in particular 2-8 Pa s, more in particular 4-6 Pa s.

[0030] In an exemplary embodiment of the present device the elastic material has a tensile strength (EN ISO 1421) of 1-10 N / mm2, in particular 3.5-8 N / mm2, more in particular 6-7.5 N / mm2.

[0031] In an exemplary embodiment of the present device the elastic material has a strength at break (EN ISO XYZ) of 5-25 N / mm, in particular 10-20 N / mm, more in particular 12-18 N / mm. In an exemplary embodiment of the present device the elastic material comprises 0.1-10 wt.% plasticizer, in particular 0.5-4 wt.%, such as 1-3 wt.%, such as silicone oil.

[0032] The above specifics of the elastic material are found to contribute to the performance of the present ultra sonic wave coupler, and more in particular the receptacle thereof. Reflectance by the present receptacle / coupler of ultra sonic waves, transmitted by the present transmitter, is minimized, a field of view of the ultrasonic waves is not much impaired, contact with a skin of a skull is optimized, focusing remains good, etc.

[0033] In an exemplary embodiment of the present device the receptacle (21) is a hollow elastic body having a wall, and is selected from the elastic body having an outer diameter Oa, and from a conus shaped elastic body, the conus shaped elastic body having a tip or a flattened tip and in particular having a cross-section selected from circular, ellipsoid, triangular, rectangular, hexagonal, octagonal, and multigonal, the elastic body having a height H, the elastic body having a volume V, wherein the wall has a thickness ti of 0.001-5 mm, and / or wherein the elastic body has a cross-sectional shape selected from ellipsoidal and circular, and / or wherein a side of the receptacle has a surface area of 20-50 mm2, preferably 30-40 mm2, such as 35 mm2.

[0034] In an exemplary embodiment of the present device the elastic body of the receptacle is a one piece body, such as obtained by 3D-printing, or by moulding.

[0035] In an exemplary embodiment of the present device an acoustic reflectance of the receptacle is < 10%, in particular < 1%, more in particular < 10'2%, relative to an input signal.

[0036] In an exemplary embodiment of the present device the receptacle comprises at least one outlet for releasing fluid, in particular for releasing gas.

[0037] In an exemplary embodiment of the present device at least one of the at least one inlet and at least one outlet is provided with a valve, in particular a one way valve providing one of liquid inlet and liquid outlet only, respectively.

[0038] In an exemplary embodiment of the present device the at least one transducer provides focused ultrasonic waves.

[0039] In an exemplary embodiment of the present device the receptacle comprises at least one inlet for releasing fluid from the receptacle, or for filling the receptacle with fluid.

[0040] In an exemplary embodiment of the present device the receiver part is configured to receive the receptacle.

[0041] In an exemplary embodiment of the present device the ultrasonic wave coupler has a width of 1-20 cm, a height of 1-10 cm, and a length of 1-20 cm, in particular wherein the ultrasonic wave coupler is balloon shaped.

[0042] In an exemplary embodiment of the present device the device is configured to provide ultrasonic waves.

[0043] In an exemplary embodiment of the present device the device is a handheld device, a mechanically held device, or a wearable device.

[0044] In an exemplary embodiment of the present device the coupler comprises a coupler fixator (25) for fixing the coupler to the ultrasonic transmitter. In an exemplary embodiment of the present device the restrictor comprises two sub-parts 24a, b, wherein the two sub-parts are configured to partially incorporate the receptacle, and wherein the two sub-parts are removably attached to one and another. Hence the receptacle is also removably attached.

[0045] In an exemplary embodiment of the present device the restrictor is provided as a connector for permanently fixing a top part of the receptacle to a bottom part of the receptacle, such as a ring, in particular an elastic ring, more in particular an elastic ring of the same material as the receptacle, even more in particular wherein the connector is configured for connecting the receptacle to the ultrasound transmitter.

[0046] In an exemplary embodiment of the present device the liquid is a de-gassed liquid, such as de-gassed water, or oil.

[0047] In an exemplary embodiment of the present device the ultrasound transmitter (10) is configured to provide pulses with a frequency of 5-700 kHz, an amplitude of 10 pW / cm2-100000 mW / cm2, in particular 10-30 mW / cm2’ -during a period of time of 0.1-3600 sec, in particular 30- 1200 sec, and with a total (integrated) power of 1-1000 W / cm2.

[0048] In an exemplary embodiment of the present device the ultrasound transmitter (10) is configured to provide alternating pulses with an intermittent idle period, wherein a time of each pulse individually is from 10 pse-1000 msec, in particular 0.5-500 msec, more in particular 1- 100 msec, and wherein a time of each intermittent idle period individually is from 70 psec - 10000 msec, in particular 2-1000 msec, more in particular 50-200 msec, and / or to provide alternating pulses with a pulse / idle frequency of 0.1-1000 Hz, in particular a pulse / idle frequency of 1-300 Hz, more in particular a pulse / idle frequency of 2-100 Hz.

[0049] In an exemplary embodiment the present device comprises a head fixator for fixing the device to a person's head, such as an adhesive material (107), a strap, a headset, a belt, and an elastic band, and an adhesive material, wherein the fixing means is preferably size adjustable.

[0050] In an exemplary embodiment the present device further comprises at least one of an amplifier, a controller, a storage unit, a connector, a power supply , a memory, a transceiver, an on-off switch, a status indicator 4, ventilation openings, at least one sensor in transceiving connection with the controller, in particular wherein the at least one sensor is selected from a temperature sensor, and a pressure sensor, wherein the temperature sensor is configured to measure a temperature in the liquid of the receptacle, and wherein the pressure sensor is configured to measure pressure in the liquid of the receptacle, and software stored on the memory. The at least one controller may be used for read-out, for control of sensors, for control of the device, for control of TUS measurement, for providing a TUS measurement protocol, etc.

[0051] In an exemplary embodiment of the present device at least one of the electrical pulse generator, the processor, the controller, the sensor, an amplifier, a controller, a storage unit, a connector, a power supply, a memory, a transceiver, an on-off switch, a status indicator, ventilation openings, and software stored on the memory, are provided in a central part of the device for placement on a head of the person, such as to a side of the forehead, preferably in one housing. In an exemplary embodiment the present method TUS is applied for a predetermined duration of time of 1 sec - 2 hours.

[0052] In an exemplary embodiment the present method TUS is applied with a predetermined constant amplitude of 0.001 pW / cm2- 10000 mW / cm2, in particular 1-10 mW / cm2.

[0053] In an exemplary embodiment the present method TUS is applied with a varying amplitude of between 1-10000 pW / cm2.

[0054] In an exemplary embodiment the present method TUS is applied with intermittent bursts of a predetermined time of 2 msec-1 sec and with a predetermined interval of 2 msec- 1 sec.

[0055] In an exemplary embodiment the present method a total number of TUS periods is limited to a predetermined number, in particular 10-103.

[0056] In an exemplary embodiment the present method through wireless contact settings are adapted, such as a frequency, impedance, amplitude, duration of time, moment of application of TUS, delay, constant amplitude, varying amplitude, temperature of the liquid in the receptacle, pressure of the liquid in the receptacle, duration of bursts, and number of TUS periods, and / or wherein statistical data is gathered.

[0057] In an exemplary embodiment of the present method an amount of fluid in the receptacle is changed, selected from release of gas, release of fluid, and addition of fluid.

[0058] The invention is further detailed by the accompanying figures and examples, which are exemplary and explanatory of nature and are not limiting the scope of the invention.

[0059] SUMMARY OF FIGURES

[0060] Figures la-b show a prior art device, fig. 2a the present coupler, fig. 2b the present device, fig. 3 a the present receptacle, and fig. 3b schematics of the present coupler.

[0061] DETAILED DESCRIPTION OF FIGURES

[0062] In the figures:

[0063] 100 wearable device

[0064] 10 An ultrasound transmitter

[0065] 110 at least one transducer

[0066] 11 a transmitter body

[0067] 20 an ultrasonic wave coupler

[0068] 21 el asti c receptacl e

[0069] 22 fluid

[0070] 23 opening

[0071] 24 restrictor

[0072] 25 coupler fixator

[0073] 26 receiver part coupler

[0074] H height couple

[0075] Od outer dimension coupler

[0076] Figures la shows a prior art device, in particular a handheld device, attached to a power cable, and ultrasound waves, and fig. lb shows a slightly enlarged portion of fig. la. Fig. 2a shows the present coupler 20, having a height H, the elastic receptacle 21, filled with fluid 22, and two-part restrictor (top and bottom) 24a, b.

[0077] Fig. 2b shows the present device 100, including the present coupler 20 attached to the ultrasound transmitter 10, in particular to transmitter body 11.

[0078] Fig. 3a shows the present receptacle with holes for allowing screws to be used to attach top part of the restrictor 24a to a bottom part 24b thereof.

[0079] Fig. 3b shows schematics of the present coupler 20, with an outer dimension Od, a receiver part 26 for the coupler, and a central opening 23.

[0080] For the silicone material Wacker Elastosil Vario 15 + Catalyst Vario was used. For better processability, a silicone oil, such as Silicone oil 5 cSt, may be added, typically in small quantities (0.1-10 wt.%).

[0081] Experiment

[0082] Avoidance behaviour is considered to be a key predictive factors in maintaining pervasive emotional disorders, such as anxiety. Previous studies have shown that the Amygdala are important regions involved in threat-assessment, and consequent avoidance, when people make approach or avoid decisions, based on predicted reward or punishment. Disruption or ablation of the amygdala in animal models results in reduced avoidance and increased approach behaviour, allowing animals to gain rewards even in the presence of threat. Being able to disrupt amygdala activity might provide a way to reduce avoidance biases in patients with anxiety-related disorders, allowing them to benefit from exposure treatment.

[0083] Until recently, the only way to influence deep neural structures, such as the amygdala, was to open the skull and insert a deep-brain electrode. However, newly developed Transcranial, typically focused, Ultrasound Stimulation (TUS) is found to target and to modulate neural activity in these deep structures, such as the amygdala, non-invasively. The inventors performed a study which is aimed at manipulating approach / avoi dance behaviour, through modulation of amygdala and ventral striatum by TUS, whilst participants make approach / avoi d decisions based on threat (electrical shocks) and reward information (monetary bonusses). Transcranial Ultrasonic Stimulation (TUS) is a non-invasive neuromodulation technique that can achieve focal modulation of deep brain structures. The outcomes of this study provide a first stepping-stone for the development of TUS based interventions aimed at reducing anxiety disorders. The primary objective is to influence amygdala and ventral striatal neuronal activity, thereby changing their influence on consequent approach / avoi dance decisions. Inventors are able to (1) discern the neuromodulatory effects of amygdala-TUS on standard physiological indices of decision making under threat, such as increases in pupil size as recorded with an eye-tracker and heart rate, recorded using ECG electrodes (2) to use computational modelling of choice data to determine the influence of TUS on subjective value of threat and reward offers, thereby clarifying each regions’ role in balancing threat and reward information. Heart rate (HR): is used index responses to different reward and shock levels on offer, and the potential change in HR during modulation. HR is measured using electrocardiography (ECG), using lead electrodes attached to the skin surface. Pupil diameter (PD): is used to index differential pupil dilation responses to the stimuli in separate modulation conditions. PD is recorded by video-based eye-tracking.

[0084] Transcranial Ultrasonic Stimulation (TUS) is delivered using a NeuroFUS Pro™ system (Sonic Concepts Inc. Bothell, Washington, USA) using two piezoelectric ultrasound transducers. The transducers have a centre frequency of 500 or 250 kHz. The choice of 250 vs 500 kHz transducer is based on simulation of effects; depending on the ability to focus specifically enough on the (relatively small) ventral striatum inventors select the more focal 500 kHz, or the less focal 250 kHz transducer. TUS is delivered using a solid water coupling system between the transducer and the scalp. Each transducer is appropriate for neuromodulatory use in the context of the experiment.

[0085] Inventors apply conventional TUS parameters (5-1000 Hz pulse repetition frequency, 10- 50% duty cycle, that is a ratio between active / inactive) that are proven to be safe in humans. The exact parameters of the TUS protocol is determined based on testing on the pilot-participant group, for finding protocols that can be masked using an auditory mask. The TUS pulses are delivered interleaved over the left and right amygdala, or ventral striatum, to avoid ultrasonic wave interference from the two modulation sites. Trial-level ultrasonic stimulus duration is 3 seconds. Cumulative ultrasonic stimulus duration for the each modulation session in the experiment is 300 seconds. Verum TUS will be delivered at an intracranial spatial-peak pulse-averaged intensity (Isppa) below 20 W / cm2, in line with international guidelines and the Donders SOP. In general, the duty cycle is lower for protocols with a lower pulse-repetition frequency and for protocols with a higher intensity. All safety parameters fall within the guidelines specified in the Donders NIBS standard operating procedures (i.e. mechanical index < 1.0, Isppa intracranial < 20 W / cm2, thermal rise in the brain < 1 °C, acoustic peak pressure below 2 MPa).

[0086] Preparation:

[0087] The present coupler (balloon) is placed on the transducer. Ultrasound gel in between the coupler and the transducer is preferred for proper coupling.

[0088] Typically a participant's structural MRI head scan is prepared, in order to better direct the ultrasound waves into the head to a required location. The MRI scan is always collected in an earlier session. Before the start of the experiment the target region is highlighted in the MRI scan, to ensure easy targeting.

[0089] When the participant arrives:

[0090] 1. Explaining procedure and signing informed consent.

[0091] 2. Inventors then locate the participant's head in the room using infrared trackers. This involves placing a tracker on the participant's head, after which the head shape is recorded and overlayed with the head shape obtained from the MRI. This ensures that ultrasound localisation software is capable of identifying a location of the participants brain is in the room. Neuronavigation: the participant’s anatomical scan is loaded into a neuronavigation system (Localite) and registered to their actual head. The TUS device will also be registered in the neuronavigation system. This standard procedure allows accurate targeting of TUS to the appropriate targets throughout the experiment.

[0092] 3. The next step is to see approximately where the ultrasound modulators are best placed (not exactly known yet at this stage). This is done by sliding the transducer over the head until inventors observe that the ultrasound beam overlaps with the highlighted target area. Then, inventors can draw a circle for quick placement.

[0093] 4. Then the hair or skull is prepared, i.e. ultrasound gel is smeared between the hairs so that there are no air bubbles between hair and skull.

[0094] 5. Next, inventors couple the present device to the skull. o When no balloon is used (prior art), inventors place a gel pad, which is placed and massaged until there is no more air between gel pad and skin. Then the ultrasound transducer is placed in the correct place and should not come loose anymore from the gel pad. If the coupling is released even for a small moment, air can get between the elements and step 5 needs to start again. This applies to the whole experiment. The gel pad is often supported with tape and other hang-ups to make it slide less [prior art]. As reported earlier, this does happen often. o When the present balloon is used, the transducer can be aimed, moved, repositioned, and shifted, without any problems. If the coupling comes loose for a moment, this actually no longer is an issue, as one can immediately reposition it. Nothing slides away either.

[0095] 6. Once the transducers are in the right place, they are fixated and the experiment starts with online or offline modulation.

[0096] During the experiment, the participant and the transducer coupling are then continuously monitored. If the gel pad slips, the coupling, including aiming, preparing, and smearing gel in the hair, starts again.

[0097] With the present device clear transcranial stimulation with ultrasound is established, without the adverse effects of the prior art.

[0098] The invention although described in detailed explanatory context may be best understood in conjunction with the accompanying examples and figures.

Claims

CLAIMS1. A transcranial ultrasonic stimulation (TUS) device, in particular a wearable device (100) for non-invasive stimulation of brain activity, in particular of brain cells, comprisingAn ultrasound transmitter (10) comprising at least one transducer (110) for providing ultrasonic waves, and a transmitter body (11) for incorporating the at least one transducer, an ultrasonic wave coupler (20) for transmitting sound waves in ultrasonic wave contact with the a least one transducer and configured to provide ultrasonic wave contact to a human skull, wherein the ultrasonic wave coupler comprises at least one elastic receptacle (21), the receptacle comprising a fluid (22), in particular a liquid, an opening (23) configured to let ultrasound wave through, and a restrictor (24) configured for attaching the ultrasonic wave coupler into the ultrasound transmitter.

2. The device according to claim 1, wherein the elastic material is selected from elastomers, from polymers, from copolymers, such as from natural rubbers, from synthetic rubbers, in particular from poly siloxanes, such as polydimethylsiloxanes (PDMS), such as natural and synthetic polymers, in particular natural and synthetic rubbers, such as diene-comprising polymers, in particular polyisoprene, polybutadiene, fluoro-elastomers, and polychloroprene, non-diene-comprising polymers, in particular butyl rubber, polyisobutylene, polysiloxanes, polyurethane, thermoplastic polymers, in particular SIS and SBS block copolymers, and urethanes.

3. The device according to any of claims 1-2, wherein the elastic material has a bulk modulus of 0.5 -10 GPa, such as 1-5 GPa (ISO 9110-1 : 1990 EN), and / or a density p of 0.8-3 kg / dm3in particular according to ISO 12154:2014(en), preferably a material with a Poisson’s ratio of 0.48-0.50 in particular according to ASTM D638, ISO 527, in particular about or exactly 0.50, and / or a shore A hardness (ASTM D 2240; ISO 7619-1) of 10-100, and / or self-bleeding, and / or a shrinkage of < 1%, in particular < 0.2%, and / or a tensile strength of 1-10 N / mm2, and / or a viscosity of 1-10 Pa- s, and / or a tensile strength (EN ISO 1421) of 1-10 N / mm2, and / or a strength at break (EN ISO XYZ) of 5-25 N / mm, and / or comprising 0.1-10 wt.% plasticizer, such as silicone oil.

4. The device according to any of claims 1-3, wherein the receptacle (21) is a hollow elastic body having a wall, and is selected from the elastic body having an outer diameter Oa, and from a conus shaped elastic body, the conus shaped elastic body having a tip or a flattened tip and in particular having a cross-section selected from circular, ellipsoid, triangular, rectangular, hexagonal, octagonal, and multigonal, the elastic body having a height H, the elastic body having a volume V, and / or wherein the elastic body of the receptacle is a one piece body, such as obtained by 3D- printing, or by moulding, and / or wherein the wall has a thickness ti of 0.001-5 mm, and / orwherein the elastic body has a cross-sectional shape selected from ellipsoidal and circular, and / or wherein a side of the receptacle has a surface area of 20-50 mm2, preferably 30-40 mm2, such as 35 mm2, and / or wherein the ultrasonic wave coupler comprises at least one elastic receptacle (21), the receptacle comprising a fluid (22), wherein the fluid is enclosed between the ultrasound transmitter 10 and the receptacle, wherein the elastic receptacle has one layer of elastic material, or elastic layers attached to one and another, further comprising an opening (23) configured to let ultrasound wave through, and a restrictor (24) configured for attaching the ultrasonic wave coupler into the ultrasound transmitter5. The device according to any of claims 1-4, wherein an acoustic reflectance of the receptacle is < 10%, in particular < 1%, more in particular < 10'2%, relative to an input signal.

6. The device according to any of claims 1-5, wherein the at least one transducer provides focused ultrasonic waves.

7. The device according to any of claims 1-6, wherein the receptacle comprises at least one inlet for releasing fluid from the receptacle, or for filling the receptacle with fluid, and / or wherein the receptacle comprises at least one outlet for releasing fluid, in particular for releasing gas, and / or wherein at least one of the at least one inlet and at least one outlet is provided with a valve, in particular a one way valve providing one of liquid inlet and liquid outlet only, respectively.

8. The device according to any of claims 1-7, further comprising a receiver part (26), wherein the receiver part is configured to receive the receptacle.

9. The device according to any of claims 1-8, wherein the ultrasonic wave coupler has a width of 1-20 cm, a height of 1-10 cm, and a length of 1-20 cm, in particular wherein the ultrasonic wave coupler is balloon shaped.

10. The device according to any of claims 1-9, wherein the device is configured to provide ultrasonic waves.

11. The device according to any of claims 1-10, wherein the device is a handheld device, a mechanically held device, or a wearable device.

12. The device according to any of claims 1-11, wherein the coupler comprises a coupler fixator (25) for fixing the coupler to the ultrasonic transmitter.

13. The device according to any of claims 1-12, wherein the restrictor comprises two sub-parts 24a, b, wherein the two sub-parts are configured to partially incorporate the receptacle, and wherein the two sub-parts are removably attached to one and another, or wherein the restrictor is provided as a connector for permanently fixing a top part of the receptacle to a bottom part of the receptacle, such as a ring, in particular an elastic ring, more in particular an elastic ring of the same material as the receptacle, even more in particular wherein the connector is configured for connecting the receptacle to the ultrasound transmitter.

14. The device according to any of claims 1-13, wherein the liquid is a de-gassed liquid, such asde-gassed water, or oil.

15. The device according to any of claims 1-14, wherein the ultrasound transmitter (10) is configured to provide pulses with a frequency of 5-700 kHz, an amplitude of 10 pW / cm2-100000 mW / cm2, in particular 10-30 mW / cm2’ -during a period of time of 0.1-3600 sec, in particular 30- 1200 sec and with a total (integrated) power of 1-1000 W / cm2, and / or to provide alternating pulses with an intermittent idle period, wherein a time of each pulse individually is from 10 pse-1000 msec, in particular 0.5-500 msec, more in particular 1-100 msec, and wherein a time of each intermittent idle period individually is from 70 psec -10000 msec, in particular 2-1000 msec, more in particular 50-200 msec, and / or to provide alternating pulses with a pulse / idle frequency of 0.1-1000 Hz, in particular a pulse / idle frequency of 1-300 Hz, more in particular a pulse / idle frequency of 2-100 Hz..

16. The device according to any of claims 1-15, comprising a head fixator for fixing the device to a person's head.

17. The device according to any of the preceding claims, further comprising at least one of an amplifier, a controller, a storage unit, a connector, a power supply, a memory, a transceiver, an on-off switch, a status indicator 4, ventilation openings, at least one sensor in transceiving connection with the controller, in particular wherein the at least one sensor is selected from a temperature sensor, and a pressure sensor, wherein the temperature sensor is configured to measure a temperature in the liquid of the receptacle, and wherein the pressure sensor is configured to measure pressure in the liquid of the receptacle, and software stored on the memory.

18. The device according to any of the preceding claims, wherein at least one of the electrical pulse generator, the processor, the controller, the sensor, an amplifier, a controller, a storage unit, a connector, a power supply, a memory, a transceiver, an on-off switch, a status indicator, ventilation openings, and software stored on the memory, are provided in a central part of the device for placement on a head of the person, such as a forehead, , preferably in one housing.

19. A kit of parts comprising the ultrasonic wave coupler (20) according to any of claims 1-18, and optionally the ultrasound transmitter (10).

20. A method of Transcranial ultrasonic stimulation (TUS), comprising the steps of:Providing the device according to any of claims 1-18,Bringing the device to a person’s head, andProviding ultrasonic waves to the head.

21. The method according to claim 20, wherein TUS is applied for a predetermined duration of time of 1 sec - 2 hours.

22. The method according to any of claims 20-21, wherein TUS is applied with a predetermined constant amplitude of 1 pW / cm2- 10000 mW / cm2.

23. The method according to any of claims 20-22, wherein TUS is applied with a varying amplitude of between 1-10000 pW / cm2.

24. The method according to any of claims 20-23, wherein TUS is applied with intermittent bursts of a predetermined time of 2 msec-1 sec and with a predetermined interval of 2 msec- 1sec.

25. The method according to any of claims 20-24, wherein a total number of TUS periods is limited to a predetermined number.

26. The method according to any of claims 20-25, wherein through wireless contact settings are adapted, such as a frequency, impedance, amplitude, temperature of the liquid in the receptacle, pressure of the liquid in the receptacle, duration of time, moment of application of TUS, delay, constant amplitude, varying amplitude, duration of bursts, and number of TUS periods, and / or wherein statistical data is gathered.

27. The method according to any of claims 20-26, wherein an amount of fluid in the receptacle is changed, selected from release of gas, release of fluid, and addition of fluid.

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