Systems and methods for combined ultrasound and electrical stimulation for treating subject

Abstract

To provide systems and methods for combined ultrasound and electrical stimulation for treating inflammation, autoimmune disorders, rheumatoid arthritis, and the like.SOLUTION: Noninvasive ultrasound stimulation may be applied to a spleen, joints, limbs, or a region experiencing pain that has local swelling, and electrical stimulation may be applied to a face, neck, or other body region to access a peripheral nerve, vagus nerve, trigeminal nerve, or other nerves in appropriately-timed patterns to drive therapeutic effects. Stimulation timings or delay timings may be optimized based upon a desired clinical effect or treatment. Multiple targets may be stimulated in a coordinated fashion to better mimic natural physiology. A wearable ultrasound phased array device may be used to beam form energy to target the spleen while also having imaging capabilities to track motion of the spleen to maintain localized stimulation of target regions.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 816,857, filed March 11, 2019, and entitled "Systems and Methods for Combined Ultrasound and Electrical Stimulation for Treating A Subject," which is incorporated herein by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH Not applicable [Background technology]

[0003] Rheumatoid arthritis (RA) and other inflammatory conditions are often treated with disease-modifying antirheumatic drugs (DMARDs) or anti-tumor necrosis factor (anti-TNF) drugs. Although such therapies are effective for many patients, they can cause serious side effects and remain ineffective for many patients, with it being estimated that up to one-third of RA patients do not respond to their first anti-TNF drug. Unresponsive patients are often prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), which can cause toxicity and other dangerous side effects.

[0004] Recently, there has been an explosion of growth and interest in the field known as electropharmacology or bioelectronic medicine, which stimulates peripheral nerves (e.g., the vagus nerve) and end organs (i.e., organs at the distal end of nerve pathways) to treat a wide range of health disorders. For example, recent studies have shown that invasive vagus nerve stimulation can treat rheumatoid arthritis, irritable bowel syndrome, and many other health conditions such as tinnitus, depression, seizures, etc. There are also studies showing that activity within the spleen is a key component to elicit anti-inflammatory effects regulated by the vagus nerve and involved in the treatment of rheumatoid arthritis, renal failure, and liver injury, as well as having implications for cancer / tumor treatment and stroke recovery. Summary of the Invention [Problem to be solved by the invention]

[0005] The vagus nerve does not function in isolation from the spleen, and the spleen does not function in isolation from the swollen joint / limb. Vagus nerve stimulation is promising, but applying electrical stimulation to the vagus nerve is complicated because currents can flow uncontrollably through tissues and the vagus nerve is involved in many functions of the body, even vital functions such as heart rate. Accessing cells within these end organs with electrical implants is also difficult, not only to the point of implanting chips in these areas, but also to be able to target specific areas. Nevertheless, as rheumatoid arthritis affects approximately ~1% of the world's population, there remains a need for an effective non-invasive treatment that does not include the side effects of conventional drugs. If such a solution were to include other arthritis types along with autoimmune / inflammatory pathologies, potentially 100 million people could benefit. [Means for solving the problem]

[0006] The present disclosure addresses the above-mentioned shortcomings by providing a system and method for combined ultrasound and electrical stimulation to non-invasively treat inflammation and autoimmune disorders, and the like. Non-invasive ultrasound stimulation can be applied to the spleen, joints, limbs, or areas experiencing pain and having localized swelling, and electrical stimulation can be applied to the face, neck, ears, or other body areas to access peripheral, vagus, trigeminal, or other nerves. Appropriately timed coordinated patterns can be used to promote treatment effects for autoimmune and inflammatory disorders, such as rheumatoid arthritis, and the like. Stimulation or delay timing can be optimized based on the desired clinical effect or treatment. Multiple targets can be stimulated in a coordinated fashion to more closely mimic natural physiological functions. In some configurations, the longer the ultrasound or electrical treatment is administered, the greater the treatment effect. In some configurations, a wearable ultrasound phased array device can be used to beamform energy to target the spleen, while having imaging capabilities to track the movement of the spleen to maintain localized stimulation of the target area.

[0007] In one configuration, a method is provided for coordinated ultrasound and electrical stimulation of a patient. The method includes applying an ultrasound stimulus to a first target of the patient and applying an electrical stimulus to a second target of the patient. The method further includes determining stimulation parameters and a timing delay between the first target and the second target based on the applied ultrasound stimulus and the applied electrical stimulus. The coordinated ultrasound and electrical stimuli can then be applied to the patient using the determined timing delay and stimulation parameters to treat a condition of the patient.

[0008] In some configurations, determining the timing delay may include measuring the patient's body size, the transit time of the signal between the first target and the second target, the speed of the signal between the first target and the second target, the patient's heart rate, the physiological requirements of the particular disease being treated, a blood sample to assess changes in molecular and biomarkers associated with the stimulation, EEG brain activity of a localized region associated with at least one of the first or second targets, and / or the severity of inflammation in the patient. In some configurations, the timing delay may be in the range of 0 to 1000 ms, or may be 300 ms.

[0009] In some configurations, determining the stimulation parameters can include determining ultrasound stimulation parameters including duty cycle, frequency, pressure, duration, beam focus, and / or pulse pattern. In some configurations, determining the stimulation parameters can include determining electrical stimulation parameters including current, voltage, frequency, duration, phase, phase pattern, and / or pulse pattern.

[0010] In some configurations, the first target is the spleen, hi some configurations, the second target is the face, neck, ear, or a site on the patient near the vagus nerve or trigeminal nerve.

[0011] In one configuration, a system for coordinated ultrasound and electrical stimulation of a patient is provided. The system includes an ultrasound transducer used to stimulate a first target of the patient and an electrical stimulator for stimulating a second target of the patient. The system further includes a computer system configured to determine stimulation parameters and a timing delay between the first target and the second target based on the ultrasound stimulation of the first target and the electrical stimulation of the second target. The computer system is further configured to apply the coordinated ultrasound and electrical stimulation to the patient using the determined timing delay and stimulation parameters to treat a condition of the patient.

[0012] In one configuration, a computer-implemented method for generating signals to be used for coordinated ultrasound and electrical stimulation of a patient is provided. The computer-implemented method includes generating a first control signal configured to trigger ultrasound stimulation to a first target of the patient and generating a second control signal configured to trigger electrical stimulation to a second target of the patient. The computer-implemented method further includes determining stimulation parameters and a timing delay between the first target and the second target based on the first control signal for the ultrasound stimulation and the second control signal for the electrical stimulation. A third control signal for coordinated ultrasound and electrical stimulation of the patient can be generated using the determined timing delay and stimulation parameters to treat a condition of the patient.

[0013] In some configurations of the computer-implemented method, determining the timing delay includes measuring at least one of the following: a patient's body size, a transit time of the signal between the first target and the second target, a speed of the signal between the first target and the second target, the patient's heart rate, the physiological requirements of the particular disease being treated, a blood sample to assess changes in molecular and biological markers associated with the stimulation, EEG brain activity of a localized region associated with at least one of the first or second targets, and / or a severity of inflammation in the patient. In some configurations, the timing delay is in the range of 0 to 1000 ms. In some configurations, the timing delay is less than or equal to 300 ms.

[0014] In some configurations of the computer-implemented method, the first target is the spleen and the second target can be at least one of the face, neck, ear, or a site on the patient proximate to the vagus nerve or the trigeminal nerve.

[0015] In some configurations of the computer-implemented method, generating a third control signal for coordinated ultrasound and electrical stimulation of the patient includes generating the control signal for at least one wearable device positioned on the patient. Compensating for movement of the first target can be performed using ultrasound beam steering.

[0016] In some configurations of the computer-implemented method, determining the stimulation parameters includes determining ultrasound stimulation parameters including at least one of a duty cycle, a frequency, a pressure, a duration, a beam focus, and / or a pulse pattern. Determining the stimulation parameters can include determining electrical stimulation parameters including at least one of a current, a voltage, a frequency, a duration, a phase, a phase pattern, and / or a pulse pattern.

[0017] These and other aspects and advantages of the present disclosure will be apparent from the following description, in which reference is made to the accompanying drawings which form a part hereof and which show, by way of example, a preferred embodiment, which does not necessarily represent the full scope of the invention, and reference should therefore be made to the claims and this specification for interpreting the scope of the invention. [Brief description of the drawings]

[0018] [Figure 1] 1 is a non-limiting exemplary flow chart for providing coordinated ultrasound and electrical stimulation. [Figure 2A] FIG. 1 is a block diagram of an ultrasound system that can be used with the systems and methods of the present disclosure. [Figure 2B] FIG. 1 is a diagram of a non-limiting exemplary wearable electrode system. [Figure 2C] FIG. 1 is a diagram of a non-limiting exemplary combined ultrasound and electrical stimulation system. [Diagram 3] 13 is a graph depicting non-limiting example results of electrical stimulation alone. [Figure 4A-4D]Figure 4A is a graph depicting non-limiting example results using combined ultrasound and electrical stimulation where the therapeutic effect depends on the delay between the two modalities. Figure 4B is a detailed view of a portion of Figure 4A showing ultrasound and electrical stimulation timing. Figure 4C is a detailed view of another portion of Figure 4A showing ultrasound and electrical stimulation timing. Figure 4D is a detailed view of yet another portion of Figure 4A showing ultrasound and electrical stimulation timing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Systems and methods are provided for coordinated non-invasive neuromodulation. Ultrasound stimulation can be applied to the spleen and / or joints, limbs, or other areas experiencing pain and localized swelling in a properly timed pattern to promote a treatment effect for autoimmune and inflammatory disorders such as rheumatoid arthritis, combined with electrical stimulation of the neck, face, or other body areas. Coordinated or combined ultrasound and electrical stimulation approaches take advantage of natural body functions, where these different pathways and localized areas are activated in a coordinated manner to achieve a healing effect. The systems and methods of the present disclosure mimic these more natural processes to allow for greater healing than can be provided by uncoordinated stimulation or using either stimulation alone. Simply repeatedly artificially stimulating only the vagus nerve or only the spleen is expected to have substantially suboptimal effects, since different body components do not naturally function in isolation, but are linked to each other and require co-activation in a properly timed pattern to achieve synergistic and enhanced results.

[0020] The neuromodulation techniques disclosed in the present invention have the potential to directly modulate cells in the spleen or end organs. These techniques can replace drug treatments for many health disorders and reduce side effects. A significant population of RA patients who are effectively treated with anti-TNF-RA can supplement their drug therapy with the present system and method for non-invasive ultrasound and electrical stimulation to minimize undesirable side effects.

[0021] 1, a flow chart is shown depicting non-limiting example steps for coordinated ultrasound and electrical stimulation. At step 110, a site for ultrasound stimulation can be determined. Non-limiting examples of determining an ultrasound site include selecting a location on the patient for placing a body-worn ultrasound device, selecting a location on the patient for placing a conventional ultrasound probe, or adjusting an ultrasound stimulation target on or within the spleen using beam steering or the like as described below. In some configurations, the method can be implemented on or by a computer system.

[0022] At step 120, a site for electrical stimulation can be determined. The site can be determined based on access or proximity to peripheral, vagus, trigeminal, or other nerves. In some configurations, a site for non-invasive electrical stimulation (EStim) can be determined as on the face, neck, ear, or other body area for modulation of the vagus nerve pathway to the spleen and brain that can further treat a patient condition such as rheumatoid arthritis. In some configurations, the electrical stimulation can be delivered by a body-worn device or patch that can be left in place on the patient for an extended period of time while delivering treatment. The site for electrical stimulation may be based in part on how the device or patch can be physically positioned on the patient. The stimulation site can be adjusted based on the ability to modify heart rate or elicit the greatest evoked potential based on EEG recordings that can locate brainstem areas that receive projections from the vagus or trigeminal nerve pathways, for example. In some configurations, multiple electrical stimulation devices can be placed at different sites on the patient, and which electrical stimulator to activate or use can be based on feedback from the results of the ultrasound stimulation.

[0023] In step 130, timing delays for coordinated ultrasound and electrical stimulation can be determined. These timing delays between coordinated ultrasound and electrical stimulation can be optimized to achieve a desired clinical effect, such as reducing inflammation in the patient. In some configurations, the delay timing can take into consideration factors such as the patient's body size and the transit time or speed of the signal from the ultrasound or electrical stimulation to the desired site. The timing can be adapted to the particular disease or its severity being treated in an individual patient based on the desired duration or required intensity of the target anti-inflammatory state. In one configuration, measuring the stimulation of either the electrical and / or ultrasound to each site, the subsequent signal received at the other site, and the time it takes to receive this signal can be used to determine the timing delay. In some configurations, the patient's heart rate can be measured to determine the optimal timing delay based on the immediately preceding stimulation. The timing delays can range between 0 and 1000 ms between sites. In one configuration, the timing delays can be less than 100 ms. As shown in Figure 4A, more effective therapy occurred when using delays of 50 ms or shorter to treat inflammation in mice, where much longer delays such as 300 ms were not effective. These data demonstrate that an appropriate delay between ultrasound and electrical stimulation is important for the effectiveness of treatment. Larger body sizes can benefit from a larger delay range, including hundreds of milliseconds up to 1000 ms.

[0024] At step 140, optimal stimulation parameters can be determined. The optimal stimulation parameters can be determined based on desired clinical outcomes and / or desired timing delays as described above, allowing custom parameters for each patient or clinical treatment. For ultrasound stimulation, optimizing the stimulation parameters can include determining duty cycle, frequency, pressure, duration, beam focus, pulse pattern, and the like. In some configurations, 1 MHz ultrasound with 1 s on and 5 s off can be enabled at ~350 kPa, as shown in FIG. 4A. In other configurations, the ultrasound stimulation can be lower than 1 MHz. In a non-limiting example, the ultrasound stimulation can be 500 kHz. For electrical stimulation pulses, optimal parameters can include current, voltage, frequency, duration, phase, pulse pattern, and the like. In some configurations, 1 mA electrical stimulation at 1 Hz can be enabled for treatment, as shown in FIG. 3 and FIG. 4A. In other configurations, the electrical stimulation can be in the range of 25-30 Hz for an effective treatment. In yet another configuration, 500 μA electrical stimulation can be enabled for treatment. Stimulation can be repeated for 30-60 minutes per day. In some configurations, it can be performed for 2 minutes at a time as in FIG. 4A, for 12 minutes at a time, or until it produces a desired clinical outcome, such as a reduction in inflammation measured in the patient. In other configurations, stimulation can be delivered continuously by a device worn by the patient. Other parameters, such as timing between modalities, can be used to optimize treatment.

[0025] Non-limiting exemplary ultrasound stimulation parameters are listed below in Table 1, which includes expanded and optimized parameter ranges. Non-limiting exemplary electrical stimulation parameters are listed below in Table 2, which also includes expanded and optimized parameter ranges.

[0026] Table 1 - Ultrasound stimulation parameters TIFF2025022906000002.tif65169

[0027] Table 2 - Electrical stimulation parameters TIFF2025022906000003.tif53170

[0028] In some configurations, the optimal stimulation parameters include optimal stimulation pulse patterns. Non-limiting exemplary pulse patterns for ultrasound include 16.7% duty cycle with 1 s on and 5 s off, 500 ms on and 500 ms off, 50% duty cycle, and 350 ms on and 650 ms off, 35% duty cycle, or any range of pulse pattern timing and duty cycle between these parameters, and any combination thereof. Any suitable pulse pattern can be used, such as unmodulated pulse bursts, sinusoidally modulated pulse trains, chirp pulses, spike pulses, and the like. Some non-limiting exemplary pulse patterns and waveforms of electrical signals are listed in Table 3 below.

[0029] Table 3 - Pulse patterns and waveforms TIFF2025022906000004.tif21156

[0030] At step 150, the coordinated ultrasound and electrical stimulation may be applied using the timing delays and optimal parameters determined as described above. At step 160, the coordinated stimulation may be adjusted to compensate for target or patient movement or to account for other changes that may occur. The process of determining stimulation parameters and delivering coordinated ultrasound and electrical stimulation to the patient may be repeated as shown by path 170. Non-limiting examples of iteratively determining optimal parameters and providing stimulation include repeating the process of each stimulation for a determined number of stimulations, triggered by a change such as target movement or determined by a user.

[0031] 2A illustrates an example ultrasound system 200 that can be used to implement the methods described in this disclosure. The ultrasound system 200 includes a transducer array 202 that includes a plurality of individually driven transducer elements 204. The transducer array 202 can include any suitable ultrasound transducer array, including linear arrays, curvilinear arrays, phased arrays, and the like. Similarly, the transducer array 202 can include 1D transducers, 1.5D transducers, 1.75D transducers, 2D transducers, 3D transducers, and the like.

[0032] When activated by the transmitter 206, a given transducer element 204 generates a burst of ultrasonic energy. Ultrasound energy (e.g., echoes) reflected back to the transducer array 202 from the object or patient under examination is converted by each transducer element 204 into an electrical signal (e.g., echo signals) that may be separately applied to a receiver 208 through a set of switches 210. The transmitters 206, receivers 208, and switches 210 are operated under the control of a controller 212, which may include one or more computers. By way of example, the controller 212 may include a computer system.

[0033] The transmitter 206 can be programmed to transmit unfocused or focused ultrasound. In some configurations, the transmitter 206 can be programmed to transmit diverging waves, spherical waves, cylindrical waves, plane waves, or combinations thereof. Additionally, the transmitter 206 can be programmed to transmit spatially or temporally coded pulses.

[0034] The receiver 208 can be programmed to perform an appropriate detection sequence for the imaging task at hand. In some embodiments, the detection sequence can include one or more of line-by-line scanning, compound plane wave imaging, synthetic aperture imaging, and compound divergent beam imaging.

[0035] In some configurations, the transmitter 206 and receiver 208 can be programmed to perform high frame rates, such as frame rates having an acquisition pulse repetition frequency ("PRF") of at least 100 Hz. In some configurations, the ultrasound system 200 can sample and store at least 100 echo signal ensembles in the time direction.

[0036] The controller 212 can be programmed to execute the imaging sequence using techniques described in this disclosure or otherwise known in the art, In some embodiments, the controller 212 accepts user input that defines various factors used in designing the imaging sequence.

[0037] A scan may be performed by setting the switch 210 to the transmit position, thereby briefly activating the transmitter 206 to activate the transducer elements 204 during a single transmit event according to a designed imaging sequence. The switch 210 may then be set to the receive position, and subsequent echo signals generated by the transducer elements 204 in response to one or more detected echoes are measured and applied to the receiver 208. The separate echo signals from the transducer elements 204 may be combined in the receiver 208 to generate a single echo signal.

[0038] In some configurations, the ultrasound system 200 can include more than one ultrasound array 202. At least one of the arrays can be used to transmit ultrasound for a therapeutic treatment, and at least one other array can be used to transmit and / or receive ultrasound for imaging. In one non-limiting example, the frequency used for treatment can be lower than the frequency used to generate high quality images.

[0039] The echo signals are communicated to a processing unit (not shown), which may be implemented by a hardware processor and memory, for processing the echo signals or images generated therefrom. As a non-limiting example, the processing unit may target the spleen using methods described in this disclosure for ultrasound stimulation to treat inflammation. Images generated from the echo signals by the processing unit may be displayed on a display system 214.

[0040] In one non-limiting example, a wearable / miniature phased array ultrasound device can be used for the ultrasound system 200. The wearable device can be placed on the patient and worn chronically. In some configurations, a reprogrammed smart phone or tablet device can be used to control and / or monitor the stimulation. In one non-limiting example, the reprogrammed smart phone or tablet device can allow Bluetooth wireless control of the stimulation device. In some configurations, the control and / or monitoring system can be an application installed on the smart phone and tablet device, etc. In another non-limiting example, several devices distributed around the patient can be used to provide the ultrasound stimulation. When using miniature ultrasound array technology, the overall size of the wearable device can be similar to other consumer electronic wearable devices, such as a smart watch. In one non-limiting example, the overall footprint of the device can be smaller than 1.2 cm x 1.2 cm. In another non-limiting example, the footprint of the device can be smaller than 40 mm x 40 mm. In some non-limiting examples, the overall footprint of the device can be larger, such as to cover a larger area of ​​the spleen or other organs. In one non-limiting example, the footprint of the device is the same size as the spleen, which may range from 8 cm to 16 cm.

[0041] In some configurations, multiple ultrasonic transducer elements 204 may be activated in unison to form a plane wavefront, while in other configurations, they may be activated sequentially to form a gradient or focused wavefront.

[0042] In some configurations, beam steering can be used to target selected sites on or within the spleen with ultrasound stimulation. Sites can be selected to optimize treatment effects, such as by targeting neural pathways within the spleen. Optimizing effects can include modulating a cholinergic anti-inflammatory immune reflex circuit to reduce inflammation in a patient and treat rheumatoid arthritis. This anti-inflammatory reflex pathway includes circuits in the brain that project to the spleen through the vagus nerve (e.g., activation of medullary C1 neurons and hypothalamic-pituitary responses), as well as reciprocal pathways back to the brain that modulate the body's immune response.

[0043] In some configurations, the wearable energy delivery device will have the capability to image a designated target and transmit ultrasound energy thereto. Imaging and / or beam steering can be used to compensate for spleen movement, such as depth changes due to patient movement. The spleen naturally moves within the abdominal cavity during deep breathing and changes in body posture. Imaging feedback can be used to realign the ultrasound beam focus as the distance to the surface of the spleen relative to the transducer array changes. This provides the potential for closed-loop device operation with implementation of an automatic retargeting algorithm. One non-limiting example of an ultrasound device with both imaging and stimulation capabilities includes a piezoelectric micromachined ultrasound transducer (pMUT).

[0044] To effect beam steering scanning, the transmitter 206 imposes a time delay on each pulse 216 applied to the continuous transducer element 204. i When T = 0, all of the transducer elements 204 will be activated simultaneously and the resulting ultrasound beam will be directed along an axis 218 perpendicular to the face of the transducer 202 and originating at the center of the transducer array 202.i As θ increases, the ultrasonic beam is steered away from the central axis 218 by an angle θ. The time delay segments T i The relationship between is given by the following equation: JPEG2025022906000005.jpg17132(1)

[0045] where S is the equal spacing between the centers of adjacent transducer elements 204, c is the speed of sound in the object under inspection, R is the distance or depth to which the transmit beam is focused, and T o is the sum of all the calculated time delay interval values ​​T i is a delay offset that ensures that is a positive value.

[0046] The second term in equation (1) steers the beam to a desired angle θ, and the third term is employed when the transmit beam is to be focused at a fixed distance R. In successive excitations, the time delay T i A sector scan is performed by gradually changing the angle θ. In this manner, the angle θ is changed piecewise to steer the transmit beam in successive directions. Although the pulse timing is reversed when the beam direction is above the central axis 218, equation (1) still applies in this situation.

[0047] The echo signals generated by each burst of ultrasonic energy emanate from reflecting objects located at successive distances or depths R along the ultrasonic beam. These echo signals are sensed separately by each transducer element 204 in the transducer array 202, and a sample of the magnitude of each echo signal at a particular time represents the amount of reflection occurring at a particular distance R. However, due to differences in the propagation path between the focus P and each transducer element 204, these echo signals do not occur simultaneously and the signal amplitudes are not equal. The function of the receiver 208 is to amplify and demodulate these separate echo signals, giving each the appropriate time delay, and sum them together to provide a single echo signal that accurately represents the total ultrasonic energy reflected from each focus P located at successive distances R along the ultrasonic beam steered at angle θ.

[0048] Under the direction of the digital controller 212, the receiver 208 is delayed during scanning such that its steering tracks the direction of the beam steered by the transmitter 206, and such that the receiver 208 samples the echo signal at successive distances R and applies appropriate delays to dynamically focus on a point P along the beam. Thus, each emission of an ultrasonic pulse results in the acquisition of a corresponding series of data points representative of the amount of sound reflected from a series of points P located along the ultrasonic beam.

[0049] In some configurations, a physical device such as a cone can be used to steer the ultrasound beam to the target site. Those skilled in the art will recognize that other options for directing ultrasound to the target site can be used in conjunction with the present disclosure.

[0050] Referring to FIG. 2B, a non-limiting exemplary wearable electrode system 250 is shown. A power source 254 provides power to the controller 252 and the electrodes 256. The power source 254 can be a wired power source connected to an external power source, a wireless power system, and the like. The controller 252 can accept signals from an external system including stimulation parameters for controlling the electrodes 256, or can include pre-programmed stimulation parameters and instructions for controlling the electrodes 256. In some configurations, the controller 252 is wirelessly connected to an external smart phone or tablet that communicates stimulation parameters and instructions for delivering stimulation to the patient. The electrodes 256 can be a single electrical patch in connection with the patient, or can include any number of electrical patches. In one non-limiting example, the electrodes 256 include a conductive layer, such as an adhesive gel layer, for higher electrical conductivity and comfortable stimulation of the body surface.

[0051] Referring to FIG. 2C, a non-limiting example of a combined ultrasonic and electrical stimulation system 275 for coordinated stimulation is shown. The system includes an ultrasonic stimulation device 276 having an ultrasonic stimulation generator 278 and one or more electrodes 280 having an electrical stimulation generator 282. The body-worn system 290 can be coupled to an external controller 298 that can generate stimulation parameters for directing ultrasonic and electrical stimulation pulses delivered using the ultrasonic stimulation device 276 and the one or more electrodes 280, respectively. A transceiver 296 can be included to allow wireless communication of signals between the external controller 298 and the body-worn device 276. In some configurations, the external controller 298 can be a smart phone or tablet. In some configurations, the body-worn system 290 can be two separate devices, one providing ultrasonic stimulation and a second providing electrical stimulation. In other configurations, the electrical stimulator and the ultrasonic stimulator can be integrated into one component. In one or more implementations, the one or more electrodes 280 include an electrode array. One or more electrodes 280 may be strategically positioned on the housing of the body worn system 290 to touch the face, neck, ear (e.g., on top of the ear, around the pinna, or even inside the ear canal when using an in-the-ear hearing aid), or other body part.

[0052] In one or more embodiments, the body worn system 290 includes a transceiver 296 and power components (which may be incorporated into the body worn system 290 or an external controller 298 and may use, for example, Bluetooth or other communication protocols) to power the system and, for example, to enable communication of stimulation parameters and commands. The wireless transceiver and power components 296 may be worn on the body or around the neck to enable powering and control of the system for acoustic and electrical stimulation.

[0053] The device includes an ultrasound stimulus generator 278 and an electrical stimulus generator 282 configured to calculate and process different stimulation plans based on received stimulation parameters for providing ultrasound and electrical stimuli to treat a patient condition.

[0054] Referring to Figure 3, non-limiting exemplary results are shown showing that cervical surface EStim reduced inflammation. In other configurations, different sites can be used to optimize the clinical effect of combined ultrasound and electrical stimulation.

[0055] With reference to Figures 4A, 4B, 4C, and 4D, graphs are shown illustrating non-limiting exemplary results using combined ultrasound and electrical stimulation where the therapeutic effect depends on the delay between the two modalities. With reference to Figure 4A, one non-limiting example is shown in which results can be evaluated to determine optimal stimulation parameters according to step 140 of Figure 1. In particular, a data point 410 can be evaluated as improving or worsening a clinical condition based on being above or below an established threshold line 420. With reference to Figure 4B, ultrasound and electrical stimulation timing for a portion of the data of Figure 4A is shown. With reference to Figure 4C, ultrasound and electrical stimulation timing for another portion of the data of Figure 4A is shown. With reference to Figure 4D, ultrasound and electrical stimulation timing for yet another portion of the data of Figure 4A is shown.

[0056] In other configurations, curve fitting or determination of minimum / maximum values ​​in acquired data may be used to determine optimal stimulation parameters. In some configurations, blood samples may be taken to test for changes in inflammation-related biomarkers. In some configurations, evaluation of changes in quality of life using ultrasound imaging of the joints, clinical scores, health assessment questionnaires may be used to determine optimal parameters. Those skilled in the art will recognize that other methods are available for determining optimal parameters.

[0057] In one example, the therapeutic benefit of ultrasound in reducing chronic inflammation was evaluated in a mouse model of arthritis. Wild-type C57BL / 6 (B6) mice were injected intraperitoneally with arthritic serum transfer from the K / BxN transgenic mouse line. Ultrasound was applied non-invasively to the spleen daily using a single ultrasound transducer. Disease progression was monitored daily by measuring ankle thickness, weight, and clinical disease score. By monitoring reduced inflammation using ankle thickness, optimal ultrasound waveform parameters for reducing inflammation were found by exploring a wide range of different frequencies, pulse widths, and durations across many experiments.

[0058] While the present disclosure has set forth one or more preferred embodiments, it should be recognized that many equivalents, alternatives, variations, and modifications, other than those described, are possible and are within the scope of the invention.

Claims

1. 1. A method for coordinated ultrasound and electrical stimulation of a patient, comprising: applying an ultrasound stimulus to a first target on the patient; applying electrical stimulation to a second target on the patient; determining stimulation parameters and a timing delay between the first target and the second target based on the applied ultrasound stimuli and the applied electrical stimuli; applying coordinated ultrasound and electrical stimuli to the patient using the determined timing delays and stimulation parameters to treat the patient's condition; The method includes:

2. The step of determining the timing delay comprises: the patient's body size; the transit time of a signal between the first target and the second target; the speed of the signal between the first target and the second target; the patient's heart rate; the physiological requirements of the particular disease being treated; a blood sample to assess changes in relevant molecular and biomarkers associated with the stimulation; EEG brain activity of a local region associated with at least one of the first or second targets; and the severity of inflammation in said patient; measuring at least one of The method of claim 1.

3. The method of claim 1 , wherein the timing delay is in the range of 0 to 1000 ms.

4. The method of claim 3 , wherein the timing delay is less than 300 ms.

5. The method of claim 1 , wherein the first target is the spleen.

6. The second target is face, neck, Ears, or a site on the patient proximate to the vagus nerve or the trigeminal nerve; The method of claim 1 , wherein the at least one of

7. 10. The method of claim 1, wherein the coordinated ultrasound and electrical stimulation comprises using at least one wearable device positioned on the patient.

8. The method of claim 1 , further comprising compensating for motion of the first target using ultrasonic beam steering.

9. The step of determining stimulation parameters comprises: Duty cycle, frequency, pressure, Duration, Beam focus, and Pulse pattern, determining ultrasound stimulation parameters including at least one of: The method of claim 1.

10. The pulse pattern is A non-modulated burst of pulses, Sine wave modulated pulse train, Chirped pulse, and Spike pulse, At least one of:

10. The method of claim 9.

11. The step of determining stimulation parameters comprises: current, Voltage, frequency, Duration, phase, Phase pattern, and Pulse pattern, determining electrical stimulation parameters including at least one of: The method of claim 1.

12. 1. A system for coordinated ultrasound and electrical stimulation of a patient, comprising: an ultrasound transducer for stimulating a first target on the patient; an electrical stimulator for stimulating a second target on the patient; determining stimulation parameters and a timing delay between the first target and the second target based on the ultrasound stimulation of the first target and the electrical stimulation of the second target; and applying coordinated ultrasound and electrical stimuli to the patient using the determined timing delays and stimulation parameters to treat the patient's condition. A computer system configured as described above, A system including:

13. Determining the timing delay comprises: the patient's body size; the transit time of a signal between the first target and the second target; the speed of the signal between the first target and the second target; the patient's heart rate; the physiological requirements of the particular disease being treated; a blood sample to assess changes in relevant molecular and biomarkers associated with the stimulation; EEG brain activity of a local region associated with at least one of the first or second targets; and the severity of inflammation in said patient; measuring at least one of The system of claim 12.

14. The system of claim 12 , wherein the timing delay is in the range of 0 to 1000 ms.

15. The system of claim 14 , wherein the timing delay is less than 300 ms.

16. The system of claim 12 , wherein the first target is the spleen.

17. The second target is face, neck, Ears, or a site on the patient proximate to the vagus nerve or the trigeminal nerve; At least one of The system of claim 12.

18. 13. The system of claim 12, wherein the coordinated ultrasound and electrical stimulation includes using at least one wearable device positioned on the patient.

19. The system of claim 12 , wherein the computer system is further configured to compensate for motion of the first target using ultrasonic beam steering.

20. Determining the stimulation parameters may include: Duty cycle, frequency, pressure, Duration, Beam focus, and Pulse pattern, determining ultrasound stimulation parameters including at least one of: The system of claim 12.

21. The pulse pattern is A non-modulated burst of pulses, Sine wave modulated pulse train, Chirped pulse, and Spike pulse, At least one of:

21. The system of claim 20.

22. Determining the stimulation parameters may include: current, Voltage, frequency, Duration, phase, Phase pattern, and Pulse pattern, determining electrical stimulation parameters including at least one of: The system of claim 12.

23. 1. A computer-implemented method for generating signals to be used for coordinated ultrasound and electrical stimulation of a patient, comprising: generating a first control signal configured to trigger an ultrasound stimulus to a first target on the patient; generating a second control signal configured to trigger electrical stimulation to a second target in the patient; determining stimulation parameters and a timing delay between the first target and the second target based on a first control signal of the ultrasonic stimulation and a second control signal of the electrical stimulation; generating a third control signal for coordinated ultrasound and electrical stimulation of the patient using the determined timing delays and stimulation parameters to treat a condition of the patient; 4. A computer-implemented method comprising:

24. The step of determining the timing delay comprises: the patient's body size; the transit time of a signal between the first target and the second target; the speed of the signal between the first target and the second target; the patient's heart rate; the physiological requirements of the particular disease being treated; a blood sample to assess changes in relevant molecular and biomarkers associated with the stimulation; EEG brain activity of a local region associated with at least one of the first or second targets; and the severity of inflammation in said patient; measuring at least one of 24. The computer-implemented method of claim 23.

25. 24. The computer-implemented method of claim 23, wherein the timing delay is in the range of 0 to 1000 ms.

26. 26. The computer-implemented method of claim 25, wherein the timing delay is less than 300 ms.

27. 24. The computer-implemented method of claim 23, wherein the first target is the spleen.

28. The second target is face, neck, Ears, or a site on the patient proximate to the vagus nerve or the trigeminal nerve; At least one of 24. The computer-implemented method of claim 23.

29. 24. The computer-implemented method of claim 23, wherein generating the third control signal for coordinated ultrasound and electrical stimulation of the patient comprises generating the third control signal to at least one wearable device positioned on the patient.

30. 24. The computer-implemented method of claim 23, further comprising compensating for motion of the first target using ultrasonic beam steering.

31. The step of determining stimulation parameters comprises: Duty cycle, frequency, pressure, Duration, Beam focus, and Pulse pattern, determining ultrasound stimulation parameters including at least one of:

24. The computer-implemented method of claim 23.

32. The pulse pattern is A non-modulated burst of pulses, Sine wave modulated pulse train, Chirped pulse, and Spike pulse, At least one of:

32. The computer-implemented method of claim 31.

33. The step of determining stimulation parameters comprises: current, Voltage, frequency, Duration, phase, Phase pattern, and Pulse pattern, determining electrical stimulation parameters including at least one of:

24. The computer-implemented method of claim 23.

Images