ULTRASOUND INDUCED MODULATION OF BLOOD GLUCOSE LEVELS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 61/900,859, filed November 6, 2013, which is incorporated by reference in its entirety.

BACKGROUND

1. Field of the Invention

[0002] This disclosure relates to the modulation of the function of body organs by way of application of specific pulses of ultrasound applied either directly to the organ or to the nerves in and around the spine that innervates these organs. In particular, the disclosure relates to the control of blood glucose levels by application of ultrasound to body organs.

2. Description of Related Art

[0003] Ultrasound energy is widely used in diagnostic imaging, therapeutic heating, and noninvasive surgery. Ultrasound diagnostic imaging employs sound power levels and pulse protocols considered safe for human use, even in obstetrics, and its long history of use in the clinic supports this conclusion.

[0004] At much higher ultrasound power levels, the vibration of tissue can produce warmth and heating which is useful in treatment of soft tissue injuries and in certain arthritic conditions. There are also ultrasound based devices that use relatively high intensity focused energy for thermal treatment of cancers.

[0005] Ultrasound imaging in medicine operates at frequencies in the range of 2 MHz to roughly 10 MHz although there are some applications somewhat above and below these levels. The FDA regulates ultrasound power levels to the range of 720 mW/cm ² Ispta and peak pulse powers at 190 W/cm ² . Safety of ultrasound is characterized by its mechanical effects where avoidance of cavitation and also by their heating effects on tissues. The mechanical index (MI) is dependent both on the ultrasound frequency as well as its power level. Regulatory standards in the United States require the MI to be below 1.9 to avoid cavitation. The thermal index (TI) is a measure of tissue temperature rise over time and for safety is required to have a value below 1.

[0006] Ultrasound imaging machines emit microsecond-order pulses into tissues at a repetition rate that typically does not exceed 4 kHz and thus the duty cycle of the ultrasound energy is relatively low and on the order of less than one percent. Pulses of longer duration ultrasound, on the order of milliseconds and at repetition rates much lower while still emitting power levels within MI and TI safety limits can produce bioelectrical stimulatory and in some cases inhibitory effects on the brain (Tyler, Yoo, Bystrisky 2010-2012). However ultrasound is not known to produce significant effects on the peripheral nervous system sufficient to produce action events (Gavrilov et al, Colucci). Additionally it is well known that ultrasound passes through muscle tissue, even at elevated power levels, without producing direct stimulatory effects. There are however, medical therapeutic applications that would be well served if ultrasound could be applied to the body in a method that would evoke physiologic changes.

SUMMARY

[0007] Methods and apparatus for the modulation of the function of body organs (for example, the liver and pancreas) by way of application of specific pulses of ultrasound applied either directly to the organ or to the nerves in and around the spine that innervates these organs are disclosed. The modulation of organ function utilizes ultrasound pulse characteristics that are unlike those used in diagnostic imaging but still within power levels that are presently considered by the US FDA to be safe.

[0008] Certain embodiments of the present disclosure teach a method for blood glucose modulation, particularly its increase, through ultrasound energy application to the liver, pancreas, and their associated neural innervations emanating from the spinal cord and associated ganglia. This effect depends on a specific pulse protocol in the delivery of ultrasound energy to the body at a power level comparable to that used in imaging. However it differs in that the ultrasound pulses are emitted at a far lower repetition rate, have a much longer duration than used in imaging, and are applied for overall a longer period of time than typical of imaging. The application of ultrasound to the body is specific to the location of the liver, pancreas, and spinal region around the T-10 to T-12 vertebrae, particularly the T-10 vertebrae. [0009] In accordance with one exemplary embodiment, a method of changing blood glucose level comprises applying pulsed ultrasound energy to the liver. The ultrasound energy may be applied to the tissues from a transducer on the external surface of the body or from an implantable pulse generator. The ultrasound energy may be in the frequency range of 200 kHz to 5 MHz with the pulse duration in the range of 1-50 milliseconds and the pulse repetition rate within the range of 1 - 100 pulses per second. The instantaneous peak pulse power (IPPP) may be in the range of 30-300 W/cm2. The average power delivered may be within ultrasound safety limits, and the average power may be less than 750 mW/cm2. The duration of the treatment may be within the range of 10 minutes to 60 minutes. The pulse duration may also be in the range of 50 microseconds to 300 microseconds and delivered in trains of 10-100 milliseconds bursts and the repetition rate is 1-25 Hz.

[0010] In accordance with another exemplary embodiment, a method of changing blood glucose level comprises applying pulsed ultrasound energy to the spinal cord region associated with the innervation of the liver and pancreas. The ultrasound energy may be applied in the range of T- 10 to T- 12 vertebrae. The ultrasound energy may be applied to the tissues from an implantable pulse generator. The ultrasound energy may be in the frequency range of 200 kHz to 5 MHz with the pulse duration is in the range of 2-50 milliseconds and the pulse repetition rate within the range of 10 - 100 pulses per second. The instantaneous peak pulse power (IPPP) may be in the range of 50-300 W/cm2. The average power delivered may be within ultrasound safety limits, and the average power may be less than 750 mW/cm2. The duration of the treatment may be within the range of 10 minutes to 60 minutes. The pulse duration may be in the range of 50 microseconds to 300 microseconds and delivered in trains of 10-100 milliseconds bursts and the repetition rate is 1-25 Hz.

[0011] In accordance with yet another exemplary embodiment, a system for modifying blood glucose levels comprises an ultrasound pulse generator, and a transducer for applying ultrasound to liver or the thoracic spinal area, wherein the ultrasound pulse generator is configured to generate ultrasound energy in the frequency range of 200 kHz to 5 MHz, a pulse duration in the range of 1-50 milliseconds, a pulse repetition rate is within the range of 1 - 100 pulses per second, and an instantaneous peak pulse power (IPPP) in the range of 30-300 W/cm2. The pulse generator may be configured to deliver a pulse duration in the range of 50 microseconds to 300 microseconds in trains of 10-100 milliseconds bursts with a repetition rate of 1-25 Hz. The transducer may be configured to apply energy to the surface of the body. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The following drawing forms part of the present specification and is included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to the drawing in combination with the detailed description of specific embodiments.

[0013] FIG. 1 is a schematic view of an apparatus for applying ultrasound energy to a cervix in accordance with an exemplary embodiment.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0014] In the following detailed description, reference is made to the accompanying drawing, in which is shown an exemplary but non-limiting and non-exhaustive embodiment of the invention. The embodiments are described in sufficient detail to enable those having skill in the art to practice the invention, and it is understood that other embodiments may be used, and other changes may be made, without departing from the spirit or scope of the invention. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the invention is defined only by the appended claims.

[0015] We have observed that pulsed ultrasound energy applied to the liver region can cause significant increases (e.g., >30%) in blood glucose levels in test animals. Ultrasound energy is widely used in diagnostic imaging, therapeutic heating, and noninvasive surgery. Ultrasound diagnostic imaging employs sound power levels and pulse protocols considered safe for human use, even in obstetrics, and its long history of use in the clinic supports this conclusion.

[0016] Despite the widespread use of ultrasound, the stimulation of visceral tissue and organ function by ultrasound is not known. There is no general understanding at this time of how or why body organs would be responsive to ultrasound energy. Without being bound to any particular theory, one speculation is that ultrasound directly affects the cellular nature of the tissue, perhaps by triggering a bioelectrical activation that then causes a cascade of events. Most physiological processes within the body have bioelectrical correlates and processes can be modulated in their function by application of small electrical currents. Ultrasound energy is known to affect bioelectrical events in the central nervous system and have some effects on the peripheral nervous system. Thus, the observed effects of ultrasound on blood glucose presumably originating from modulation of liver function may be through interaction with a local nerve plexus that then promotes the local or more distant organ function modulation.

[0017] To modify blood sugar levels, ultrasound energy may be applied to the liver, pancreas, and/or their associated neural innervations emanating from the spinal cord and associated ganglia. The ultrasound may be applied by using a transducer applied against the external surface of the body to direct ultrasound energy to the location of the liver, pancreas, and spinal region in the range of the T-10 to T-12 thoracic vertebrae, particularly the T-10 vertebrae. Alternatively or additionally, implantable transducers may be used in the same regions.

[0018] Ultrasound at 50-300 W/cm2 is applied in the range of 1 to 50 millisecond pulses with a pulse repetition rate of 5 to 100 Hz such that the overall power level applied to tissue is less than 750 mW/cm2 and so within generally accepted levels of ultrasound power. This power level is applied over a duration of 10-30 minutes. Preferably, the ultrasound is applied in the range of 15 minutes.

[0019] Ultrasound pulses of a relatively shorter duration, 50 microseconds to 300 microseconds and delivered in trains of 10-100 milliseconds bursts may also be used. The repetition rate is then 1-25 Hz chosen to maintain an overall safe power delivery level. Thus in this approach the shorter duration pulses can use higher peak power values yet still remain within the range of safe MI and TI.

[0020] Fig. 1 shows a system 10 for applying ultrasound energy in accordance with an exemplary embodiment of the present invention. The system 10 includes a signal generator 12 which is coupled to a transducer 14 by a cable 16. The transducer 14 may be a focused transducer which uses a piezoelectric transducer to generate mechanical vibrations from electrical signals. The transducer is configured to apply ultrasound energy to the surface of the body. The signal generator 10 generates a signal to drive the transducer to generate pulsed ultrasound and may include a power supply, a function generator, and an oscilloscope to generate and monitor a signal. The signal generator 10 has controls 18 to adjust the parameters (such as pulse frequency, pulse duration, pulse repetition frequency, and instantaneous peak pulse power) of the generated signal in accordance with the values described in further detail below. [0021] In another embodiment, the transducer comprises an implantable transducer. An implantable transducer may be battery powered or wireless and may be implanted near a targeted organ to deliver ultrasound energy to the organ.

References

Each of the following references is hereby incorporated by reference in its entirety for all purposes.

Tyler, W.J., Tufail, Y., Finsterwald, M., Tauchmann, M.L., Olsen, E.J., Majestic, C, Remote Excitation of Neuronal Circuits Using Low Intensity, Low Frequency Ultrasound, PLoS One, 3(10):e3511.

Bystritsky, A., Korb, A., Douglas, P., Cohen, M., Melega, W., Mulgaonkar, A., DeSalles, A., Min, B., Yoo, S.S., A Review of Low Intensity Focused Ultrasound Pulsation, Brain Stimulation, vol. 4, no. 3, pp.125-136, (July 2011).

Yoo, S.S., Bystritsky, A., Lee, J.H., Zhang, Y., Fischer, K., Min, B.K., McDannold, N.J., Pascual-Leone, A., Jolesz, F.A., Focused Ultrasound Modulates Region-Specific Brain Activity, Neurolmage, 56(3), 1267-75, (June 2011)).

Gavrilov LR, Geshuni GV, Il'iniskii OB, Popova LA, Sirotyuk MG, Tsirul'nikov E.M., Stimulation Of Human Peripheral Neural Structures By Focused Ultrasound, Sov Phys Acoust, 19(4):332-334 (1974).

Colucci, V., Strichartz, G., Jolesz, F., Vykhodtseva, N., Hynynen, K., Focused Ultrasound Effects on Nerve Action Potential, Ultrasound in Medicine and Biology, Vol. 35. #10, pp. 1737-1747 (2009).