Device for treating dementia, method of operating said device, and program

Abstract

To provide a novel treatment method for dementia which is different from conventional medications or the like.SOLUTION: A device for treating dementia includes: a plurality of ultrasonic probes; an ultrasonic vibrator disposed on the ultrasonic probes for transmitting unfocused ultrasonic energy to brain; and an ultrasonic generator connected to the ultrasonic probes. The generated unfocused ultrasonic energy is diffused in the brain in an inverted taper shape which has a gradually increasing diameter in a direction of radiation. The ultrasonic energy is diffused in an approximately conical shape (a bottom surface part can be a curved plane).SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a device for treating dementia, a method for operating the device, and a program. [Background technology]

[0002] Currently, the number of dementia patients in Japan is said to be around 2.6 million, and is expected to increase in line with the rapid increase in the elderly population, exceeding 3 million by 2020. The number of dementia patients worldwide is estimated to be 35 million, with estimates predicting this number will reach 65 million by 2030 and 115 million by 2050. In terms of types of dementia, vascular dementia and Alzheimer's disease account for the majority of all cases, and many patients exhibit symptoms of both.

[0003] Measures to treat vascular dementia include drug treatment for hypertension, dyslipidemia, and diabetes, as well as reducing exercise, smoking, overeating, and stress, but no drugs have yet been developed to treat vascular dementia itself. Furthermore, for Alzheimer's disease, drugs that activate the acetylcholine pathway and inhibit glutamate are commercially available, but their therapeutic effects are not necessarily sufficient. Therefore, the development of effective means for treating dementia is desired.

[0004] The present inventors have previously reported on LIPUS (Low-Intensity Pulsed Laser) It has been confirmed that LIPUS (Likely abbreviation for "unfocused ultrasound") improves angiogenesis and left ventricular function in ischemic porcine hearts (Non-Patent Document 1). In recent years, LIPUS has attracted widespread attention in fields such as orthopedics, gastroenterology, neurology, and dentistry, and has already been put to clinical use in the treatment of fractures. However, there have been no reports specifically examining the therapeutic effects of unfocused ultrasound energy irradiation on dementia. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Hanawa K. Shimokawa H, et al. PLoS One.2014;9:e104863 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a new method for treating dementia that differs from conventional drug treatments and the like. [Means for solving the problem]

[0007] Under the circumstances described above, the present inventors have found that dementia can be treated by transmitting unfocused ultrasonic energy, which is emitted in a spreading manner from an ultrasonic probe, rather than focused ultrasonic energy, which is emitted in a converging manner from an ultrasonic probe, to a wide area of ​​the brain and causing angiogenesis, etc. The present invention is based on this new finding.

[0008] Therefore, the present invention provides an ultrasound generating device and a method and program for operating a device for treating dementia according to the following items: Item 1. A device for treating dementia, A plurality of ultrasonic probes; an ultrasound transducer disposed in the ultrasound probe and transmitting unfocused ultrasound energy to the brain; and an ultrasound generator connected to the ultrasound probe. An apparatus comprising:

[0009] Item 2. The device according to Item 1, wherein the unfocused ultrasonic energy is diffused in an inverse tapered shape that gradually expands in the radial direction.

[0010] Item 3. The device according to Item 2, wherein the angle of the inclined surface of the expanding, reverse-tapered unfocused ultrasonic energy is 50° to 100°.

[0011] Item 4. The device according to any one of Items 1 to 3, wherein the ultrasonic generator controls the ultrasonic vibrators so as to sequentially irradiate unfocused ultrasonic energy among a plurality of ultrasonic probes.

[0012] Item 5. An apparatus according to Item 4, wherein the irradiation of unfocused ultrasonic energy by a plurality of ultrasonic probes is performed at intervals of 0.15 / f ms or more (f represents the frequency (MHz) of the transmitted pulse).

[0013] Item 6. The device according to any one of items 1 to 5, wherein the plurality of ultrasonic probes further comprise ultrasonic receiving elements for receiving ultrasonic waves emitted from the other ultrasonic probes and transmitted through the brain.

[0014] Item 7. The device according to Item 6, further comprising a means for evaluating the therapeutic effect of ultrasound according to the received intensity of transmitted ultrasound.

[0015] Item 8. The device according to Item 6 or 7, further comprising an output adjustment means for adjusting the output power of the ultrasonic waves to be output in accordance with the received intensity of the transmitted ultrasonic waves.

[0016] Item 9. A plurality of ultrasonic probes; an ultrasound transducer disposed in the ultrasound probe and transmitting unfocused ultrasound energy to the brain; and an ultrasound generator connected to the ultrasound probe. A method for operating a device for treating dementia, comprising: The method includes controlling an ultrasonic generator to cause an ultrasonic transducer disposed in an ultrasonic probe to generate unfocused ultrasonic energy.

[0017] Item 10. A plurality of ultrasonic probes; an ultrasound transducer disposed in the ultrasound probe and transmitting unfocused ultrasound energy to the brain; and an ultrasound generator connected to the ultrasound probe. A program stored in a device for treating dementia, comprising: A program that controls an ultrasonic generator to cause an ultrasonic transducer disposed in an ultrasonic probe to generate unfocused ultrasonic energy.

[0018] Item 11. A method for treating dementia, comprising the step of transmitting unfocused ultrasonic energy generated from the ultrasonic vibrators arranged on the ultrasound probes to the brain of a patient using a plurality of ultrasound probes, ultrasound vibrators arranged on the ultrasound probes and transmitting unfocused ultrasonic energy to the brain, and an ultrasound generator connected to the ultrasound probes. [Effects of the Invention]

[0019] According to the present invention, by irradiating unfocused ultrasonic energy, ultrasonic energy can be transmitted to a wide area of ​​the brain, and dementia can be treated by inducing angiogenesis, neuron increase, etc. Therefore, according to the present invention, a new method for treating dementia that differs from conventional drug treatments, etc. can be provided. [Brief explanation of the drawings]

[0020] [Figure 1] 1 shows a schematic diagram of an exemplary embodiment of the device of the present invention; [Figure 2] A cross-sectional schematic diagram of an ultrasonic probe is shown. [Figure 3] 1 shows a schematic diagram of ultrasonic energy diffusion in one embodiment of the present invention. [Figure 4] 1 shows a side view of an ultrasonic probe 1 in an embodiment in which the probe diffuses in an inverse tapered shape, gradually expanding in the radial direction. [Figure 5] 1 shows a schematic diagram of an embodiment in which two ultrasound probes are placed on the temporal region of the head. [Figure 6] 1 illustrates an ultrasonic waveform in one embodiment. [Figure 7] ISPPA, ISPTA explanatory diagram [Figure 8]8 shows a schematic diagram of an embodiment of the method of the present invention (subject's posture). Fig. 8, top: sitting position, actually wearing a fixing headband to fix the probe. Fig. 8, bottom: lying position, actually wearing a fixing headband to fix the probe. [Figure 9] A schematic diagram of the test method in Example 1-1 is shown. Irradiation was performed three times every other day for one week after BCAS surgery: 20 minutes x 3 times / day. The degree of cerebral blood flow (CBF) was compared between groups using a laser speckle device. A cognitive behavioral test was performed on postoperative day 28. Sampling for tissue and biochemical analysis was performed on days 3, 7, and 28, respectively. [Figure 10] The outline and results of Example 1-1 are shown below. Cognitive behavior test: Suppression of cognitive decline by LIPUS treatment. Results of the Y-maze test (a method for assessing cognitive function by taking advantage of the habit of mice with normal cognitive function to choose a path different from the one they came from, i.e., A → B → C) [Figure 11] The results of Example 1-1 are shown below. [Figure 12] The results of Example 1-1 are shown below. [Figure 13] The results of Example 1-1 are shown below. [Figure 14] The results of Example 1-1 are shown. Oligodendrocyte precursor cells were found to be more numerous than in the untreated group even one month after surgery. [Figure 15] The results of Example 1-1 (evaluation of OPCs and dividing cells) are shown below. Both tend to increase with LIPUS treatment. [Figure 16] A schematic diagram of the test method in Example 1-2 is shown below. From the age of 3 months, once a month: 20 minutes x 3 times / day. After cognitive behavioral testing at 6 months of age, the mice were sacrificed. The irradiation conditions were the same as those of the BCAS model. [Figure 17] The outline and results of Example 1-2 are shown below. Cognitive function evaluation: Suppression of cognitive decline by LIPUS treatment. Results of the Y-maze test (a method for evaluating cognitive function that utilizes the habit of mice with normal cognitive function to choose a path different from the one they came from, i.e., A → B → C) [Figure 18] The results of Example 1-2 (accumulation of amyloid beta in tissues) are shown. LIPUS treatment may reduce the accumulation of amyloid beta. [Figure 19] In Example 2, a schematic diagram is shown for the case where ultrasound irradiation from one probe and another probe are started at 0.3 ms intervals (study using human skull. Relationship between bone density, bone thickness and ultrasound transmittance). The slope coincidentally coincided between 0.5 MHz and 1.0 MHz. It is thought that only thickness needs to be considered. Therefore, it is possible to predict transmittance from thickness. [Figure 20] 1 shows the test results for the relationship between bone density or bone thickness and ultrasonic transmittance in Example 2. [Figure 21] FIG. 1 shows an explanatory diagram regarding the examination of the irradiation angle for transmitting ultrasound waves to a wide area of ​​the brain in Example 2. [Figure 22] 1 shows the test results for the relationship between bone density or bone thickness and ultrasonic transmittance in Example 2. [Figure 23] An explanatory diagram is shown for the consideration of the irradiation angle for transmitting ultrasound waves over a wide area of ​​the brain in Example 2 (calculation that forms the basis of the element curvature radius. The ideal irradiation range is estimated from the head height, width, and length of the human skull. In this case, it was considered that the lens would need to bulge by 15 mm. The required irradiation angle is expected to be between 60° and 90°. [Figure 24] Treatment schedule in Example 3-1 [Figure 25] The results of Example 3-1-1 are shown below. [Figure 26] The results of Example 3-1-2 are shown below. [Figure 27] Treatment schedule in Example 3-2 [Figure 28] The results of Example 3-2-1 are shown below. [Figure 29] The results of Example 3-2-2 are shown below. [Figure 30] The results of Example 4-1 are shown below. [Figure 31] The results of Example 4-2 are shown below. [Figure 32] The results of Example 4-3 are shown below. [Figure 33] The results of Example 4-3 are shown below. DETAILED DESCRIPTION OF THE INVENTION

[0021] Devices for treating dementia The present invention will now be described with reference to the drawings. The present invention is an apparatus for treating dementia, comprising: A plurality of ultrasonic probes; an ultrasound transducer disposed in the ultrasound probe and transmitting unfocused ultrasound energy to the brain; an ultrasonic generator connected to an ultrasonic probe; An apparatus comprising:

[0022] In this specification, the "device for treating dementia" may be simply referred to as a dementia treatment device. In the present invention, "dementia" includes vascular dementia, Alzheimer's dementia, and symptoms that exhibit both of these. In addition, in the present invention, the term "dementia" also includes symptoms such as mild cognitive impairment.

[0023] FIG. 1 shows a schematic diagram of a typical embodiment of the device of the present invention. As shown in FIG. 1, the dementia treatment device of the present invention includes a plurality of ultrasound probes 1 and an ultrasound generator 2 connected to the ultrasound probes 1. FIG. 2 shows a schematic diagram of the ultrasound probes. The ultrasound probes are equipped with ultrasound transducers 3 that transmit unfocused ultrasound energy to the brain. In the present invention, typically, a single ultrasound transducer 3 is equipped for one ultrasound probe 1, as shown in FIG. 2. Electricity is transmitted from the ultrasound generator 2 via wiring or the like (not shown) to apply a voltage to the ultrasound transducer 3, causing it to vibrate. The frequency, time, timing, etc. of the vibration of the ultrasound transducer 3 are controlled by the ultrasound generator 2. Furthermore, by switching the control signal from the ultrasound generator 2, the same ultrasound transducer 3 can be used as an ultrasound receiving element.

[0024] In the present invention, by making the ultrasound irradiation surface of one ultrasound transducer into a convex curved shape so that the direction of ultrasound is unfocused, or by arranging multiple ultrasound transducers in a convex curved shape, unfocused ultrasound energy can be efficiently transmitted to the brain, and as a result, dementia can be treated by activating neurons through angiogenesis in the hippocampus and increasing the activity of oligodendrocyte precursor cells in the corpus callosum, resulting in a reduction in white matter lesions.

[0025] In the present invention, unfocused ultrasonic energy means ultrasonic energy that is diffused without being focused to one point or one line. In the present invention, it is preferable that the unfocused ultrasonic energy is diffused in an inverse tapered shape that gradually expands in diameter in the radiation direction. The angle of expansion of the inclined surface of the inverse tapered unfocused ultrasonic energy that expands in diameter is preferably 50° to 100°, and more preferably 60° to 90°. Typically, ultrasonic energy is diffused in a substantially conical shape (the bottom surface portion can be a curved surface) as shown in FIG. 3. FIG. 4 shows a side view of an ultrasonic probe 1 in an embodiment in which the ultrasonic energy is diffused in an inverse tapered shape that gradually expands in diameter in the radiation direction. In the present invention, the angle of expansion of the inclined surface of the inverse tapered unfocused ultrasonic energy that expands in diameter refers to θ in FIG. 4. In a typical embodiment, two It is preferable to place the ultrasound probe 1 on the temporal region (FIG. 5). Therefore, by diffusing unfocused ultrasound energy in an inverse tapered shape as described above, it is possible to transmit ultrasound energy to most of the brain, for example, a region including at least the hippocampus and corpus callosum, and typically to the entire brain, which is preferable (FIG. 5).

[0026] In the present invention, the amplitude (sound pressure) of the irradiated ultrasound is preferably low, for example, 3.0 MPa or less, more preferably 0.7 MPa or less, from the viewpoint of promoting angiogenesis, neuron proliferation, etc., through gentle ultrasound stimulation. On the other hand, the lower limit of the intensity of the irradiated ultrasound is not particularly limited in the present invention, but from the viewpoint of therapeutic effectiveness, it is preferably, for example, 0.1 MPa or more, preferably 0.2 MPa or more. In the present invention, the intensity of the ultrasound and the frequency of the irradiated ultrasound are not particularly limited, but can be appropriately set, for example, in the range of 0.5 to 1.5 MHz, preferably 0.5 to 1.0 MHz.

[0027] In the present invention, the material of the ultrasound transducer is not particularly limited as long as it can generate the unfocused ultrasound energy. Examples include resins (e.g., Noryl resin, polyacetal, ionomer resin, urethane resin) and metals (e.g., copper alloys). The size of the ultrasound probe's ultrasound-generating portion is not particularly limited. For example, if the ultrasound-generating portion has a substantially circular shape, its diameter is preferably 1.0 to 5.0 cm, more preferably 2.0 to 4.0 cm. The shape of the ultrasound-generating portion of the probe is not particularly limited, and can be appropriately designed to be substantially circular, substantially elliptical, polygonal (triangle, quadrangle (e.g., square, rectangle, parallelogram, trapezoid), pentagonal, hexagonal, heptagonal, octagonal, etc.), etc. The dimensions can also be appropriately set to, for example, dimensions equivalent to those described above for a substantially circular shape, so that ultrasound can be transmitted to a wider area of ​​the brain.

[0028] Furthermore, in the present invention, by using multiple ultrasonic probes and irradiating unfocused ultrasonic energy from different locations on the head, ultrasonic waves can be transmitted to a wider area of ​​the brain. In the present invention, from the viewpoint of safety, more specifically, from the viewpoint of preventing the ultrasonic energy irradiated from multiple locations from being transmitted to the brain in an overlapping manner, resulting in excessive ultrasonic energy being transmitted to the brain, it is preferable that the ultrasonic generator controls the ultrasonic vibrators to sequentially irradiate unfocused ultrasonic energy among the multiple ultrasonic probes. In the present invention, sequentially irradiating unfocused ultrasonic energy among the multiple ultrasonic probes means that, first, one of the multiple ultrasonic probes generates ultrasonic waves, while the other ultrasonic probes do not generate ultrasonic waves during that period, then another ultrasonic probe generates ultrasonic waves, while the other ultrasonic probes do not generate ultrasonic waves during that period, etc., among the multiple ultrasonic probes, only one ultrasonic probe generates ultrasonic waves at the same time, in other words, two or more ultrasonic probes do not generate ultrasonic waves simultaneously.

[0029] In the present invention, ultrasonic waves generated from an ultrasonic probe pass through the skull, propagate to the brain, are reflected by the skull on the opposite side of the skull from where the ultrasonic probe is placed, and are propagated again in the direction of the ultrasonic probe. The reflected ultrasonic waves are then reflected again by the skull on the same side of the skull where the ultrasonic probe is placed and propagate again. During this time, the ultrasonic waves are attenuated as they propagate through the brain and as they are reflected by the skull. In this way, the ultrasonic waves generated from the ultrasonic probe travel back and forth within the brain multiple times, attenuating each time they are reflected by the skull.

[0030] Therefore, in the present invention, when unfocused ultrasonic energy is sequentially irradiated between a plurality of ultrasonic probes, it is preferable to leave an interval between the generation of ultrasonic waves from the plurality of ultrasonic probes so that excessive ultrasonic stimulation does not occur even if the irradiated wave or reflected wave of unfocused ultrasonic energy generated from one ultrasonic probe is attenuated and overlaps with the unfocused ultrasonic energy generated from the next ultrasonic probe. From the above viewpoint, in the present invention, the irradiation of unfocused ultrasonic energy by the plurality of ultrasonic probes is performed at a rate of 0.15 / f (f is the frequency (MHz) of the transmitted pulse). It is preferable that the irradiation be performed at intervals of 0.60 / f (f (MHz) is as defined above) ms or more, more preferably 0.30 / fms or more. From the viewpoint of obtaining a higher therapeutic effect in a short time, it is preferable that the irradiation of unfocused ultrasonic energy by multiple ultrasonic probes be performed at intervals of 0.60 / f (f (MHz) is as defined above) ms or less, more preferably 0.30 / fms or less. In the present invention, frequency means the frequency of the transmitted ultrasonic waves.

[0031] Here, unless otherwise specified, the interval of unfocused ultrasonic energy irradiation means, for the above purpose, the time from the end of ultrasonic irradiation from one ultrasonic probe to the start of ultrasonic irradiation from the next ultrasonic probe when ultrasonic irradiation is started from one ultrasonic probe, ultrasonic irradiation from that ultrasonic probe is stopped, ultrasonic irradiation from the next ultrasonic probe is started, ultrasonic irradiation from the next ultrasonic probe is stopped, etc.

[0032] In the present invention, the irradiated ultrasound is a discontinuous wave, and the number of cycles is not particularly limited, but can be appropriately set within the range of, for example, 1 to 64 cycles, preferably 24 to 40 cycles. Here, the number of ultrasound cycles refers to the number of cycles within the width from the start of ultrasound irradiation to the end of ultrasound irradiation (also referred to as pulse width in this specification). For example, in the case of ultrasound with the waveform shown in Figure 6, the number of cycles is 32 cycles. The duration of ultrasound treatment is not particularly limited, but can be appropriately set within the range of, for example, 1 to 60 minutes per treatment, preferably 15 to 25 minutes, depending on the patient's symptoms, ultrasound intensity, etc. Furthermore, the number of times the treatment is performed per day is also not particularly limited, but can be appropriately set within the range of, for example, 1 to 4 times, preferably 2 to 3 times. Furthermore, the frequency of the treatment is also not particularly limited, but can be appropriately set within the range of, for example, 1 to 7 times per week, preferably 2 to 3 times. There are no particular limitations on the treatment interval, and for example, if one set of treatment is performed at the above frequency for 5 to 10 days (more preferably 6 to 8 days), it is preferable to perform the treatment continuously at intervals of once every 1 to 4 months (for example, once every 1 to 3.5 months) unless an adverse event occurs.

[0033] The intensity of ultrasound can be adjusted by ISPPA, ISPTA, etc. Here, ISPPA indicates the average intensity within the pulse width, and ISPTA indicates the average intensity within the repetition period. Figure 7 illustrates the ISPPA and ISPTA of ultrasound.

[0034] The ISPTA of the irradiated ultrasound is not particularly limited, but from the viewpoint of promoting angiogenesis, neuron proliferation, etc. by gentle ultrasound stimulation, for example, 720 mW / cm 2 or less, preferably 100 to 150 mW / cm 2 When multiple ultrasonic probes are used, the ISPTA is expressed as the sum of the ISPTA of the ultrasonic waves irradiated by each ultrasonic probe. In the present invention, the duty cycle of the ultrasonic waves irradiated is not particularly limited, but can be set appropriately within the range of, for example, 0.1 to 50%, preferably 0.1 to 20%.

[0035] Here, the duty ratio indicates the ratio of ultrasonic irradiation time to one cycle of time, which consists of irradiating ultrasonic waves for a certain period of time and then pausing the irradiation for a certain period of time. In other words, it indicates the ratio of ultrasonic irradiation time to [ultrasonic irradiation time + irradiation pause time] in one cycle. When multiple ultrasonic probes are used, the duty ratio is expressed as the sum of the duty ratios of the ultrasonic waves irradiated by each ultrasonic probe.

[0036] As will be described later, ultrasonic waves generated from an ultrasonic probe are significantly attenuated when passing through the skull. The degree of attenuation varies depending on the thickness of the skull through which the ultrasonic waves pass. Therefore, it is preferable that the thickness of the skull is input to the ultrasonic generator based on a head CT image or the like taken at the time of diagnosing dementia, and the device calculates an appropriate estimated output value based on the numerical value of the skull thickness, and emits therapeutic ultrasonic waves. In this embodiment, the ultrasonic generator includes a means for inputting the numerical value of the skull thickness, a means for calculating an appropriate estimated output value from the input value, and a means for inputting the numerical value of the skull thickness. The system will be provided with a calculation means.

[0037] Furthermore, in the present invention, it is preferable that the multiple ultrasonic probes further include ultrasonic receiving elements for receiving ultrasonic waves emitted from the other ultrasonic probes and transmitted through the brain. In an embodiment including such receiving elements, it is possible to monitor whether the intensity of the ultrasonic waves emitted from the ultrasonic probes and transmitted through the brain is within a predetermined range, which is preferable. It is also possible to receive and use the transmitted ultrasonic waves from the ultrasonic probes themselves. As described above, an ultrasonic transducer can also be used as a receiving element by switching a control signal from an ultrasonic generator. Therefore, in the present invention, a device in which "multiple ultrasonic probes further include ultrasonic receiving elements for receiving ultrasonic waves emitted from the other ultrasonic probes and transmitted through the brain" also includes a device in which each ultrasonic probe includes an ultrasonic transducer and uses the ultrasonic transducer as a receiving element. In such an embodiment, for example, an ultrasonic transducer included in some of the multiple ultrasonic probes (e.g., one ultrasonic probe) can be used as a receiving element, and an ultrasonic transducer included in the other ultrasonic probes can be used as a transmitting element. Furthermore, after a certain period of time has elapsed, at least some of the transmitting elements / receiving elements of the plurality of ultrasonic transducers may be switched for use.

[0038] It is also preferable to further include a means for evaluating the therapeutic effect of ultrasound according to the received intensity of the transmitted ultrasound. For example, this means can calculate the integrated value of the intensity of the received ultrasound and use this integrated value as an index to evaluate the therapeutic effect, or when the integrated value reaches a predetermined value, it can be evaluated that the treatment has been completed with a certain degree of effect.

[0039] It is also preferable to further include an output adjustment means for adjusting the output power of the ultrasonic waves to be output according to the reception intensity of the transmitted ultrasonic waves. More specifically, the output adjustment means may include a feedback means (processor) that reduces the output power when the sound pressure of the ultrasonic waves received by the receiving element is equal to or greater than a predetermined value.

[0040] The reference value for reducing the output when the intensity of ultrasonic energy received by the receiving element is equal to or greater than a predetermined value is not particularly limited, but can be appropriately set, for example, to a sound pressure of 0.1 MPa or less, preferably 0.05 MPa or less, taking safety standards into consideration. In a preferred embodiment of the present invention, the output can be preset to be reduced when the receiving element receives ultrasonic waves with an intensity exceeding an upper limit set within the above range. In addition, the device of the present invention may be provided with a document or the like that describes the procedures for performing the operating method or treatment method of the device of the present invention described below.

[0041] Method of operating a device for treating dementia, method of treating dementia The present invention further provides a method for detecting an ultrasound wave, comprising: an ultrasound transducer disposed in the ultrasound probe and transmitting unfocused ultrasound energy to the brain; an ultrasonic generator connected to an ultrasonic probe; A method for operating a device for treating dementia, comprising: A method is provided that includes controlling an ultrasound generator to cause an ultrasound transducer disposed in an ultrasound probe to generate unfocused ultrasound energy.

[0042] In a typical embodiment, as shown in FIG. 1, the method of the present invention is carried out with an ultrasonic probe 1 applied to the head. There are no particular limitations on the location where the ultrasonic probe 1 is applied, but it is preferable to apply it to the temporal region (temple) because the skull is relatively thin and ultrasonic waves can be easily transmitted to the brain. To efficiently transmit ultrasonic waves to the brain, gel may be applied to the ultrasonic wave generating portion of the ultrasonic probe 1 and / or the part of the head where the ultrasonic probe is applied. Furthermore, as shown in FIG. 1, the ultrasonic probe 1 may be fixed with a hair band 4. Furthermore, as shown in FIG. 8, the posture of the subject may be either a sitting position or a lying position. Furthermore, subjects to be treated by the method of the present invention include mammals such as mice, rats, humans, monkeys, dogs, and pigs, and preferably humans.

[0043] The present invention also provides a method for treating dementia, comprising the step of transmitting unfocused ultrasonic energy generated from the ultrasonic transducers arranged on the ultrasonic probes to the brain of a patient using a plurality of ultrasonic probes, ultrasonic transducers arranged on the ultrasonic probes and configured to transmit unfocused ultrasonic energy to the brain, and an ultrasonic generator connected to the ultrasonic probes.

[0044] The apparatus and ultrasonic irradiation conditions used in these methods of the present invention are as follows: Devices for treating dementia " can be adopted.

[0045] program The present invention includes a plurality of ultrasonic probes, an ultrasound transducer disposed in the ultrasound probe and transmitting unfocused ultrasound energy to the brain; and an ultrasound generator connected to the ultrasound probe. A program stored in a device for treating dementia, comprising: A program is provided that controls an ultrasonic generator to cause an ultrasonic transducer disposed in an ultrasonic probe to generate unfocused ultrasonic energy.

[0046] The program of the present invention can be used to generate unfocused ultrasonic energy in the aforementioned dementia treatment device (a computer built into the device). Furthermore, in an embodiment of the device of the present invention, in which the multiple ultrasonic probes further include ultrasonic receiving elements for receiving ultrasonic waves emitted from the other ultrasonic probes and transmitted through the brain, the program of the present invention may cause the device to execute a function of evaluating the therapeutic effect of ultrasonic waves according to the received intensity of the transmitted ultrasonic waves. For example, the program may calculate an integrated value of the intensity of the received ultrasonic waves, use the integrated value as an index, and compare it with a preset value to evaluate the therapeutic effect. The program may also calculate an integrated value of the intensity of the received ultrasonic waves, and evaluate that a certain level of effective treatment has been completed when the integrated value reaches a predetermined value. In this embodiment, the device may also include a display unit for such evaluation. In this case, the program of the present invention may cause the device (computer) to execute a function of displaying the evaluation obtained above on the display unit. Furthermore, in this embodiment, the program of the present invention may also cause the device (computer) to execute an output adjustment function of adjusting the output power of the ultrasonic waves to be output according to the received intensity of the transmitted ultrasonic waves. More specifically, for example, when the sound pressure of the ultrasonic waves received by the receiving element is equal to or greater than a predetermined value, a feedback means (processor) that reduces the output may be made to adjust the output.

[0047] Although the present invention has been described above based on drawings showing specific embodiments, it is clear that the present invention is not limited to these embodiments. For example, the connection between the ultrasound probe and the ultrasound generator may be wired as shown in FIG. 1 or wirelessly. Regarding the number of ultrasound probes, although an embodiment using two ultrasound probes has been described, three or more ultrasound probes may also be used. For example, two ultrasound probes may be placed on both sides of the head (temples) and another ultrasound probe may be placed on the boundary between the occipital region and the nape (foramen magnum) to irradiate ultrasound. [Example]

[0048] The present invention will now be illustrated by specific examples, but the present invention is not limited to these examples.

[0049] Example 1: Verification of the effectiveness of ultrasound therapy in treating dementia Example 1-1 Vascular Dementia Model (BCAS (Bilateral Common Carcinoma) Carotid Artery Stenosis Model Chronic cerebral ischemia is thought to be an important pathological mechanism in subcortical vascular dementia, which accounts for the majority of vascular dementia cases. In the BCAS model, prolonged cerebral ischemia leads to the formation of white matter lesions similar to those in humans, resulting in higher-level functional impairment. Therefore, it is currently the most standard vascular dementia model. Therefore, in this example, ultrasound was irradiated to the entire brain of the BCAS model to verify the therapeutic effect on dementia.

[0050] Specifically, 9- to 12-week-old C57Bl / 6 male mice (n = 10-15) were treated with the method described in the literature (Shibata M, et al. Stroke. 2004 Nov;35(11):2598-603) to create a BCAS model. The Sham group consisted of 9- to 12-week-old C57Bl / 6 male mice that were not subjected to the BCAS treatment.

[0051] Ultrasound was administered three times a week after BCAS surgery (1 day, 3 days, and 5 days after BCAS surgery). Ultrasound was administered for 20 minutes three times a day.

[0052] Using a laser speckle device (OMEGAWAVE, OMEGAZONE mini2), the cerebral blood flow (CBF) was measured in each of the BCAS preoperative, 1-day, 2-day, 4-day, 7-day, and 28-day groups. Furthermore, various immunostaining (fluorescent immunostaining) of brain tissue samples, protein expression analysis using Western blotting, and gene expression analysis using RNA-sequence were performed.

[0053] The irradiation conditions were as follows: area 3.75 cm 2A rectangular ultrasound probe (1.5 cm x 2.5 cm) was used to transmit ultrasound waves throughout the model's brain. Irradiation conditions: ·Intensity (ISPTA): 100mW / cm 2 Frequency: 1.875MHz Number of Cycles: 32 cycles Repetition rate: 6kHz Figure 9 shows an outline of this study. Figure 10 shows the results of the cognitive behavior test. Here, "number of entries" refers to the total number of arm entries, and "spontaneous alternation" refers to the spontaneous alternation behavior of the mice ([number of entries into three different arms in a row] / [number of entries into all arms of the Y-maze - 2]). Ultrasound treatment significantly suppressed cognitive decline in the cognitive behavior test.

[0054] Assessment of white matter lesions (corpus callosum) As shown in Figure 11, ultrasound treatment significantly preserved myelin structure and increased the number of mature oligodendrocytes that form myelination. To the left of Figure 11, "Preservation of myelin structure by LIPUS treatment," is a KB-stained image of the corpus callosum. In the graph to the right of Figure 11, "white matter lesion" indicates the extent of demyelinating lesions in the white matter of the corpus callosum. To the left of Figure 11, "Increase in mature oligodendrocytes in the LIPUS treatment group," is a GST-p immunostained image of the corpus callosum. In the graph to the right of Figure 11, the vertical axis, "number of GST-p positive cells," indicates the number of mature oligodendrocytes per unit area. As shown in Figure 11, ultrasound treatment significantly preserved myelin structure and increased the number of mature oligodendrocytes that form myelination. In Figure 12, "Increase in immature neurons in the LIPUS group," is a DCX immunostained image. To the left of "Increase in hippocampal capillaries by LIPUS treatment," in the bottom of Figure 12, is a CD31 immunostained image of the hippocampus. In the graphs on the right and bottom of Figure 12, the number of CD31-positive cells on the vertical axis represents the number of capillaries per unit area. As shown in Figure 12, the number of immature neurons in the hippocampus is increasing, and the number of capillaries is also increasing. there was.

[0055] Figure 13 shows a Ki67 immunostained image in the upper left and an Olig2 immunostained image in the lower left. In the graph on the right, the number of Ki67-positive cells and Olig2-positive cells on the vertical axis represent the number of dividing cells and oligodendrocyte precursor cells, respectively. Figure 13 shows an acute tissue evaluation. Ultrasound treatment tended to increase the number of proliferating cells in the corpus callosum, as well as an increase in Olig2-positive cells. We then used fluorescent double immunostaining to confirm whether the dividing and proliferating cells were oligodendrocyte precursor cells. We found that they had indeed merged, and that the dividing and proliferating cells were oligodendrocyte precursor cells (OPCs). Gene-wide analysis using RNA sequencing also confirmed changes in genes involved in oligodendrocyte differentiation and proliferation, such as Olig2.

[0056] Figure 14 (left) shows an image of Olig2 immunostaining in the corpus callosum. In the graph on the right, the vertical axis, the number of Olig2-positive cells, represents the number of oligodendrocyte precursor cells 28 days after surgery. Therefore, as shown in Figure 14, the number of Olig2-positive cells was significantly increased in the ultrasound treatment group even one month after surgery, suggesting a sustained effect. Figure 15 shows images of Olig2 immunostaining and Ki67 immunostaining in the hippocampus three days after surgery. As shown in Figure 15, the number of Olig2-positive cells and Ki67-positive cells also tended to increase in the hippocampus, consistent with the results shown in Figure 11 (evaluated one month after surgery). These findings suggest that the proliferation of OPCs in the corpus callosum and the increase in angiogenesis and immature neurons in the hippocampus contribute to the improvement of cognitive function.

[0057] Example 1-2 Alzheimer's disease model (genetic modification) Using a genetically modified mouse (5XFAD), a mouse model of Alzheimer's disease, ultrasound treatment was performed in the same manner as the BCAS model, according to the protocol shown in Figure 16. The 5XFAD model received one set of ultrasound treatment once a month, and was observed until the age of 6 months.

[0058] The results are shown in Figures 17 and 18. As shown in Figure 17, ultrasound treatment prevented the decline in cognitive function. Figure 18 shows a 4G8 immunostaining image (amyloid beta staining). As shown in Figure 18, it was suggested that ultrasound treatment may reduce the accumulation of amyloid beta. Molecular expression analysis showed that ultrasound treatment significantly expressed eNOS (endothelial nitric oxide synthase), suggesting that this eNOS may contribute to the improvement of cognitive function.

[0059] Example 2: Examination of ultrasound irradiation methods in humans, taking safety into consideration The safety standards for ultrasonic exposure are as follows: (1) Global maximum acoustic output (AO) is recommended. Recommended 720mW / cm 2 below (2) Tyles's stated limit is recommended at 500 mW / cm 2 below Therefore, in the following discussion, ISPTA, 250 mW / cm 2 It was carried out in the following range:

[0060] We clinically examined factors that may affect the intensity of therapeutic ultrasound using human skulls.Temporal bones were collected from seven donated individuals, both male and female, aged 67 to 96 years, and their bone mineral density and thickness were measured, followed by the ultrasound transmittance of each.

[0061] The test was performed at 0.5MHz and 1.0MHz. As a result, at 0.5MHz, the correlation coefficient between permeability and bone thickness was -0.53, and the correlation coefficient between bone mineral density and permeability was 0.30. At 1.0MHz, the correlation coefficient between permeability and bone thickness was -0.88, and the correlation coefficient between permeability and bone mineral density was -0.30. When multivariate analysis was performed for 1.0MHz, for example, the correlation coefficient between permeability and bone thickness was significant at P<0.001, but the correlation coefficient between permeability and bone mineral density was significant at P<0.001. No significant trends were observed for permeability and bone mineral density. These results suggest that bone thickness alone is sufficient as a patient-related parameter. The adjusted R-squared (coefficient of determination corrected for degrees of freedom) was 0.7472, suggesting that it is possible to predict permeability from bone thickness. Regression analysis confirmed a correlation between bone thickness and ultrasound permeability. Figure 19 shows the results of further multivariate analysis. While there was no correlation between bone mineral density and ultrasound permeability, there was a significant correlation between bone thickness and ultrasound permeability. Furthermore, the high R-squared at 1.0 MHz indicated that permeability can be predicted from thickness values. This indicates that bone thickness is the only necessary patient-related parameter for transcranial ultrasound irradiation.

[0062] Furthermore, for a typical human temporal bone thickness of around 2-3mm, at a frequency of 0.5MHz, the ultrasound transmittance for a single bone-to-brain transmission is 25-50% in terms of power (50-70% in terms of amplitude) (Figure 20). Therefore, the power of the ultrasound emitted from the ultrasound probe has already attenuated by 25-50% by the time it reaches the brain.

[0063] When irradiating two points alternately from the probes on the left and right temporal regions (Figure 21), if the propagation speed of ultrasound in the brain is 1540 m / s, the wavelength of 500 kHz is 3.08 mm, and 32 waves is 1 packet. Figure 21 shows the average values ​​of head width, total head height and head length for adults listed in the AIST Human Body Dimension Database (Japanese Head Dimension Database 2001) (https: / / www.dh.aist.go.jp / database / head / #stats). From these values, the shortest diameter of the head is calculated as 174 mm (database The time it takes to reach the contralateral skull is 0.1 74m / 1540m / s=0.113ms.

[0064] On the other hand, the brain's ultrasonic absorption becomes stronger as the frequency increases (approximately 1 dB / cm / MHz). The power is reduced to 1 / 100 when attenuated by 20 dB, so if we assume 0.2 dB / cm at 0.5 MHz (see the table on page 731 of Ultrasound Handbook, Maruzen Publishing Co., Ltd., published in 1999), then 100 cm of propagation is required for the power to be reduced to 1 / 100. In other words, if radiation is emitted at intervals of 1 m / 1540 m / s = 0.00065 s = 0.65 ms, the effect of the previously emitted wave will be It is considered to be negligible.

[0065] In reality, when propagating for 100cm, the radiation is reflected by the bone 100cm / 17.4cm=6 times, making it even safer from the effects of reflection (passing out through the bone).

[0066] In the study using the human skull mentioned above, the attenuation of ultrasound waves after a single bone-brain pass was about half to 70% of the amplitude, which corresponds to a power of 25% to 50%. From this, it is believed that there is no problem with irradiating at 0.3 ms intervals (the power is halved when passing through the bone, and is attenuated to 1 / 50 of its original power by the brain).

[0067] Therefore, when ultrasonic irradiation from one probe and ultrasonic irradiation from another probe are started at an interval of 0.3 ms (Fig. 22), the duty ratio is 10cm / 50cm=20% at 0.5MHz. From the above, it is thought that there is no possibility of local energy increase due to interference waves if the duty ratio is less than 20% at 0.5MHz.

[0068] In addition, if the diameter of the part of the cylindrical probe that is irradiated with ultrasound is 33 mm, the width of the subject's head is 70-80 mm, and the height of the head is 100-130 mm, then it is thought that if ultrasound waves are irradiated from the temple so that the angle of the expanding inclined surface of the expanding reverse-tapered unfocused ultrasound energy is 77° (Figure 23), it will be possible to transmit ultrasound waves to the entire brain.

[0069] By irradiating with ultrasound under the above conditions, the following effects were observed in humans, as in Example 1: It is believed that the physical stimulation of ultrasound can have a therapeutic effect on dementia.

[0070] Example 3: Tests to support the efficacy of the device To clarify the effectiveness of this device for two major forms of dementia, vascular dementia (VaD) and Alzheimer's disease (AD), we conducted studies using mouse models of each. The following are the results demonstrating the device's primary effectiveness. Among these results, we present graphs of cognitive function tests, which are likely to be clinical endpoints, and cerebral blood flow, which is considered to be the most important factor in investigating its mechanism.

[0071] 3-1 Study using VaD model mice Mice with bilateral common carotid artery stenosis (BCAS) were created as a VaD model and assigned to either a LIPUS group (treatment group) or a control group (non-treatment group). LIPUS was irradiated to the entire brain starting the day after BCAS surgery, and treatment was performed according to the schedule shown in Figure 24. After LIPUS treatment, the patients were observed for up to 28 days after surgery, and cerebral blood flow measurements and cognitive behavioral tests were performed. In addition, biochemical analysis based on comprehensive analysis using RNA-sequencing and Bio-plex was performed using whole brain tissue, and evaluation was performed using tissue immunostaining.

[0072] 3-1-1 Analysis of time-dependent changes in cerebral blood flow using VaD model mice Cerebral blood flow was measured 2 hours, 4 days, and 28 days after treatment. The LIPUS group showed a significant reduction in the decrease in cerebral blood flow (Figure 25) (n=9-10, Sham-Free; n=20-25, BCAS) (*P<0.05; ***P<0.0005; two-way ANOVA, multiple t-test). All results are expressed as mean ± standard error.

[0073] 3-1-2 Cognitive function test using VaD model mice Twenty-eight days after treatment, Y-maze and passive avoidance tests were performed, demonstrating a significant reduction in cognitive decline in the LIPUS group (Figures 26A and 26B) (Sham; n = 12-16, BCAS; n = 13-17) (*P < 0.05, **P < 0.005; two-way ANOVA, multiple t-test). All results are expressed as mean ± standard error. This effect was maintained up to 3 months after surgery (P < 0.05).

[0074] 3-1-3 Biochemical analysis of the effects of ultrasound therapy using VaD model mice Ultrasound treatment significantly increased the expression of angiogenesis- and oligodendrocyte progenitor cell-related genes (Olig2; P<0.05, eNOS; P<0.05, CXCR4; P<0.05, FGF2; P<0.05). Western blotting analysis also revealed significant increases in the expression of angiogenic molecules (eNOS; P<0.05, CXCR4; P<0.05, FGF2; P<0.005, VEGF; P<0.05), as well as neurotrophic factors (BDNF; P<0.05, NGF; P<0.05). Here, Olig2 is oligodendrocyte transcription factor 2, eNOS is endothelial nitric oxide synthase, CXCR4 is CXC chemokine receptor 4, FGF2 is fibroblast growth factor 2, VEGF is vascular endothelial growth factor, BDNF is brain-derived neurotrophic factor, and NGF is nerve growth factor.

[0075] 3-1-4 Histological analysis of the effects of ultrasound treatment using VaD model mice Ultrasound treatment reduced white matter damage (P<0.05), promoted angiogenesis and proliferation of oligodendrocyte precursor cells (P<0.05 each), and increased immature neurons (P<0.05).

[0076] 3-2 Study using AD model mice The efficacy and safety of this treatment for AD were confirmed using 5XFAD genetically modified mice as an AD model. Evaluation methods followed those used in the VaD model. Patients were divided into a LIPUS group (treatment group) or a control group (non-treatment group), and LIPUS was irradiated to the entire brain. Treatment was performed according to the schedule shown in Figure 27. After LIPUS treatment, the patient was observed for up to 28 days after surgery, and cerebral blood flow measurements and cognitive behavioral tests were performed. In addition, biochemical analysis based on comprehensive analysis using RNA-sequence and Bio-plex was performed using whole brain tissue, and evaluation was performed using tissue immunostaining.

[0077] 3-2-1 Analysis of temporal changes in cerebral blood flow using AD model mice Three months after the initial treatment, blood flow throughout the brain was significantly maintained in the LIPUS group (Figure 28) (n=14 per group) (*P<0.05, t-test). All results are expressed as mean ± standard error.

[0078] 3-2-2 Cognitive function test using AD model mice After treatment, a Y-maze test was performed, and cognitive decline was significantly suppressed in the LIPUS group three months after the initial treatment (Figure 29) (n = 18 per group) (***P < 0.0005, t-test). All results are expressed as mean ± standard error.

[0079] 3-2-3 Biochemical analysis of the effects of ultrasound treatment using AD model mice (neurotrophic factors) The LIPUS group showed a significant increase in the expression of eNOS and neurotrophic factors (eNOS; P<0.05, BDNF; P<0.05, NGF; P<0.05), as well as a decrease in amyloid beta (42) (P<0.05).

[0080] 3-2-4 Biochemical analysis of the effects of ultrasound therapy using AD model mice (amyloid beta) Ultrasound therapy significantly reduced the accumulation of amyloid beta (42) in the whole brain (P<0.05), significantly reduced microgliosis (P<0.05), and tended to promote angiogenesis (P=0.19).

[0081] Example 4: Tests supporting the use of the device 4-1 Consideration of optimal frequency conditions In an ultrasound transmittance evaluation using the human temporal bone (the site where the treatment device was planned to be extrapolated), the transmittance was higher the lower the frequency (y = -0.098x + 0.59, predicted transmittance at 2 cm of the skull: 60.6% at 0.5 MHz, y = -0.098x + 0.78, predicted transmittance at 2 cm of the skull: 41.6% at 1.0 MHz) (Figure 19). Furthermore, although this is a report on focused ultrasound, the relationship between frequency and mechanical index (MI) and thermal index (TI) is shown, and a basic study using mice with a frequency of 99 mW / cm was shown to be effective. 2The frequency that provides the conditions for no cavitation in the brain (MI value 0.25; one-quarter of the worst-case MI value of 1.0, which is the cavitation condition in water) and no excessive temperature rise (TI does not rise by more than 2°C) is around 0.5 MHz. Furthermore, in an in vitro experiment using human umbilical vein endothelial cells, an increase in VEGF expression was observed even at a frequency of 0.5 MHz (P<0.05) (Figure 30). From the above, it is believed that 0.5 MHz is optimal when considering permeability and safety.

[0082] 4-2 Consideration of the optimum duty ratio In an in vitro experiment using human umbilical vein endothelial cells, the frequency was fixed at 0.5 MHz, and the duty ratio was varied to evaluate the change in VEGF expression. As a result, no increase in VEGF expression was observed at duty ratios of 1% and 40%, but a significant increase in VEGF expression was observed at a duty ratio of 20% (P<0.05) (Fig. 3 1) From the above, it is thought that a duty ratio of around 20% is optimal at a frequency of 0.5MHz, but considering safety calculations regarding interference waves, a duty ratio of 20% or less is desirable, so the optimal duty ratio is thought to be 20% (10% from each probe).

[0083] 4-3 Consideration of optimal treatment conditions We investigated therapeutic irradiation conditions using cultured vascular endothelial cells. We irradiated cultured vascular endothelial cells with ultrasound at sound pressures ranging from 0.05 to 2.2 MPa, which is the range of sound pressure that can be set with a convex transducer, and evaluated the mRNA expression of VEGF, FGF2, and eNOS. The effectiveness of this product is thought to be correlated with the expression levels of VEGF, FGF2, and eNOS, and in this study, we determined that the irradiation conditions were effective when the mRNA expression levels were significantly higher than in the control group.

[0084] As shown in Figure 32, it was shown that it is important to set the tissue amplitude to 0.05-0.5 MPa. To achieve this sound pressure in brain tissue, it was estimated that the sound pressure directly below the element should be in the range of 0.1-1.5 MPa.

[0085] Next, taking into consideration the increase in contact temperature at the patient contact area, the expression levels of VEGF were evaluated using cerebrovascular endothelial cells under two conditions: Condition 1: sound pressure directly below the element of 1.3 MPa (tissue amplitude 0.15 MPa), total duty ratio 5%, and Condition 2: sound pressure directly below the element of 0.9 MPa (tissue amplitude 0.1 MPa), total duty ratio 10%. As a result, the expression levels of VEGF were significantly higher under Condition 1, and therefore Condition 1 was determined to be the preferable treatment condition.

[0086] 4-4 Setting optimal treatment time and duration In a basic study using two different AD model mice, efficacy was confirmed with a 20-minute x 3-session treatment. Furthermore, in a vascular dementia model, follow-up observations were conducted up to 3 months after treatment, and the suppression of cognitive decline observed in the ultrasound treatment group was maintained up to 3 months after surgery (P<0.05). Based on these findings, it is believed that a 20-minute x 3-session, 3-month treatment interval is appropriate. [Industrial Applicability]

[0087] As mentioned above, the number of dementia patients in Japan alone is approximately 2.6 million, and this number is continuing to increase, so the development of new treatments is eagerly awaited. Therefore, the present invention, which can provide a new dementia treatment method that differs from conventional drug treatments, etc., is extremely useful.

Claims

1. A device for enhancing the expression of eNOS, A plurality of ultrasonic probes; an ultrasound transducer disposed in the ultrasound probe and transmitting discontinuous, unfocused ultrasound energy to the brain; and an ultrasound generator connected to the ultrasound probe. An apparatus comprising: the ultrasonic generator controls the ultrasonic transducers to sequentially irradiate unfocused ultrasonic energy among the plurality of ultrasonic probes; The irradiation of unfocused ultrasonic energy by the plurality of ultrasonic probes is carried out in a state where the ultrasonic probes are placed on the surface of the head, A device that irradiates unfocused ultrasound energy in a tapered shape that gradually expands in diameter in the direction of radiation, transmitting it to the entire brain.

2. The device described in claim 1, wherein the ultrasonic treatment time is 1 to 60 minutes.

3. 3. The device according to claim 1, wherein the angle of the inclined surface of the expanding, inversely tapered unfocused ultrasonic energy is 50° to 100°.

4. The device according to any one of claims 1 to 3, wherein the plurality of ultrasonic probes further comprise ultrasonic receiving elements for receiving ultrasonic waves emitted from the other ultrasonic probes and transmitted through the brain.

5. The device according to claim 4, further comprising means for evaluating the effectiveness of ultrasound treatment according to the received intensity of the transmitted ultrasound.

6. 6. The device according to claim 4, further comprising an output adjusting means for adjusting the output power of the ultrasonic waves according to the received intensity of the transmitted ultrasonic waves.

7. A plurality of ultrasonic probes; an ultrasound transducer disposed in the ultrasound probe and transmitting discontinuous, unfocused ultrasound energy to the brain; and an ultrasound generator connected to the ultrasound probe. A method for operating a device for enhancing eNOS expression, comprising: The method includes controlling an ultrasonic generator to generate unfocused ultrasonic energy from an ultrasonic transducer disposed in the ultrasonic probe; the ultrasonic generator controls the ultrasonic transducers to sequentially irradiate unfocused ultrasonic energy among the plurality of ultrasonic probes; The irradiation of unfocused ultrasonic energy by the plurality of ultrasonic probes is performed in an open state with the ultrasonic probes in contact with the surface of the head, A method in which unfocused ultrasound energy is irradiated so that it spreads in an inverse tapered shape that gradually expands in the direction of radiation and is transmitted to the entire brain.

8. The method described in claim 7, wherein the ultrasonic treatment time is 1 to 60 minutes.

9. A plurality of ultrasonic probes; an ultrasound transducer disposed in the ultrasound probe and transmitting discontinuous, unfocused ultrasound energy to the brain; and an ultrasound generator connected to the ultrasound probe. A program installed in an apparatus for enhancing eNOS expression, comprising: By controlling the ultrasonic generator, the ultrasonic transducer disposed in the ultrasonic probe performs a function of generating unfocused ultrasonic energy; the ultrasonic generator controls the ultrasonic transducers to sequentially irradiate unfocused ultrasonic energy among the plurality of ultrasonic probes; The irradiation of unfocused ultrasonic energy by the plurality of ultrasonic probes is performed in an open state with the ultrasonic probes in contact with the surface of the head, A program in which unfocused ultrasound energy is diffused in an inverted taper shape that gradually expands in the direction of radiation, and is irradiated so that it is transmitted to the entire brain.

10. The program described in claim 9, wherein the ultrasound treatment time is 1 to 60 minutes.

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