WO2017063172A1 - 超音波刺激头盔 - Google Patents

超音波刺激头盔 Download PDF

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Publication number
WO2017063172A1
WO2017063172A1 PCT/CN2015/092005 CN2015092005W WO2017063172A1 WO 2017063172 A1 WO2017063172 A1 WO 2017063172A1 CN 2015092005 W CN2015092005 W CN 2015092005W WO 2017063172 A1 WO2017063172 A1 WO 2017063172A1
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Prior art keywords
ultrasonic
brain
head
ultrasonic probe
ultrasound
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PCT/CN2015/092005
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English (en)
French (fr)
Inventor
杨逢羿
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FARMAR LICENSING Co Ltd
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FARMAR LICENSING Co Ltd
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Priority to PCT/CN2015/092005 priority Critical patent/WO2017063172A1/zh
Priority to EP15906057.3A priority patent/EP3363497B1/en
Priority to US15/767,516 priority patent/US10940335B2/en
Priority to JP2018518737A priority patent/JP6670485B2/ja
Priority to CN201580083270.6A priority patent/CN108136204B/zh
Publication of WO2017063172A1 publication Critical patent/WO2017063172A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/22—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods
    • A61B17/22—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for
    • A61B17/225—Implements for squeezing-off ulcers or the like on inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; for invasive removal or destruction of calculus using mechanical vibrations; for removing obstructions in blood vessels, not otherwise provided for for extracorporeal shock wave lithotripsy [ESWL], e.g. by using ultrasonic waves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61H—PHYSICAL THERAPY APPARATUS, e.g. DEVICES FOR LOCATING OR STIMULATING REFLEX POINTS IN THE BODY; ARTIFICIAL RESPIRATION; MASSAGE; BATHING DEVICES FOR SPECIAL THERAPEUTIC OR HYGIENIC PURPOSES OR SPECIFIC PARTS OF THE BODY
    • A61H23/00—Percussion or vibration massage, e.g. using supersonic vibration; Suction-vibration massage; Massage with moving diaphragms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0004—Applications of ultrasound therapy
    • A61N2007/0021—Neural system treatment
    • A61N2007/0026—Stimulation of nerve tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0073—Ultrasound therapy using multiple frequencies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0078—Ultrasound therapy with multiple treatment transducers

Definitions

  • the invention provides a supersonic stimulation helmet, in particular to a supersonic stimulation helmet for regulating brain endogenous neurotrophic factors and protein expression related to neurodegenerative diseases, in order to prevent and treat brain degeneration and other brains. Ministry of disease.
  • Brain neurodegenerative diseases including Alzheimer's disease, depression or Parkinson's disease
  • the current treatment method is mainly to implant drugs, nerve growth factors or stem cells into the brain region in an invasive manner to promote brain nerves. Cell regeneration to achieve a strategy for treating neurodegenerative diseases in the brain.
  • this invasive method requires the opening of the Blood-Brain Barrier (BBB), there are doubts such as damage to the blood-brain barrier and damage to the brain tissue.
  • BBB Blood-Brain Barrier
  • the current therapeutic drugs are only used to control or slow down the symptoms of neurodegenerative diseases in the brain, and can not completely cure this type of disease, and long-term use of drugs can cause side effects such as nausea and vomiting, diarrhea, lethargy, hallucinations.
  • the present invention provides a supersonic stimulation helmet for regulating brain endogenous neurotrophic factor or neurodegenerative disease-related protein expression (expression), including: a body, which can be worn on a patient's head.
  • the body has a forehead head circumference adjusting button, a head head circumference adjusting button, a fixing bracket and a plurality of position adjusting buttons; and a plurality of ultrasonic probes detachably mounted on the body for generating ultrasonic waves, the super
  • the sound wave probe has a frequency adjustment button and an intensity adjustment button for respectively adjusting the output frequency and the output intensity of the ultrasonic probe, and the other ultrasonic parameters and the angle of the ultrasonic probe itself can also be adjusted; wherein the fixing bracket can be based on The patient's head is sized to adjust the length of the body, and the ultrasonic probe is coupled to the position adjustment knob of the body such that The ultrasonic probe is movable up, down, left, and right relative to the patient's head.
  • the number of the ultrasonic probes is 2-8. Preferably, the number of the ultrasonic probes is eight.
  • the body further has a wire fixing portion for fixing the wire of the ultrasonic probe.
  • the ultrasonic probe further includes a switch for activating or deactivating the ultrasonic probe.
  • the output frequency of the ultrasonic wave is 20K-10M Hz.
  • the output intensity (I SPTA ) of the ultrasonic wave is 1 mW/cm 2 -10 W/cm 2 .
  • Another aspect of the present invention provides a method for regulating expression of a protein related to endogenous neurotrophic factor or neurodegenerative disease in a brain, comprising: placing a supersonic stimulation helmet of the present invention on an individual; adjusting the ultrasonic stimulation helmet Ultrasonic probe parameters to increase or decrease the expression levels of endogenous neurotrophic factors or neurodegenerative disease-associated proteins in the brain of an individual.
  • the regulation comprises an increase or decrease.
  • the parameter comprises other parameters such as output intensity (I SPTA ), output frequency or action time.
  • the output intensity is from 1 mW/cm 2 to 1 W/cm 2
  • the output frequency is from 20 K to 10 M Hz
  • the action time is from 30 seconds to 60 minutes.
  • the brain endogenous neurotrophic factor is selected from the group consisting of Brain-derived neurotrophic factor (BDNF) and Glial cell-derived neurotrophic factor (GDNF).
  • BDNF Brain-derived neurotrophic factor
  • GDNF Glial cell-derived neurotrophic factor
  • VEGF Vascular Endothelial Growth Factor
  • the neurodegenerative disease-associated protein is selected from one or more of TrkB, beta-amyloid or acetyl coenzyme A.
  • 1A is a front elevational view of an ultrasonic stimulation helmet of the present invention comprising two ultrasonic probes.
  • Figure 1B is a side elevational view of the ultrasonic stimulation helmet of the present invention comprising two ultrasonic probes.
  • FIG. 2 is a schematic view of the ultrasonic stimulation helmet of the present invention worn on a patient's head.
  • Figure 3A is a left side view of the position of eight ultrasonic probes of the helmet of the present invention.
  • Figure 3B is a schematic side elevational view of the position of eight ultrasonic probes of the helmet of the present invention.
  • Figure 4A shows the effect of ultrasound stimulation on the production of BDNF by brain astrocytes.
  • Figure 4B shows the effect of ultrasound stimulation on the production of GDNF by brain astrocytes.
  • Figure 4C shows the effect of ultrasound stimulation on the production of VEGF by brain astrocytes.
  • Figure 5A shows the effect of ultrasound on the expression of BDNF in the brain at different times after stimulation of brain astrocyte cells.
  • Figure 5B shows the effect of ultrasound on the expression of c-Fos in the brain at different times after stimulation of brain astrocyte cells.
  • Figure 6 shows the effect of ultrasound stimulation on intracellular calcium concentration in brain cells.
  • Figure 7 shows the effect of ultrasound stimulation on the expression of TrkB phosphorylation in brain cells.
  • Figure 8A shows the effect of ultrasound stimulation on the expression of beta-amyloid.
  • Figure 8B shows the effect of ultrasound stimulation on the expression of acetyl coenzyme A.
  • Figure 9A shows the results of the transmission latency of mice in different situations.
  • Figure 9B shows the results of Aquisition latency and Retention latency for mice in different situations.
  • Figure 10 shows the results of hematoxylin-eosin staining of mice in different conditions.
  • Figure 11A shows the effect of different ultrasound application days on BDNF expression.
  • Figure 11B shows the effect of different ultrasonic application days on GDNF expression.
  • Figure 11C shows the effect of different days of ultrasound on the expression of VEGF.
  • the ultrasonic stimulation helmet 100 of the present invention can be used for regulating the expression amount (expression amount) of a brain endogenous neurotrophic factor or a neurodegenerative disease-related protein.
  • the "neurotrophic factor” in the present invention includes Brain-derived neurotrophic factor (BDNF), Glial cell-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (Vascular endothelial). Growth factor, VEGF) or c-fos protein.
  • BDNF Brain-derived neurotrophic factor
  • GDNF Glial cell-derived neurotrophic factor
  • Vascular endothelial growth factor Vascular endothelial growth factor
  • Growth factor VEGF
  • c-fos protein c-fos protein
  • the "neurodegenerative disease-associated protein” described in the present invention comprises TrkB, beta-amyloid or acetyl coenzyme A.
  • the “modulation” as used in the present invention includes an increase or decrease in the expression level of a brain endogenous neurotrophic factor or a neurodegenerative disease-related protein.
  • the ultrasonic stimulation helmet 100 of the present invention comprises: a body 1 that can be worn on a patient's head (Fig. 2); and a plurality of ultrasonic probes 2 that are detachably mounted on the body 1.
  • the body 1 has: a wire fixing portion 11 for fixing the wire of the ultrasonic probe 2; the forehead head circumference adjusting button 12 can be adjusted according to the size of the patient's head circumference; the head head circumference adjusting button 13 is matched with the The forehead head circumference adjustment knob 12 is adjusted so that the ultrasonic stimulation helmet 100 can be fixed to the patient's head through the design of the forehead support to avoid the ultrasonic stimulation helmet 100 sliding; the fixing bracket 14 can be based on the patient's head The length of the body 1 is adjusted; and a plurality of position adjustment knobs 15 are connected to the ultrasonic probe 2, so that the ultrasonic probe 2 can move up, down, left, and right with respect to the patient's head.
  • the body 1 is made of plastic hardware and metal brackets, and a cushion is used on the inner side to reduce the interference of the ultrasonic stimuli on the helmet 100 and the patient's head.
  • the ultrasonic stimulation helmet 100 of the present invention may comprise 2-8 ultrasonic probes 2, the position of which is placed, 3A, 3B, trans-orbital 21, frontal-temporal cortex 22, temporal window 23, sub-mandibular 24, and lower pillow (sub) relative to the patient's head. -occipital) 25.
  • Figures 1A, 1B show only two ultrasonic probes 2, which are placed in a temporal window 23 relative to the patient's head (as shown in Figure 2).
  • Ultrasonic probes 2 each incorporating a piezoelectric piece (not shown) for generating ultrasonic waves, each having a switch (not shown), a frequency adjustment button (not shown), and an intensity adjustment button (Fig. Displayed, wherein the switch can individually activate or deactivate the ultrasonic probe 2, so that the ultrasonic stimulation helmet 100 of the present invention can apply ultrasonic waves at a desired treatment position according to the symptoms of different patients.
  • the frequency adjustment button and the intensity adjustment button are used to separately adjust the output frequency and output intensity of the ultrasonic probe 2, and other ultrasonic parameters can also be adjusted, and the ultrasonic probe 2 itself can be adjusted to the required application.
  • the angle of the hitting so when the ultrasonic probe 2 is placed at different positions, different output frequencies and output intensities can be used together, so that the ultrasonic stimulating helmet 100 of the present invention has a nerve nourishing factor that simultaneously increases a certain part of the brain. And reduce the efficacy of nerve nourishment factors in another part of the brain.
  • the parameter of the ultrasonic probe 2 is set to have a lower applied energy, wherein the output intensity (I SPTA ) is 1 mW/cm 2-1 W/cm 2 and the output frequency is 20K-10 MHz, so during the treatment,
  • the ultrasonic waves applied by each ultrasonic probe 2 do not increase or decrease the neurotrophic factor, calcium ion or TrkB content of the path, but the content of neurotrophic factor, calcium ion or TrkB in the ultrasonic focusing region. Can increase or decrease.
  • the ultrasonic probe 2 has both detection and treatment effects, so that when the amount of neurotrophic factor, calcium ion or TrkB in the brain cells of the patient is detected to be excessive or too small, the ultrasonic probe can be changed in real time. Parameters such as frequency, intensity and duration of action are beneficial for the treatment of patients.
  • Example 1 Effect of ultrasonic stimulation on endogenous neurotrophic factors in the brain
  • the left and right hippocampus of the Sprague-Dawley (SD) male rats were continuously subjected to a low-intensity pulsed ultrasonic wave with an output frequency of 0.3-1.0 MHz and an output intensity (I SPTA ) of 10-720 mW/cm 2 for seven days (experimental group). Each time the application time was 15 minutes, the SD male rats were sacrificed seven days later, and the expression levels of BDNF, GDNF and VEGF in the brain of SD male rats were observed by Western blotting. The results are shown in Figures 4A, 4B and 4C. It is shown that the control group is the hippocampus of the left and right sides of the SD male mouse which is not subjected to low-intensity pulsed ultrasonic waves.
  • SD rats ie, experimental group
  • brain endogenous neurotrophic factors including BDNF (Fig. 4A) and GDNF (Fig. 4B)
  • BDNF Fig. 4A
  • GDNF Fig. 4B
  • VEGF Fig. 4C
  • BDNF and c-Fos were applied to rat stellate cell RBACs (CTX TNA2) several times (experimental group).
  • the application time was 15 minutes, and the protein expression of BDNF and c-Fos was measured by Western blotting before the application (ie, the control group) and the 4, 8, 12, and 24 hours after the application.
  • BDNF Fig. 5A
  • c-Fos Fig. 5B
  • Low-intensity pulsed ultrasonic waves with an output frequency of 0.3-1.0 MHz and an output intensity (I SPTA ) of 10-720 mW/cm 2 were applied to rat stellate cell RBACs (CTX TNA2) several times (experimental group), each time.
  • the application time was 5 minutes, and the intracellular calcium ion concentration was measured before the application (ie, the control group) and the Western blotting at 0, 30, 60, and 120 seconds after the application.
  • the calcium ion concentration in the cells of the experimental group increased as the time of the ultrasonic application was increased as compared with the control group.
  • Example 4 Effect of ultrasound stimulation on the expression of proteins related to neurodegenerative diseases
  • the SD male rats were divided into 4 groups: control group, ultrasonic group, aluminum chloride group and experimental group.
  • the control group was not applied with low-intensity pulsed ultrasonic wave and fed with water; the ultrasonic group was output frequency 0.3. -1.0MHz MHz, output intensity (I SPTA ) 10-720mW/cm 2 low-intensity pulsed ultrasonic wave for 49 days; aluminum chloride group for 0-7 days without any treatment, then 8-49 Continuous feeding of 100mg/kg aluminum chloride in the day; the experimental group also applied a low-intensity pulsed ultrasonic wave with an output frequency of 0.3-1.0MHz MHz and an output intensity (I SPTA ) of 10-720mW/cm 2 for 49 days.
  • the SD male rats of the aluminum chloride group had higher expression levels of amyloid (A ⁇ 1-42) than the control group, while in the experimental group, due to the application of low-intensity pulsed ultrasonic waves, The expression level of amyloid (A ⁇ 1-42) was significantly decreased.
  • the acetylcholinesterase activity of the forebrain of SD rats in the aluminum chloride group was significantly increased (0.07 ⁇ 0.01 to 0.21 ⁇ 0.01; p ⁇ 0.05), as shown in Fig. 8B.
  • SD male rats had a significant decrease in acetylcholinesterase activity in the forebrain due to low-intensity pulsed ultrasound (0.21 ⁇ 0.01 to 0.16 ⁇ 0.01; p ⁇ 0.05).
  • the results show that low-intensity pulsed ultrasound can suppress the expression of proteins associated with neurodegenerative diseases.
  • SD male rats were divided into 4 groups: control group, ultrasonic group, vascular type dementia group and experimental group.
  • control group the difference between the control group and the vascular dementia group was only in the control group, and the bilateral carotid arteries were not blocked.
  • vascular dementia group the bilateral carotid arteries were permanently blocked during the operation; the ultrasound group and
  • experimental group the ultrasound was first administered for 14 days after the 14-day waiting period. The ultrasound group did not do any treatment before the onset period, while the experimental group was implemented on both sides. Carotid artery occlusion surgery.
  • the four groups of SD male rats were placed in the elevated plus maze test, and their transmission latency was measured. The results are shown in Fig. 9A in the control group.
  • the transmission delay time of the SD male rats decreased significantly on the 29th day.
  • the SD male mice of the vascular dementia group had no significant difference in the transmission delay time on the 28th and 29th days.
  • the transmission delay time of the SD male mice stimulated with vascular dementia with low-intensity pulsed ultrasound was significantly shortened on the 29th day compared with the 28th day.
  • Fig. 10 The right column of Figure 10 is an enlarged view of the hippocampus back to the area indicated by the arrow in the left column.
  • the results showed that the SD male rats in the vascular dementia group were significantly damaged and sparsely distributed.
  • the damaged nerve cells were significantly improved, and the distribution was similar to that of the control group.
  • Example 6 Effect of different ultrasonic application days on the expression of endogenous neurotrophic factor protein
  • the hippocampus of Sprague-Dawley (SD) male rats were repeatedly subjected to low-intensity pulsed ultrasonic waves with an output frequency of 0.3-1.0 MHz and an output intensity (I SPTA ) of 10-720 mW/cm 2 for one, three, five and seven days respectively.
  • I SPTA output intensity
  • each time the application time was 15 minutes the SD male rats were sacrificed after seven days, and the expression levels of BDNF, GDNF and VEGF in the brain of SD male rats were observed by Western blotting.
  • the results are shown in Fig. 11A. , 11B, 11C, the hippocampus of the SD male mouse in which the low-intensity pulsed ultrasonic wave was not applied was the control group.
  • the ultrasonic stimulating helmet and method provided by the present invention can be used for regulating brain endogenous neurotrophic factors and protein expression related to neurodegenerative diseases, thereby preventing and treating brain neurodegenerative diseases. efficacy.
  • the ultrasonic stimulating helmet of the present invention has a forehead head circumference adjusting button and a back head head adjusting button, so that it can adapt to the head circumference of different users, and is convenient for the user to directly adjust when wearing.

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Abstract

用于调控脑部内生性神经滋养因子或神经退化性疾病相关蛋白质表达的超音波刺激头盔（100），包括：一本体（1），具有前额头围调整钮（12）、后脑头围调整钮（13）、固定支架（14）及复数个位置调整钮（15）；以及复数个超音波探头（2），可拆地架设于本体上（1），超音波探头（2）具有频率调整钮及强度调整钮，用以分别调控该超音波探头（2）的输出频率及输出强度，而其他超音波参数及该超音波探头（2）本身的角度也可以调整；其中所述固定支架（14）可依据患者头部大小调整所述本体（1）的长度，且超音波探头（2）与所述位置调整钮（15）连接，使超音波探头（2）可相对于患者头部上下左右的移动。

Description

超音波刺激头盔 技术领域
本发明提供一种超音波刺激头盔，特别是一种用来调控脑部内生性神经滋养因子以及与神经退化性疾病相关蛋白质表达量的超音波刺激头盔，以达到预防与治疗神经退化性等脑部疾病。
背景技术
脑部神经退化性疾病，包括阿兹海默症、忧郁症或帕金森氏症等，目前的治疗方法主要是以侵入性方式植入药物、神经生长因子或干细胞到脑部区域以促进脑神经细胞再生，达到治疗脑部神经退化性疾病策略。但由于此侵入性方式需要开启血脑障壁(Blood–Brain Barrier，BBB)，因此有血脑屏障被破坏、脑组织损伤等疑虑。
此外，目前的治疗药物亦仅用于控制或减缓脑部神经退化性疾病的症状，并无法完全治愈此类型疾病，且长期服用药物会导致患者产生恶心呕吐、腹泻、嗜睡、幻觉等副作用。
发明内容
有鉴于此，本发明提供一种超音波刺激头盔，用以调控脑部内生性神经滋养因子或神经退化性疾病相关蛋白质表现量(表达量)，包括：本体，可穿戴于患者头部，所述本体具有前额头围调整钮、后脑头围调整钮、固定支架及复数个位置调整钮；以及复数个超音波探头，可拆地架设于所述本体上，用以产生超音波，所述超音波探头具有频率调整钮及强度调整钮，用以分别调控超音波探头的输出频率及输出强度，而其他超音波参数及所述超音波探头本身的角度也可以调整；其中所述固定支架可依据患者头部大小调整本体的长度，且该超音波探头与该本体之该位置调整钮连接，使 所述超音波探头可相对于患者头部上下左右的移动。
在本发明实施例中，其中所述超音波探头数目为2-8个。较佳的，所述超音波探头数目为8个。
在本发明实施例中，其中所述本体进一步具有导线固定处，用以固定该超音波探头的导线。
在本发明实施例中，其中的、所述超音波探头进一步包含开关，用以启动或关闭超音波探头。
在本发明实施例中，其中所述超音波的输出频率为20K-10M Hz。
在本发明实施例中，其中所述超音波的输出强度(ISPTA)为1mW/cm2-10W/cm2。
本发明另一方面提供一种调控脑部内生性神经滋养因子或神经退化性疾病相关蛋白质表达量的方法，包括：将本发明的超音波刺激头盔置于个体上；调整所述超音波刺激头盔的超音波探头的参数，以增加或减少个体脑内的内生性神经滋养因子或神经退化性疾病相关蛋白质的表达量。
在本发明实施例中，所述调控是包含增加或减少。
在本发明实施例中，其中所述参数包含输出强度(ISPTA)、输出频率或作用时间等其他参数。较佳地，所述输出强度为1mW/cm2至1W/cm2，所述输出频率为20K-10M Hz，所述作用时间为30秒-60分钟。
在本发明实施例中，其中所述脑部内生性神经滋养因子选自由脑衍生神经滋养因子(Brain-derived neurotrophic factor，BDNF)、神经胶衍生神经滋养因子(Glial cell-derived neurotrophic factor，GDNF)、血管内皮生长因子(Vascular endothelial growth factor，VEGF)或c-fos蛋白所中的一种或多种。
在本发明实施例中，其中所述神经退化性疾病相关蛋白质选自由TrkB、乙型-淀粉样蛋白(β-amyloid)或乙酰辅酶A(acetyl coenzyme A)中的一种或多种。
附图说明
图1A是本发明含两个超音波探头的超音波刺激头盔的正面示意图。
图1B是本发明含两个超音波探头的超音波刺激头盔的侧面示意图。
图2是本发明超音波刺激头盔穿戴于患者头部的示意图。
图3A为本发明头盔的8个超音波探头的位置的左侧面示意图；
图3B为本发明头盔的8个超音波探头的位置的右侧面示意图。
图4A为超音波刺激对大脑星状胶细胞产生BDNF的影响。
图4B为超音波刺激对大脑星状胶细胞产生GDNF的影响。
图4C为超音波刺激对大脑星状胶细胞产生VEGF的影响。
图5A为超音波刺激大脑星状胶细胞后不同的时间对脑内BDNF表达量的影响。
图5B为超音波刺激大脑星状胶细胞后不同的时间对脑内c-Fos表达量的影响。
图6为超音波刺激对脑细胞内钙离子浓度的影响。
图7为超音波刺激对脑细胞内TrkB磷酸化表达的影响。
图8A为超音波刺激对乙型-淀粉样蛋白(β-amyloid)表达的影响。
图8B为超音波刺激对乙酰辅酶A(acetyl coenzyme A)表达的影响。
图9A为不同状况下的老鼠其传输延迟时间(Transfer latency)的表现结果。
图9B为不同状况下的老鼠其取得延迟时间(Aquisition latency)、保留延迟时间(Retention latency)的表现结果。
图10为不同状况下的老鼠的苏木素-伊红组织染色切片结果。
图11A为不同的超音波施打天数对BDNF表达的影响。
图11B为不同的超音波施打天数对GDNF表达的影响。
图11C为不同的超音波施打天数对VEGF表达的影响。
附图标记说明
1、本体；11、导线固定处；12、前额头围调整钮；13、后脑头围调整 钮；14、固定支架；15、位置调整钮；2、超音波探头；21、眼窝；22、额颞皮层；23、太阳穴；24、下颚；25、下枕；100、超音波刺激头盔。
具体实施方式
本发明的超音波刺激头盔100，可用于调控脑部内生性神经滋养因子或神经退化性疾病相关蛋白质的表现量(表达量)。
本发明中所述“神经滋养因子”包含脑衍生神经滋养因子(Brain-derived neurotrophic factor，BDNF)、神经胶衍生神经滋养因子(Glial cell-derived neurotrophic factor，GDNF)、血管内皮生长因子(Vascular endothelial growth factor，VEGF)或c-fos蛋白。
本发明中所述“神经退化性疾病相关蛋白质”包含TrkB、乙型-淀粉样蛋白(β-amyloid)或乙酰辅酶A(acetyl coenzyme A)。
本发明中所述“调控”包含增加或减少脑部内生性神经滋养因子或神经退化性疾病相关蛋白质的表达量。
如图1A、1B，本发明超音波刺激头盔100包括：本体1，可穿戴于患者头部(图2)；以及复数个超音波探头2，可拆地架设于本体1上。
图1A、1B，本体1具有：导线固定处11，用以固定超音波探头2的导线；前额头围调整钮12，可依据患者的头围大小作调整；后脑头围调整钮13，配合所述前额头围调整钮12进行调整，使超音波刺激头盔100能透过此前额支撑的设计，固定于患者的头部，以避免超音波刺激头盔100滑动；固定支架14，可依据患者头部的大小调整本体1的长度；以及复数个位置调整钮15，与所述超音波探头2连接，因此所述超音波探头2可相对于患者头部上下左右的移动。此外，本体1的材质以塑料硬件及金属支架为主，其内侧使用软垫，以减少超音波刺激头盔100与患者头部的摩擦。
本发明超音波刺激头盔100，可包含2-8个超音波探头2，其摆放的位置， 如图3A、3B，相对于患者头部的眼窝(trans-orbital)21、额颞皮层(frontal-temporal cortex)22、太阳穴(temporal window)23、下颚(sub-mandibular)24及下枕(sub-occipital)25。图1A、1B仅显示出含有两个超音波探头2，且其摆放位置为相对于患者头部的太阳穴(temporal window)23(如图2所示)。
超音波探头2，每个内置一压电片(图中未显示)，用以产生超音波，并各自具有开关(图未显示)、频率调整钮(图未显示)以及强度调整钮(图未显示)，其中所述开关可以单独启动或关闭所述超音波探头2，使本发明超音波刺激头盔100能根据不同病人的症状，于所需治疗的位置施打超音波。此外，所述频率调整钮及所述强度调整钮是用以分别调控超音波探头2的输出频率及输出强度，而其他超音波参数也可以调整，且超音波探头2本身可调整至所需施打的角度，因此当所述超音波探头2置于不同位置时，可搭配使用不同的输出频率及输出强度，使本发明超音波刺激头盔100具有同时增加脑部某一部位的神经滋养因子，并减少脑部另一部位的神经滋养因子的功效。
其中，所述超音波探头2的参数设定为具有较低的施打能量，其中输出强度(ISPTA)为1mW/cm2-1W/cm2，输出频率为20K-10MHz，因此于治疗过程中，各超音波探头2施打出来的超音波，不会使其经过路径的神经滋养因子、钙离子或TrkB含量等增加或减少，但于超音波聚焦区域的神经滋养因子、钙离子或TrkB的含量能增加或减少。此外，所述超音波探头2同时具有侦测与治疗的功效，因此当侦测到患者脑细胞内的神经滋养因子、钙离子或TrkB含量过多或过少时，能实时改变所述超音波探头2的频率、强度及作用时间等参数，利于对患者进行治疗。
实施例
实施例一、超音波刺激对大脑产生内生性神经滋养因子的影响
将Sprague-Dawley(SD)公鼠的左右两边海马回以输出频率0.3-1.0MHz、 输出强度(ISPTA)10-720mW/cm2的低强度脉冲式超音波连续施打七天(实验组)，每次施打时间为15分钟，七天后牺牲SD公鼠，并以西方式点墨法(Western blotting)观察SD公鼠脑内BDNF、GDNF及VEGF的表达量，结果如图4A、4B、4C所示，其中对照组为未施打低强度脉冲式超音波的SD公鼠的左右两边海马回。
由试验结果可知，与对照组相比，以低强度脉冲式超音波刺激SD公鼠(即实验组)，可使其大脑内生性神经滋养因子，包括BDNF(图4A)、GDNF(图4B)及VEGF(图4C)的蛋白质表达量增加。
此外，将输出频率0.3-1.0MHz、输出强度(ISPTA)10-720mW/cm2的低强度脉冲式超音波施打于大鼠星状胶细胞RBACs(CTX TNA2)数次(实验组)，每次施打时间为15分钟，并于施打前(即对照组)与施打后4、8、12及24小时以西方式点墨法(Western blotting)测量BDNF及c-Fos的蛋白质表达量，结果如图5A、5B所示，BDNF(图5A)及c-Fos(图5B)在超音波刺激下，其蛋白质表达量皆较对照组高。
实施例二、超音波刺激对细胞内钙离子浓度的影响
将输出频率0.3-1.0MHz、输出强度(ISPTA)10-720mW/cm2的低强度脉冲式超音波施打于大鼠星状胶细胞RBACs(CTX TNA2)数次(实验组)，每次施打时间为5分钟，并于施打前(即对照组)与施打后0、30、60及120秒以西方式点墨法(Western blotting)测量细胞内钙离子浓度。
结果如图6所示，与对照组相比，实验组细胞内的钙离子浓度随着超音波施打时间的增加而增加。
实施例三、超音波刺激对细胞内TrkB磷酸化表现的影响
将输出频率0.3-1.0MHz、输出强度(ISPTA)10-720mW/cm2的低强度脉冲式超音波施打于大鼠星状胶细胞RBACs(CTX TNA2)数次(实验组)，每次施打时间为5分钟，并于施打前(即对照组)与施打后0.5、1、2及4小时以西方式点墨法(Western blotting)测量细胞内TrkB磷酸化表达量。
结果如图7所示，实验组细胞内TrkB磷酸化程度较对照组高，且磷酸 化的TrkB(p-TrkB)于超音波刺激后的4小时表达量最高。
实施例四、超音波刺激对神经退化性疾病相关蛋白质表现的影响
将SD公鼠分为4组即控制组、超音波组、氯化铝组及实验组，其中控制组为未施打低强度脉冲式超音波并以水喂食；超音波组是以输出频率0.3-1.0MHz MHz、输出强度(ISPTA)10-720mW/cm2的低强度脉冲式超音波连续施打49天；氯化铝组为第0-7天未经任何处理，之后第8-49天连续喂食100mg/kg氯化铝；实验组同样以输出频率0.3-1.0MHz MHz、输出强度(ISPTA)10-720mW/cm2的低强度脉冲式超音波连续施打49天，且于第8-49天喂食100mg/kg氯化铝。所有组别的SD公鼠于第49天执行完喂食或施打超音波后牺牲，并以西方式点墨法(Western blotting)测量SD公鼠皮质区(Cortex)及海马回的淀粉样蛋白(β-amyloid)及前脑的乙酰辅酶A(acetyl coenzyme A)的含量。
如图8A所示，氯化铝组的SD公鼠较控制组有较高的淀粉样蛋白(Aβ1-42)的表达量，而在实验组，因有施打低强度脉冲式超音波，其淀粉样蛋白(Aβ1-42)的表达量则明显下降。
此外，与控制组相比，氯化铝组的SD公鼠，其前脑的乙酰胆碱酯酶活性有显著增加(0.07±0.01to 0.21±0.01；p<0.05)，如图8B所示，在实验组中，SD公鼠因有施打低强度脉冲式超音波，其前脑的乙酰胆碱酯酶活性有显著减少(0.21±0.01to 0.16±0.01；p<0.05)。综合以上结果显示，低强度脉冲式超音波可抑制与神经退化性疾病相关的蛋白质的表达量。
实施例五、动物行为测试
将SD公鼠分为4组即控制组、超音波组、血管型失智症组及实验组。控制组和血管型失智症组差别在控制组只有动手术并没有将双侧颈动脉阻塞起来，而血管型失智症组则是在手术中将双侧颈动脉永久阻塞；超音波组和实验组，都是先经过十四天的发病等待期再连续施打十四天超音波，其中超音波组于发病等待期之前没有做任何处理，而实验组则是实施双侧 颈动脉阻塞手术。
于第28天及第29天时，将四组SD公鼠分别置于高架十字迷宫中(elevated plus maze test)，并分别测量其传输延迟时间(Transfer latency)，结果如第图9A，在控制组与超音波组中，SD公鼠的传输延迟时间于第29天均明显下降，相反的，血管型失智症组的SD公鼠，其第28天及第29天的传输延迟时间无明显差异；而在实验组中，以低强度脉冲式超音波刺激血管型失智症的SD公鼠后，其传输延迟时间在第29天明显较第28天缩短。
此外，将四组SD公鼠进行被动回避测试(Passive Avoidance Test)，结果如图9B所示，四组SD公鼠的取得延迟时间(Acquisition Latency)并无明显差异，但血管型失智症组的SD公鼠的保留延迟时间(Retention Latency)明显较低，然而以低强度脉冲式超音波刺激血管型失智症的SD公鼠(即实验组)，其保留延迟时间(Retention Latency)明显恢复至与控制组、超音波组四相同。
再者，将控制组、超音波组、血管型失智症组及实验组的SD公鼠的海马回进行苏木素-伊红组织染色(hematoxylin and eosin stain)，结果如图10、所示，其中图10右栏为左栏箭头处所指海马回一区的放大图。结果显示，血管型失智症组的SD公鼠，其神经细胞明显受损，并分布稀疏。然而在实验组中，以低强度脉冲式超音波刺激两周后，受损的神经细胞显著改善，且分布与控制组近似，较为集中。
实施例六、不同的超音波施打天数对内生性神经滋养因子蛋白质表现的影响
将Sprague-Dawley(SD)公鼠的海马回以输出频率0.3-1.0MHz、输出强度(ISPTA)10-720mW/cm2的低强度脉冲式超音波分别连续施打一、三、五、七天(实验组)，每次施打时间为15分钟，七天后牺牲SD公鼠，并以西方式点墨法(Western blotting)观察SD公鼠脑内BDNF、GDNF及VEGF的表达量，结果如图11A、11B、11C所示，其中未施打低强度脉冲式超音波的SD公鼠的海马回为控制组。
由试验结果可知，与控制组相比，以低强度脉冲式超音波刺激SD公鼠， 可使其大脑内生性神经滋养因子，包括BDNF(图11A)、GDNF(图11B)及VEGF(图11C)的蛋白质表达量随着超音波施打天数的增加而增加。
综合以上说明，本发明所提供的超音波刺激头盔及方法，可用于调控脑部内生性神经滋养因子以及与神经退化性疾病相关蛋白质的表达量，因此具有预防与治疗脑部神经退化性疾病的功效。此外，本发明的超音波刺激头盔设计具有前额头围调整钮及后脑头围调整钮，使其能适应不同使用者的头围大小，并于穿戴时方便使用者直接调整。

Claims (13)

  1. 一种用于调控脑部内生性神经滋养因子或神经退化性疾病相关蛋白质表达量的超音波刺激头盔，其特征是，包括：
    本体，可穿戴于患者头部，所述本体具有前额头围调整钮、后脑头围调整钮、固定支架及复数个位置调整钮；以及
    复数个超音波探头，可拆地架设于所述本体上，用以产生超音波，所述超音波探头具有频率调整钮及强度调整钮，分别用以调控所述超音波探头的输出频率及输出强度，而其他超音波参数及所述超音波探头本身的角度也可以调整；
    其中所述固定支架可依据患者头部大小调整所述本体的长度，且该超音波探头与该本体之该位置调整钮连接，使所述超音波探头可相对于该患者头部上下左右的移动。
  2. 如权利要求1所述的超音波刺激头盔，其特征是，所述超音波探头数目的个数为2-8个。
  3. 如权利要求1所述的超音波刺激头盔，其特征是，所述本体进一步具有导线固定处，用以固定所述超音波探头的导线。
  4. 如权利要求1所述的超音波刺激头盔，其特征是，所述超音波探头进一步包含开关，用以启动或关闭所述超音波探头。
  5. 如权利要求1所述的超音波刺激头盔，其特征是，所述超音波的输出频率为20K-10M Hz。
  6. 如权利要求1所述的超音波刺激头盔，其特征是，所述超音波的输出强 度(ISPTA)为1mW/cm2-10W/cm2。
  7. 一种用于调控脑部内生性神经滋养因子或神经退化性疾病相关蛋白质表达量的方法，包括：
    1)将如权利要求1所述的超音波刺激头盔置于个体上；
    2)调整所述超音波刺激头盔的超音波探头的参数，以增加或减少所述个体脑内的内生性神经滋养因子或神经退化性疾病相关蛋白质的表达量。
  8. 如权利要求7所述的方法，其特征是，步骤2)中所述调整的超音波探头的参数包含输出强度(ISPTA)、输出频率或作用时间。
  9. 如权利要求8所述的方法，其特征是，所述输出强度为1mW/cm2至1W/cm2。
  10. 如权利要求8所述的方法，其特征是，所述输出频率为20K-10M Hz。
  11. 如权利要求8所述的方法，其特征是，所述作用时间为30秒-60分钟。
  12. 如权利要求7所述的方法，其特征是，所述内生性神经滋养因子选自由脑衍生神经滋养因子(Brain-derived neurotrophic factor，BDNF)、神经胶衍生神经滋养因子(Glial cell-derived neurotrophic factor，GDNF)、血管内皮生长因子(Vascular endothelial growth factor，VEGF)或c-fos蛋白中的一种或多种。
  13. 如权利要求7所述的方法，其特征是，所述神经退化性疾病相关蛋白质选自由TrkB、乙型-淀粉样蛋白(β-amyloid)或乙酰辅酶A(acetyl coenzyme A)中的一种或多种。
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