WO2023134322A1 - 用于传递可变脉冲的装置 - Google Patents

用于传递可变脉冲的装置 Download PDF

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WO2023134322A1
WO2023134322A1 PCT/CN2022/135868 CN2022135868W WO2023134322A1 WO 2023134322 A1 WO2023134322 A1 WO 2023134322A1 CN 2022135868 W CN2022135868 W CN 2022135868W WO 2023134322 A1 WO2023134322 A1 WO 2023134322A1
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rtms
variable
pulse
variable pulse
determined
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PCT/CN2022/135868
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English (en)
French (fr)
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何康伟
金兆赫
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凡尼塔斯研究中心股份有限公司
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Priority to AU2022433364A priority Critical patent/AU2022433364A1/en
Priority to IL311406A priority patent/IL311406A/en
Priority to US18/705,127 priority patent/US20240299763A1/en
Priority to JP2024517512A priority patent/JP2024531806A/ja
Priority to CA3235934A priority patent/CA3235934A1/en
Priority to EP22919955.9A priority patent/EP4395298A1/en
Priority to KR1020247009779A priority patent/KR20240050398A/ko
Publication of WO2023134322A1 publication Critical patent/WO2023134322A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/02—Magnetotherapy using magnetic fields produced by coils, including single turn loops or electromagnets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/02—Details
    • A61N1/04—Electrodes
    • A61N1/0404—Electrodes for external use
    • A61N1/0408—Use-related aspects
    • A61N1/0456—Specially adapted for transcutaneous electrical nerve stimulation [TENS]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/36014—External stimulators, e.g. with patch electrodes
    • A61N1/3603—Control systems
    • A61N1/36034—Control systems specified by the stimulation parameters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/004—Magnetotherapy specially adapted for a specific therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/004—Magnetotherapy specially adapted for a specific therapy
    • A61N2/006—Magnetotherapy specially adapted for a specific therapy for magnetic stimulation of nerve tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N2/00—Magnetotherapy
    • A61N2/004—Magnetotherapy specially adapted for a specific therapy
    • A61N2/008—Magnetotherapy specially adapted for a specific therapy for pain treatment or analgesia
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04N—PICTORIAL COMMUNICATION, e.g. TELEVISION
    • H04N5/00—Details of television systems
    • H04N5/30—Transforming light or analogous information into electric information
    • H04N5/33—Transforming infrared radiation

Definitions

  • the present invention relates to a device that uses repetitive transcranial magnetic stimulation (rTMS) to regulate brain activity in mammals.
  • the rTMS with variable pulse intervals is given to a time sufficient to regulate brain activity to achieve improvement. Purpose of physiological condition or clinical condition.
  • the pulse interval of rTMS ranged from 66.00 milliseconds (ms) to 200.00 milliseconds.
  • the present invention relates to electrical stimulation of the brain by administering variable electrical pulse intervals at times sufficient to modulate brain activity to achieve improvements in physiological or clinical conditions. Variable EMP intervals are delivered in a random fashion.
  • the setting of the pulse interval time in the aforementioned magnetic stimulation and electrical stimulation does not depend on or be derived from electroencephalography (Electroencephalography, EEG), other mammalian biometric data (biometric data).
  • EEG Electroencephalography
  • biometric data biometric data
  • the present invention also includes electromagnetic stimulation devices for providing variable pulse intervals of electrical or magnetic stimulation, preferably the variable pulses are not based on the patient's EEG data, but are derived from EEG data or other biometric measurements.
  • Repetitive transcranial magnetic stimulation has been used to treat many psychological and medical conditions, such as major depressive disorder, Parkinson's disease, post-traumatic stress disorder, Alzheimer's disease, autism spectrum disorder (ASD), thinking Sensory disorders, pain management, etc.
  • US Patent Publication No. 2009/0082690 disclosed a treatment protocol using rTMS in which the magnetic field output of rTMS is adjusted according to the patient's EEG natural frequency in an attempt to change the patient's natural EEG frequency.
  • US Pat. No. 9,308,385 uses a different approach to manage rTMS, which is based on the frequency of a biological metric, or harmonics of a characteristic metric.
  • rTMS therapy has consisted of delivering a single frequency at a preset intensity as electromagnetic stimulation.
  • the present invention provides a novel rTMS delivery system that delivers rTMS or electrical stimulation with variable pulse intervals, the probability of the pulse intervals being dependent on a given type of noise function, Examples include Gaussian, pink noise, or white noise.
  • the power/intensity of electromagnetic stimulation can also be varied.
  • electrical and magnetic stimulation devices are programmed to deliver variable pulse intervals of magnetic or electrical stimulation.
  • the present invention offers significant advantages over prior art techniques that use single frequency magnetic or electrical stimulation delivery. Existing technologies provide a fixed frequency of stimulation, or require (a) the patient's EEG or ECG; and (b) analysis of the biometric data for a clearer detection pattern, followed by subjective interpretation of the data.
  • the device for regulating the brain activity of mammals is realized by administering repetitive transcranial magnetic stimulation (rTMS) with pulse intervals varying between 66.00 milliseconds (ms) and 200.00 milliseconds to mammals.
  • rTMS repetitive transcranial magnetic stimulation
  • the device could also be used to administer variable electrical stimulation to the brain.
  • the device is effective for treating brain dysfunction diseases or physical conditions.
  • the variable pulse intervals used for magnetic and electrical stimulation are generated by a preprogrammed noise generator, such as Gaussian, pink noise, or white noise, and truncated to match the rhythm of brain activity.
  • This setup does not use EEG data, is derived from EEG data, or other biometrics (eg, heart rate, respiration rate, or the like).
  • the physiological and medical conditions that can be improved by modulating brain activity according to the present invention can be any condition in which abnormal brain activity creates a specific condition.
  • the diseases to be treated include but are not limited to autism spectrum disorder (ASD), Alzheimer's disease (Alzheimer's Disease, AD), post-traumatic stress disorder (Post Traumatic Stress Disorder, PTSD), traumatic brain injury (traumatic brain injury, TBI), memory impairment, depression, pain, addiction, substance use disorder (substance use disorder, SUD), obsessive-compulsive neurosis (Obsessive Compulsive disorders, OCD), anxiety disorder, Parkinson's disease, High blood pressure, libido dysfunction, abnormal motor function, short stature in children, stress, obesity, sleep disorders, eating disorders, inattention, language disorders, mental retardation, cognitive impairment, attention deficit hyperactivity disorder (Attention Deficit Hyperactivity Disorders, ADHD), schizophrenia, lethargy, bipolar disorders, tinnitus, fibromyalgia, chronic Lyme disease, rheuma
  • rTMS repetitive transcranial magnetic stimulation
  • the aforementioned improvement refers to the improvement observed both from the clinical assessment of the patient and the patient's healthcare professional.
  • the power or intensity of the magnetic stimulation is typically below the patient's motor threshold, preferably 50% to 90% of the patient's motor threshold, but may be higher or lower in intensity.
  • the TMS involved in the present invention is also suitable for electrical stimulation of the brain, for example, through deep brain stimulation (deep brain stimulation), or transcutaneous electrical stimulation (such as Alpha-Stim cranial electrotherapy stimulation (CES)) device .
  • the brain activity of mammals is adjusted by administering electrical stimulation with variable electrical pulse intervals to mammals, the duration of which is sufficient to regulate brain activity, resulting in an improvement in its physiological or clinical condition.
  • electrical stimulation is performed in a random fashion.
  • the pulse intervals of the random variable are spaced time periods according to a Gaussian distribution having a determined peak and established cut-off point. This embodiment applies to the treatment of multiple frequencies/multiple regions of specific brain waves associated with specific brain dysfunction diseases or physical conditions described herein.
  • Figure 1 is an example of a patient being treated with an rTMS device.
  • Figure 2 is an example of a patient being treated with an electrical stimulation device.
  • TTL Transistor-transtor-logic
  • Figure 4 is a Gaussian distribution probability map.
  • the term "mammal” includes any mammal, especially a human, and non-human mammals include non-human primates, zoo animals, companion animals (dogs, cats) and performance animals (eg, racehorses and breeding animals). Any reference to “human” herein applies to other mammals exhibiting the same physiological or medical condition. Any reference to a “patient” herein is applicable to any mammal, preferably a human being, who may experience the particular condition of the referenced patient.
  • the terms "variable pulsed interval, random pulsed interval, variable pulsed interval, random variable pulsed interval” mean that magnetic stimulation is delivered at different time intervals over time.
  • variable time intervals are generated completely randomly by a software program, and the probability of each pulse included in the treatment protocol is weighted by a Gaussian distribution with a given mean and standard deviation.
  • Random pulse intervals can also be based on white noise functions or/and pink noise functions.
  • pre-programmed white noise generators and pink noise generators can be used to determine random pulse intervals.
  • a patient whose brain activity is at least in part responsible for a physical or medical condition has been diagnosed by administering TMS pulses varying between 66.00 milliseconds (ms) and 200.00 ms for treatment.
  • the computer program is used to generate TTL pulses or other triggers, and then through the TMS device to generate variable pulse intervals, preferably random pulse intervals.
  • the transcranial magnetic stimulation is delivered in the form of repetitive transcranial magnetic stimulation (rTMS).
  • rTMS is administered to patients at variable pulse intervals, long enough to modulate brain activity to improve physiological or clinical conditions at the time of treatment.
  • randomly variable pulse intervals are applied to rTMS manipulations of sufficient duration to modulate brain activity to improve physiological or clinical conditions.
  • the treatment is given daily for one week, after which time the patient's progress will be reassessed.
  • the exact timing of the repetitive pulses is not critical.
  • the variability in pulse intervals can be predetermined by the healthcare professional choosing a particular pulse interval that defines a therapy. However, it is best to program the rTMS device to provide a random pulse interval of 66.00ms to 200.00ms. Training in six-second pulses per minute for 30 minutes is a good way to generate a 30-minute treatment session.
  • the maximum intensity of the magnetic pulses is usually set at or below the patient's motor threshold, but can be managed at the patient's motor threshold.
  • the peak pulse power/intensity of rTMS is preferably set at approximately 50-90% of the patient's motor threshold. Typically, the power/intensity may be 0.1-99% of motor threshold, 10-90% of motor threshold, or 40-85% of motor threshold.
  • variable pulse intervals are spaced apart continuous time intervals according to a Gaussian distribution with a defined peak value and predetermined cutoffs at both ends of the continuous time intervals. point.
  • This embodiment can be used to treat specific brain wave frequencies/regions associated with specific brain dysfunction diseases or medical conditions.
  • the value of the peak of the Gaussian distribution and the cutoff points on either side of the peak are not critical to the practice of the invention and will be based on various factors considered by the patient's healthcare professional. For example, when treating diseases or diseases related to ⁇ -brain wave dysfunction, the peak value of the pulse interval is 100.00ms, the cut-off point is 125.00ms and 83.00ms, and the pulse intervals of each sequence are randomly generated within this time interval.
  • FIG. 4 an example of the time interval map presented in it presents a Gaussian distribution, and the X-axis of the map shows the time interval (in milliseconds), and the Y-axis shows the relationship of probability.
  • the center line C2 represents the peak of the Gaussian distribution. Cutoffs C1 and C3 represent cutoffs on either side of C2.
  • the application revealed by the Gaussian distribution shown in Fig. 4 is that when C1 is 125.00ms, C2 is 100.00ms, and C3 is 83.00ms, that is, the time interval range of the random pulse interval is between 83.00ms and 125.00ms.
  • the distance between C1 and C2 on the X-axis is the same as the distance between C2 and C3 on the X-axis
  • the axes are equidistant.
  • the Gaussian-distributed value of the random pulse interval refers to the number of times it occurs per second.
  • the rTMS treatment of the present invention is carried out by using the existing treatment plan through the magnetic coil.
  • the timing of actual magnetic stimulation within the set time interval will vary according to each clinical presentation.
  • the magnetic stimulation administered is optimally performed in rTMS sessions (rTMS session) for 6 consecutive seconds per minute. Sessions can last from 15 to 60 minutes, with 30 minutes being optimal.
  • the magnetic coil may be placed near or against the patient's head, preferably near the frontal lobe.
  • Graph in Table 1 listing the random magnetic pulse intervals during the 30 min treatment period.
  • the left hand column (downwards) corresponds to the training number, i.e. there is a 6 second treatment every minute.
  • the horizontal row corresponds to the start time in milliseconds (ms) of 127 ms between pulses from each particular training session (ie T1, T2, T3...etc).
  • T1 is triggered 127ms after the initial pulse
  • T2 is triggered 95ms after T1
  • T3 is triggered 70ms after T2, and so on for the horizontal row of training #1.
  • Training #1 lasted 6 seconds.
  • each 6-minute training burst is newly randomly generated.
  • training #2 starts the same way.
  • T11 to T43 are omitted, but they are random pulses.
  • Figure 3 shows the variability of TLL pulses during a 6 second treatment period in accordance with the present invention, in contrast to a scheme employing a single frequency where all pulses would be equidistant from each other within a 6 second treatment period.
  • FIG. 1 shows a magnetic stimulation device of the present invention, including a coil 201 , a power supply 202 and a computer 203 for controlling stimulation parameters of variable pulses.
  • the power supply 202 and the computer 203 can be manufactured as a single unit control module (not shown). In general, the control module controls the TTL pulses and the delivery of magnetic stimulation by the coil 201 .
  • the control module controls the TTL pulses and the delivery of magnetic stimulation by the coil 201 .
  • the power supply 202 is turned on, current passes through the coil to generate a magnetic field, and the computer 203 is programmed to drive the coil 201 to generate the variable pulses described in the present invention.
  • the encapsulated magnetic coil assembly is positioned on or adjacent to the head for therapy.
  • An electrical stimulation device comprising two or more electrode pads (electrode pads) to be attached to the scalp, a power source configured to generate current to the electrodes of the aforementioned electrode pads, and a computer program to guide the aforementioned electrode pads. Electrical stimulation with variable pulses.
  • the power source of the electro-stimulation device is a battery, making it convenient to use in the medical treatment of over-the-counter home transcutaneous electrical nerve stimulation (TENS unit) devices.
  • TESS unit transcutaneous electrical nerve stimulation
  • deep brain stimulation deep brain stimulation
  • electrodes are implanted in dysfunctional areas of the brain.
  • the electrodes deliver electrical impulses to targeted areas of the brain, and the electrodes are connected by wires to a pulse generator or neurostimulator.
  • a pulse generator or neurostimulator supplies electrical current to the electrodes, delivering random electrical impulses to targeted brain regions.
  • the pulse generator or neurostimulator is programmed to deliver random electrical pulses when needed.
  • a pulse generator/neurostimulator is usually surgically implanted under the skin. The delivery of random electrical pulses is not based on or derived from the patient's EEG data.
  • Fig. 2 shows the battery-powered electric stimulation device of the present invention, which includes an electric pulse generator 301 powered by a battery (not shown), and a pair of electrode patches 304, 305 connected to the electric pulse generator 301 through wires 302, 303. module.
  • the control module is grounded through the ground wire.
  • the digital or computer program of the control module directs the variable electrical stimulation according to the invention.
  • Example 1 Treating PTSD (Post Traumatic Stress Disorder) and Substance Use Disorder (SUD)
  • rTMS random variable repetitive transcranial magnetic stimulation
  • On subsequent follow-up examinations of the patient nocturnal sleep, mood, tinnitus, muscle pain, cessation of alcohol consumption, cessation of marijuana use, and attention span, all improved after 4 days of daily treatment.
  • a 56-year-old female patient was diagnosed with long-term COVID-19 and didn't smelled for more than a year. She was treated with repeated transcranial magnetic stimulation (rTMS) for two weeks with a random variable of the present invention. Prior to rTMS treatment, patients' motor thresholds were determined. Patients received 6 seconds of randomized magnetic stimulation every 60 seconds for 30 minutes at a power of 80% of the patient's motor threshold. After the first treatment, her sense of smell returned immediately. In subsequent follow-up examinations of the patient, she reported improvements in nighttime sleep, fatigue, muscle pain, and shortness of breath.
  • rTMS repeated transcranial magnetic stimulation
  • rTMS random variable repetitive transcranial magnetic stimulation
  • rTMS repeated transcranial magnetic stimulation
  • rTMS random variable repetitive transcranial magnetic stimulation
  • the motor threshold of the racers was determined.
  • the racers received 6 seconds of randomized magnetic stimulation every 60 seconds for 30 minutes at 70% of the patient's motor threshold.
  • rTMS randomized variable repetitive transcranial magnetic stimulation
  • Paralyzed males were treated with random variable repetitive transcranial magnetic stimulation (rTMS) of the present invention for 6 weeks (Monday to Friday).
  • rTMS random variable repetitive transcranial magnetic stimulation
  • motor thresholds were determined in paralyzed divers. Paralyzed divers received 6 seconds of randomized magnetic stimulation every 60 seconds for 30 minutes at a power of 70% of the patient's motor threshold. 2 weeks after the start of treatment, the diver was able to feel his legs and move his toes. At the end of five weeks, the divers were able to stand up.
  • Example 8 Reduces seizures and improves cognition, coordination, and muscle control
  • Example 9 Treatment of Alzheimer's patients with rTMS based on Gaussian distribution
  • rTMS randomized variable repetitive transcranial magnetic stimulation
  • Pulses were administered in a Gaussian distribution pattern with a peak at 100 ms and cutoffs at 83 ms and 125 ms.
  • rTMS treatment determine the patient's motor threshold. Patients received 6 seconds of randomized magnetic stimulation every 60 seconds for 30 minutes at a power of 80% of the patient's motor threshold.
  • the male reported problems with nocturnal sleep, memory, speaking and reading, and attention span, which improved after 2 days of daily treatment.

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Abstract

一种可编程rTMS装置，包括用于传递具有多变的脉冲间隔的rTMS脉冲的磁线圈。该多变的脉冲间隔是随机变量的脉冲间隔，该多变的脉冲间隔是由高斯分布、白噪音函数或粉红噪音函数来决定。此外，该多变的脉冲间隔的时间介于66.00ms至200.00ms。该装置对于治疗脑功能障碍是有效的。多变的脉冲间隔的设定不是基于EEG数据，源自EEG数据或其他生物特征的测量。

Description

用于传递可变脉冲的装置
本申请要求于2022年01月12日提交美国专利局、申请号为63/299,002的美国临时专利申请以及于2022年06月30日提交美国专利局、申请号为63/357,624的美国临时专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明关于一种采用重复经颅磁刺激(repetitive transcranial magnetic stimulation,rTMS)调节哺乳动物脑活动的装置，是将具有多变的脉冲间隔的rTMS施予至足以调节脑活动的时间，以达到改善生理状况或临床状况的目的。rTMS的脉冲间隔的范围介于66.00毫秒(ms)至200.00毫秒。此外，本发明涉及透过在足以调节脑活动的时间，施予可变电脉冲间隔来电刺激脑部，以实现改善生理状况或临床状况。可变电磁脉冲间隔以随机形式传送。前述磁刺激和电刺激中的脉冲间隔时间的设定不仰赖于或衍生自脑电图(Electroencephalography,EEG)、哺乳动物的其他生物特征数据(biometric data)。本发明还包括用于提供电或磁刺激的多变的脉冲间隔的电磁刺激设备，较佳可变脉冲不是基于患者的EEG数据，源自EEG数据或其他生物特征的测量。
背景技术
重复经颅磁刺激已被用于治疗许多心理和医疗疾病，例如重度抑郁症、帕金森病、创伤后压力症、阿兹海默症、自闭症类群障碍(autism spectrum disorder,ASD)、思觉失调症、疼痛管理(pain management)等。最近，Jin和Phillips在美国专利公开号2009/0082690中公开了一种使用rTMS的治疗方案，其rTMS的磁场输出是根据患者的EEG固有频率作调整，以尝试改变患者的固有EEG频率。美国专利US9,308,385使用不同的方法来管理rTMS，该方法是基于生物特征测量(biological metric)的频率、或特征测量的谐波。
其他治疗方法使用多种方法来准确识别用于治疗患者的最佳频率。所有涉及脑电磁刺激的既有技术治疗方法，都使用患者的EEG数据来决定用于管理电磁刺激的电磁频率。
在本发明之前，rTMS治疗已包括以预设强度来传递单一频率作为电磁刺激。
发明内容
本发明提供了一种新颖的rTMS传递系统，其传递的rTMS或电刺激具有多变的脉冲间隔(variable pulse intervals)，脉冲的时间间隔的概率取决于给定类型的噪声函数(noise function)，例如高斯、粉红噪音或白噪音。电磁刺激的功率/强度也可以是多变。此外，电和磁刺激装置被编程用于传递磁刺激或电刺激的多变的脉冲间隔。与使用单一频率磁或电刺激传递的既有技术相比，本发明提供巨大的优势。既有技术提供固定频率的刺激，或需要(a)患者的EEG或ECG；和(b)分析生物特征数据以获得更清楚的检测图谱(pattern)，然后对数据进行主观解释。
而本发明，调节哺乳动物脑活动的装置，是透过将66.00毫秒(ms)和200.00毫秒之间的变化的脉冲间隔的重复经颅磁刺激(rTMS)，施予哺乳动物来实现的。该装置也可以用于管理施予大脑的可变电刺激。对于治疗脑功能障碍疾病或身体状况，该装置是有效的。用于磁刺激和电刺激的多变脉冲间隔，是由预编程的噪声产生器(noise generator)产生，例如高斯、粉红噪音或白噪音，并截断与大脑活动节律相匹配的范围。此设定方式不使用EEG数据、衍生自EEG数据、或其他生物特征(例如心率、呼吸率、或类似特征)。
能透过本发明调节脑活动所改善的生理状况和医疗状况，可以是异常脑活动所造成特定条件的任何状况。治疗的病症包括但不限于自闭症类群障碍(autism spectrum disorder,ASD)、阿兹海默症(Alzheimer's Disease,AD)、创伤后压力症(Post Traumatic Stress Disorder,PTSD)、创伤性脑损伤(traumatic brain  injury,TBI)、记忆障碍、抑郁症、疼痛、成瘾、物质使用障碍(substance use disorder,SUD)、强迫性精神官能症(Obsessive Compulsive disorders,OCD)、焦虑症、巴金森氏症、高血压、性欲功能障碍、运动功能异常、儿童矮小、压力、肥胖、睡眠障碍、进食障碍、注意力不集中、语言障碍、智能障碍、认知障碍、注意力不足及过动症(Attention Deficit Hyperactivity Disorders,ADHD)、思觉失调症、昏睡、双相情绪障碍(bipolar disorders)、耳鸣、纤维肌痛、慢性莱姆病、类风湿性关节炎(Rheumatoid Arthritis,RA)、其他自身免疫性疾病、痛风、糖尿病、关节炎、创伤康复、运动表现、认知改善、长新冠(long COVID)症状(特别是嗅觉和/或味觉丧失)和中风。
在实践本发明中特别感兴趣的是，患者施予具有随机变量脉冲间隔的重复经颅磁刺激(rTMS)，施予时间足以调节患者的大脑活动，使其生理状况或临床状况达到改善。前述改善指的是指同时从患者和患者的医疗保健专业人员的临床评估观察到的改善。磁刺激的功率或强度通常低于患者的运动阈值，较佳为患者运动阈值的50％至90％，但强度也可以更高或更低。
本发明涉及的TMS同样适用于脑的电刺激，例如，透过脑深层刺激(deep brain stimulation)、或经皮电刺激(例如Alpha-Stim经颅电流刺激治疗(cranial electrotherapy stimulation,CES))装置。哺乳动物的脑活动是透过施予哺乳动物具有可变电脉冲间隔的电刺激来调整，施予时间足以调节脑活动的时间，使其生理状况或临床状况的达到改善。较佳地，电刺激是以随机形式进行。
在本发明的另一个实施例中，随机变量的脉冲间隔是间隔开来的时间区间(time period)，该时间区间根据高斯分布而定，该高斯分布具有决定峰值以及在连续时间区间的两端的既定截止点。该实施例应用于治疗本文所述特定脑功能障碍疾病或身体状况相关的特定脑电波的多个频率/多个区域。
附图说明
图1为使用rTMS设备治疗的患者的示例。
图2为使用电刺激装置治疗的患者的示例。
图3为电或磁脉冲的晶体管-晶体管逻辑(transitor-transtor-logic,TTL)序列在六秒治疗周期内的可变性。
图4为高斯分布概率图。
具体实施方式
与本发明的目的相关的定义说明如下。本文使用的术语「哺乳动物」包括任何哺乳动物，尤其是人类，非人类哺乳动物包括非人类灵长类动物、动物园动物、伴生动物(狗、猫)和表演动物(如赛马和繁殖动物)。本文所述的任何提及「人」内容，适用于表现出相同生理或医疗状况的其他哺乳动物。本文中使用任何提及「患者」的内容，适用于任何哺乳动物(较佳为人类)可能经历该提及患者的特定病症。当提到rTMS时，术语「多变的脉冲间隔(variable pulsed interval)、随机脉冲间隔、可变脉冲间隔、随机变量脉冲间隔」是指磁刺激随着时间传递时，是以不同的时间间隔来传递，而不是以相等的时间间隔(即频率)来传递。多变的时间间隔是由软件程序完全随机地生成，治疗方案中包含的每个脉冲的概率，是由具有给定平均值和标准偏差的高斯分布来加权。随机脉冲间隔也可以基于白噪音函数或/及粉红噪音函数。较佳地，预编程的白噪音产生器和粉红噪音产生器可以用来决定随机脉冲间隔。
在实施本发明时，有一患者，其脑活动是至少部分导致身体或医疗状况，而被诊断出具有该身体或医疗状况，透过施予66.00毫秒(ms)和200.00ms之间变化的TMS脉冲进行治疗。计算机程序用于生成TTL脉冲或其他触发器，再透过TMS设备生成多变的脉冲间隔，较佳为随机脉冲间隔。较佳地，经颅磁刺激是 以重复经颅磁刺激(rTMS)的形式传递。rTMS是以多变的脉冲间隔施予患者，施予时间足以调节大脑活动，以改善生理状况或治疗时的临床状况。
在较佳实施例中，随机变量脉冲间隔应用于rTMS操作，该操作的时间足以调节大脑活动，而改善生理状况或临床状况。较佳地，该治疗是每天进行并持续一周，之后将重新评估患者的进展。重复脉冲的确切时间并不重要。脉冲间隔的可变性可以由医疗保健专业人员选择定义治疗的特定脉冲间隔来预先确定。但是，最佳是对rTMS设备进行编程，以提供66.00ms到200.00ms的随机脉冲间隔。每分钟以六秒脉冲训练并持续30分钟，是产生30分钟的治疗期的较佳方式。磁脉冲的最大强度的设定通常受限在患者的运动阈值或较低，但可以在患者的运动阈值以进行管理。rTMS的峰值脉冲功率/强度较佳设置为患者运动阈值的约50-90％。通常，功率/强度可以是运动阈值的0.1-99％、运动阈值的10-90％或运动阈值的40-85％。
在本发明的另一实施例中，多变的脉冲间隔是间隔开来的连续时间区间，该连续时间区间根据高斯分布而定，该高斯分布具有决定峰值以及在连续时间区间的两端的既定截止点。该实施例可用于治疗与特定脑功能障碍疾病或身体状况相关的特定脑电波频率/区域。高斯分布的峰值和峰值两侧的截止点的数值对本发明的实施并不重要，其将基于患者的医疗保健专业人员考虑的各种因素。例如，在治疗与α脑波功能障碍相关的疾病或病症时，脉冲间隔的峰值为100.00ms，截止点为125.00ms和83.00ms，每一个时序的脉冲间隔皆在此时间区间之中随机产生。
请参阅图4，其呈现的时间区间图谱的示例呈现高斯分布，图谱显示的X轴为时间区间(单位毫秒)、Y轴为概率的关系。中心线C2代表高斯分布的峰值。截止点C1和C3代表C2两侧的截止点。图4所示高斯分布揭示的应用为，当C1为125.00ms、C2为100.00ms、C3为83.00ms，即是，随机脉冲间隔的时间区间范围在83.00ms和125.00ms之间。值得一提，若将图谱显示的X轴单位从时间区间转换为其倒数，(即，将时间区间转换为每秒出现的次数)，则C1至C2在X轴的距离与C2至C3在X轴的距离为等距。换句话说，随机脉冲间隔呈现高斯分布的数值，指的是其每秒出现的次数。
本发明的rTMS治疗，是采用透过磁线圈的既有的治疗方案进行。设定的时间区间内实际磁刺激的时间，将根据每个临床表现而变化。施予的磁刺激最佳是在rTMS疗程(rTMS session)以每分钟的进行连续6秒。疗程可以持续15到60分钟，最佳为30分钟。磁线圈可以放置在靠近或靠着患者的头部，较佳为靠近额叶。
表1的图表，列出了30分钟治疗期间的随机磁脉冲间隔。左手边的列(向下)对应训练编号，即每分钟有一次6秒的治疗。水平行对应从每个特定训练(即T1、T2、T3…等)的脉冲之间，以毫秒(ms)为单位的起始时间为127ms。例如，T1在初始脉冲后127ms触发，T2在T1后95ms触发，T3在T2后70ms触发，依此类推进行训练#1的水平行。训练#1历时6秒。较佳地，每一6分钟训练的脉冲是新随机生成的。一分钟后，训练#2以相同方式起始。由于篇幅限制，T11到T43被省略，但它们是随机脉冲。图3显示了根据本发明，在6秒治疗期中TLL脉冲 的可变性，这与采用单一频率的方案形成对比，在单频方案中所有脉冲将在6秒治疗段中彼此等距。
表1
Figure PCTCN2022135868-appb-000001
图1绘示本发明的磁刺激装置，包含线圈201、电源202和控制可变脉冲的刺激参数的计算机203。电源202和计算机203可以制造成单一的单元控制模块(图未示)。一般而言，控制模块控制TTL脉冲、以及由线圈201传递磁刺激。当电源202开启时，电流通过线圈产生磁场，计算机203被编程以驱动线圈201来产生本发明所述的可变脉冲。在对患者施予磁刺激治疗时，封装的磁线圈组件定位在或邻近头部，以接受治疗。
一种电刺激设备，包括两个或更多个电极贴片(electrode pad)以黏贴在头皮、电源被配置为产生电流至前述电极贴片的电极、以及计算机程序来引导前文所述的该可变脉冲的电刺激。在电刺激设备的较佳实施例中，电刺激设备的电源是电池，使其能在非处方的家用经皮电神经刺激(TENS单元)装置的医疗治疗中方便使用。在对患者施予电刺激治疗时，电极贴片被定位在接续位置(contiguous placement)直接接触、或邻近接受治疗的身体部位。
在本发明的另一个实施例中，脑深层刺激(deep brain stimulation,DBS)是以随机电脉冲施予患者，以控制多种脑功能障碍。在脑深层刺激时，电极被植入大脑功能失调的区域。电极传递电脉冲到大脑的目标区域，并且电极透过电线连接到脉冲产生器或神经刺激器。脉冲产生器或神经刺激器提供电流至电极，将随机电脉冲传递到目标大脑区域。在需要时，脉冲产生器或神经刺激器被编程以用于提供随机电脉冲。脉冲产生器/神经刺激器通常通过手术植入皮下。随机电脉冲的传递不是基于患者的EEG数据或来自患者的EEG衍生数据。
图2示出了本发明以电池供电的电刺激装置，其包含电脉冲产生器301由电池(图未示)供电、一对电极贴片304,305透过导线302,303连接到电脉冲产生器 301的控制模块。控制模块透过接地线接地。控制模块的数字或计算机程序引导根据本发明的可变电刺激。
以下示例说明如何实践本发明，但不应解释为限制申请专利范围。在这些示例中，没有使用EEG数据或EEG衍生数据来编程可变脉冲间隔或随机脉冲间隔。
示例1：治疗PTSD(创伤后压力症候群)和物质使用障碍(SUD)
一名25岁男性退伍军人患者，被诊断患有PTSD和SUD，采用本发明的随机变量重复经颅磁刺激(rTMS)治疗四天。在rTMS治疗之前，确定患者的运动阈值。患者以每60秒接受6秒的随机磁刺激，持续30分钟，功率为患者运动阈值的80％。在随后对患者进行的后续检查中，反应出夜间睡眠、情绪、耳鸣、肌肉疼痛、停止饮酒、停止吸食大麻和注意力持续时间，在每日治疗4天后有所改善。
示例2：治疗长新冠(long COVID)
一名56岁的女性患者，被诊断出患有长期新冠病毒，并且一年多没有闻到气味。采用本发明的随机变量重复经颅磁刺激(rTMS)治疗她两周。在rTMS治疗之前，确定了患者的运动阈值。患者以每60秒接受6秒的随机磁刺激，持续30分钟，功率为患者运动阈值的80％。第一次治疗后，她的嗅觉立即恢复了。在随后对患者进行的后续检查中，她反应夜间睡眠、疲劳、肌肉疼痛和呼吸急促有所改善。
示例3：治疗阿兹海默症
一名72岁女性患者，被诊断患有中度阿兹海默症，采用本发明的随机变量重复经颅磁刺激(rTMS)治疗两周，总共进行10次rTMS治疗。在rTMS治疗之前，确定了患者的运动阈值。患者以每60秒接受6秒的随机磁刺激，持续30分钟，功率为患者运动阈值的75％。在随后对女性患者的后续检查中，反应夜间睡眠、记忆力、说话和阅读的问题、处理新情况的问题以及注意力持续时间，在每日治疗4天后有所改善。
示例4：治疗自闭症谱系障碍
一名非语言(non-verbal)16岁男性患者，被诊断患有自闭症谱系障碍
(ASD)，采用本发明的随机变量重复经颅磁刺激(rTMS)治疗两天。在rTMS治疗之前，确定患者的运动阈值。患者以每60秒接受6秒的随机磁刺激，持续30分钟，功率为患者运动阈值的80％。在两次rTMS治疗后的第三天，患者开始说出单个单词。治疗2周后，患者开始说句子。
示例5：提高体能
一位54岁的Baha 1000男性赛车手希望提高他的耐力，以便在长距离赛车中更有竞争力，接受了采用本发明的随机变量重复经颅磁刺激(rTMS)治疗5周。在rTMS治疗之前，确定赛车手的运动阈值。赛车手以每60秒接受6秒的随机磁刺激，持续30分钟，功率为患者运动阈值的70％。治疗开始六周后，根据他在Baha 1000比赛中的表现，他的注意力、耐力和注意力明显改善。
示例6：改善注意力缺陷障碍(ADD)和焦虑
一名60岁的男性患者具有慢性注意力缺陷障碍(ADD)和焦虑，采用本发明的随机变量重复经颅磁刺激(rTMS)治疗。在rTMS治疗之前，确定患者的运动阈值。患者以每60秒接受6秒的随机磁场，持续30分钟，功率为患者运动阈值的80％。在随后对患者进行的后续检查中，他反应在这种每日治疗4天后，夜间睡眠、情绪和注意力持续时间有所改善。
示例7：从下半身瘫痪复原
一名41岁的男性，为经验丰富的深海水肺潜水员，参与了在海平面以下150英尺以下的潜水，但因过快重新浮出水面，导致腰部以下瘫痪7.5年。瘫痪男性采用本发明的随机变量重复经颅磁刺激(rTMS)治疗6周(周一至周五)。在rTMS治疗之前，确定了瘫痪潜水员的运动阈值。瘫痪的潜水员以每60秒接受6秒的随机磁刺激，持续30分钟，功率为患者运动阈值的70％。在治疗开始后的2周，潜水员能够感觉到他的腿和移动他的脚趾。在五周结束时，潜水员能够站起来。
示例8：减少癫痫发作并改善认知、协调和肌肉控制
一名8岁的女性患者自三岁起就无法行走、说话或使用左臂，并且每天有70到100次或更多无法控制的癫痫大发作。在使用随机脉冲rTMS治疗之前，该女孩每天癫痫发作70-100次或更多。采用本发明的随机变量重复经颅磁刺激(rTMS)治疗女孩3周(周一至周五)。在rTMS治疗之前，确定了女孩的运动阈值。女孩以每60秒接受6秒的随机磁刺激，持续30分钟，功率为女孩运动阈值的85％。治疗开始后的3周内(15次疗程)，女孩能够走路、说话并能用左手抓东西。女孩的每日癫痫发作次数从70-100次减少到每天不到20次。
示例9：基于高斯分布使用rTMS治疗阿兹海默症患者
一名83岁的男性患者，被诊断患有中度至重度阿兹海默症，接受随机变量重复经颅磁刺激(rTMS)治疗，在两周内总共进行10次rTMS治疗，脉冲间隔介于83毫秒和125毫秒。脉冲以高斯分布模式进行管理，峰值在100毫秒，截止点在83毫秒和125毫秒。在rTMS治疗之前，确定患者的运动阈值。患者以每60秒接受6秒的随机磁刺激，持续30分钟，功率为患者运动阈值的80％。在随后对男性患者进行的后续检查中，该男性患者反应夜间睡眠、记忆力、说话和阅读的问题以及注意力持续，在每日治疗2天后有所改善。
在不背离本发明的精神或本质特征的情况下，本发明可以以其他特定形式体现。所描述的实施例在所有方面都被认为仅是说明性的而不是限制性的。因此，本发明的范围由所附申请专利范围而不是由前述描述指示。在申请专利范围的等效含义和范围内的所有变化都应包含在其范围内。

Claims (14)

  1. 一种可编程rTMS装置，其特征在于，包括磁线圈，所述磁线圈用于传递具有多变的脉冲间隔的rTMS脉冲，所述多变的脉冲间隔是随机变量的脉冲间隔，所述多变的脉冲间隔是由高斯分布、白噪音函数或粉红噪音函数来决定。
  2. 根据权利要求1所述的可编程rTMS装置，其特征在于，还包括计算机程序，所述计算机程序用于引导所述磁线圈用来传递具有所述多变的脉冲间隔的rTMS脉冲。
  3. 根据权利要求1所述的可编程rTMS装置，其特征在于，所述多变的脉冲间隔由所述白噪音函数或/及所述粉红噪音函数来决定。
  4. 根据权利要求1所述的可编程rTMS装置，其特征在于，所述多变的脉冲间隔是间隔开来的连续时间区间，所述连续时间区间根据高斯分布而定，所述高斯分布具有决定峰值以及在所述连续时间区间的两端的既定截止点。
  5. 根据权利要求4所述的可编程rTMS装置，其特征在于，所述决定峰值为100.00ms的脉冲，第一个所述既定截止点为125.00ms的脉冲，第二个所述既定截止点为83.00ms的脉冲。
  6. 根据权利要求1所述的可编程rTMS装置，其特征在于，所述多变的脉冲间隔的时间介于66.00ms至200.00ms。。
  7. 一种rTMS装置和可编程系统，其特征在于，包括磁线圈，所述磁线圈用于传递具有多变的脉冲间隔的rTMS脉冲，所述多变的脉冲间隔是随机变量的脉冲间隔，所述多变的脉冲间隔是由高斯分布、白噪音函数或粉红噪音函数来决定。
  8. 一种电刺激装置，其特征在于，包括：
    a.二个或更多个电极贴片；
    b.电源，用于产生电流至所述电极贴片；
    c.数字程序，用于引导具有可变脉冲的电刺激，其特征在于，
    所述可变脉冲是以多变的脉冲间隔来传递，所述多变的脉冲间隔是由高斯分布、白噪音函数或粉红噪音函数来决定。
  9. 根据权利要求8所述的电刺激装置，其特征在于，所述电源是电池。
  10. 根据权利要求8所述的电刺激装置，其特征在于，所述电刺激装置为经皮神经电刺激装置(TENS Unit)或深部脑刺激器(DBS)。
  11. 根据权利要求8至10中任一项所述的电刺激装置，其特征在于，所述多变的脉冲间隔是由所述白噪音函数或/及所述粉红噪音函数来决定。
  12. 根据权利要求8至10中任一项所述的电刺激装置，其特征在于，所述多变的脉冲间隔是间隔开来的连续时间区间，所述连续时间区间根据高斯分布而定，所述高斯分布具有决定峰值以及在所述连续时间区间的两端的既定截止点。
  13. 根据权利要求12所述的电刺激装置，其特征在于，所述决定峰值为100.00ms的脉冲，第一个所述既定截止点为125.00ms的脉冲，第二个所述既定截止点为83.00ms的脉冲。
  14. 根据权利要求8至10中任一项所述的电刺激装置，其特征在于，所述多变的脉冲间隔的时间介于66.00ms至200.00ms。
PCT/CN2022/135868 2022-01-12 2022-12-01 用于传递可变脉冲的装置 WO2023134322A1 (zh)

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