Electrical stimulation device

Abstract

The invention discloses an electrical stimulation device which comprises an electrode assembly and an electrical stimulator. The electrical stimulator generates an electrical stimulation signal and is coupled to the electrode assembly. The electrical stimulation signal is transmitted to the target region via the electrode assembly. The electrical stimulation signal comprises a plurality of burst signals, the burst frequency of the burst signals ranges from 0.1 Hz to 1000 Hz, each burst signal comprises a plurality of pulses, and the pulse frequency of the pulses ranges from 20 kHz to 1000 kHz. The electrical stimulation signal does not induce activation of upstream or downstream neural structures of the target region.

Description

Technical Field

[0001] The present invention relates to an electrical stimulation technology, and more particularly to an electrical stimulation device. Background Art

[0002] Electrical stimulation technology has a long history of treating or relieving various pains. However, most common electrical stimulation technologies treat or relieve various pains by activating nerve signals through action potentials generated by low-frequency electrical stimulation (40 Hz~100 Hz). The aforementioned common electrical stimulation technology is to treat or relieve various pains through the Gate Control Theory of Pain. The gate control theory of pain is to activate nerves with electrical stimulation signals to trigger action potentials, and then the corresponding sensory signals can be measured in the brain to prevent or interfere with the transmission of pain signals to the central nervous system. When the pain signals received by the brain decrease, the pain sensation will also decrease. In other words, activating / activating nerves that transmit pain signals through electrical stimulation to generate sensory signals can interfere with the transmission of pain signals, thereby treating or relieving pain. Summary of the invention

[0003] However, there is no electrical stimulation technology that can achieve nerve regulation without activating nerves to generate sensory signals. In view of this, the present invention provides an electrical stimulation device that does not induce activation of upstream or downstream neural structures in the target area.

[0004] In some embodiments, an electrical stimulation device includes an electrode assembly and an electrical stimulator. The electrical stimulator generates an electrical stimulation signal and is coupled to the electrode assembly. The electrical stimulation signal is transmitted to a target area via the electrode assembly. The electrical stimulation signal includes a plurality of burst signals, the burst frequencies of the burst signals range from 0.1 Hz to 1000 Hz, and each burst signal includes a plurality of pulses, the pulse frequencies of the pulses range from 20 kHz (kilohertz) to 1000 kHz. The electrical stimulation signal does not induce activation of upstream neural structures or downstream neural structures of the target area.

[0005] In some embodiments, activation of the upstream neural structure generates an action potential for the upstream neural structure, and activation of the downstream neural structure generates an action potential for the downstream neural structure.

[0006] In some embodiments, the neural structure upstream of the target area is a cranial nerve or a spinal cord.

[0007] In some embodiments, the neural structure downstream of the target area is the sciatic nerve, the sacral nerve, or a peripheral nerve.

[0008] In some embodiments, the electrical stimulation signal has a voltage threshold sufficient to reduce nerve sensitivity.

[0009] In some embodiments, when the electrical stimulation signal has a voltage strength greater than 1.5 times the voltage threshold, the electrical stimulation signal still does not induce activation of an upstream neural structure or an activation of a downstream neural structure of the target area.

[0010] In some embodiments, the pulse frequency of the electrical stimulation signal ranges from 100 kHz to 750 kHz.

[0011] In some embodiments, the upstream neural structure or the downstream neural structure is outside a 3 cm radius of the target area.

[0012] In some embodiments, the cumulative time of the electrical stimulation signal is less than 12 hours per day. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 is a functional block diagram of an electrical stimulation device according to some embodiments;

[0014] Figure 2A for Figure 1 A schematic diagram of an exemplary electrical stimulation device;

[0015] Figure 2B for Figure 1 A schematic diagram of an exemplary use of an electrical stimulation device;

[0016] Figure 3 for Figure 1 A schematic diagram of another exemplary embodiment of an electrical stimulation device;

[0017] Figure 4 for Figure 1 A schematic diagram of another exemplary embodiment of an electrical stimulation device;

[0018] Figure 5A for Figure 1 A schematic diagram of an exemplary electrical stimulation signal generated by an electrical stimulator;

[0019] Figure 5B for Figure 1 A schematic diagram of another exemplary embodiment of an electrical stimulation signal generated by an electrical stimulator;

[0020] Figure 5C for Figure 1 A schematic diagram of another exemplary embodiment of an electrical stimulation signal generated by an electrical stimulator;

[0021] Figure 6 This is the result of the hind paw withdrawal threshold test of rats in experimental group A;

[0022] Figure 7 This is the result of the hind paw withdrawal threshold test of rats in experimental group B;

[0023] Figure 8This is the result of the hind paw withdrawal threshold test of rats in experimental group C;

[0024] Fig. 9 This is the result of the rat brain nerve stimulation threshold test;

[0025] Fig.10 This is the result of the rat sciatic nerve stimulation threshold test;

[0026] Fig.11 This is the result of the rat brain nerve stimulation threshold test;

[0027] Fig.12 This is the result of the rat sciatic nerve stimulation threshold test;

[0028] Wherein, the reference numerals are:

[0029] 10, 10a, 10b, 10c: electrical stimulation device;

[0030] 11: electrode assembly;

[0031] 111: electrode pair;

[0032] 112: electrode wire;

[0033] 113: ring electrode;

[0034] 12: electrical stimulator;

[0035] B, B1, B2: burst signal;

[0036] CH1, CH2: output terminal;

[0037] ES, ES2: electrical stimulation signal;

[0038] N: target nerve;

[0039] P: pulse;

[0040] P1, P3: positive phase pulse;

[0041] P2, P4: negative phase pulse;

[0042] T: target area;

[0043] t: cycle time;

[0044] V: voltage intensity;

[0045] Wp, Wp1, Wp2: pulse width;

[0046] Wb, Wb2: wave width. DETAILED DESCRIPTION

[0047] In this article, the term "action potential" refers to the change in membrane potential caused by rapid, short-term and conductive stimulation of the cell membrane. When the membrane potential exceeds the threshold potential, the muscle cell or neuron will generate an action potential. The action potential is the physiological basis for the conduction of nerve signals. The transmission of the action potential will cause the relevant nervous system to react. If the intensity of the electrical stimulation is lower than the threshold potential, no action potential will be generated.

[0048] The term "neural structure" refers to a structure including neural tissue and non-neural tissue, wherein the neural tissue includes neurons. Non-neural tissue includes neuroglial cells, myelin sheath, immune cells, connective tissue, epithelial cells, cardiovascular cells and / or blood cells. Glial cells include astrocytes, oligodendrocytes, ependymal cells, radial glial cells, Schwann cells, satellite cells, microglia and / or pituitary cells.

[0049] The term "electrical stimulation signal" refers to an electrical signal transmitted from an electrical stimulator to a biological body through an electrode assembly. For example, the electrical stimulation signal can be measured by voltage, current, power or other means.

[0050] The term "organism" can refer to either a human or an animal.

[0051] The term "target region" refers to a neural or non-neural structure that receives an electrical stimulation signal.

[0052] The term "neuron or neural structure activation, neuronor neural structure activated" means that at least one action potential is generated or initiated by the nerve or neural structure in response to a certain stimulus and propagates along the nerve or neural structure.

[0053] It should be understood that, unless clearly defined otherwise, the “one” or “a” mentioned herein is not intended to be limited to only one, but may refer to a single one, any one of a plurality of ones, or one type within a reasonable scope.

[0054] Figure 1 is a functional block diagram of an electrical stimulation device according to some embodiments. Figure 1The electrical stimulation device 10 includes an electrode assembly 11 and an electrical stimulator 12. The electrical stimulator 12 is coupled to the electrode assembly 11 and generates an electrical stimulation signal ES. The electrode assembly 11 receives the electrical stimulation signal ES and transmits it to the target area T to electrically stimulate the target area T (please refer to Figure 2B ). In other words, the electrical stimulation signal ES is transmitted to the target area T via the electrode assembly 11. In some embodiments, the electrical stimulation device 10 can be a transcutaneous, transcranial, partially invasive, minimally invasive or implantable electrical stimulation device 10. In some embodiments, the target area T is where the electrical stimulation device 10 is to be electrically stimulated, such as the central nervous system and its tissues, or the peripheral nervous system and its tissues. Among them, the central nervous system and its tissues include the brain, brainstem and spinal cord; the peripheral nervous system and its tissues include nerves, nerve roots and root ganglia outside the brain, brainstem and spinal cord. In some embodiments, peripheral nerves and their tissues are divided into the autonomic nervous system and the somatic nervous system according to their functions, including, for example, cranial nerves, vagus nerves, occipital nerves, trigeminal nerves, hypoglossal nerves, sphenopalatine ganglion, sacral nerves, lumbar nerves, pudendal nerves, sacral nerves, and coccygeal nerves.

[0055] In some embodiments, the electrode assembly 11 and the electrical stimulator 12 may be detachable components connected to each other or integrally formed. The detachable electrode assembly 11 and the electrical stimulator 12 are directly or indirectly coupled (for example, in the form of snapping, buckling, pluggable or electrically coupled) together.

[0056] In some embodiments, one or more electrical stimulation devices 10 may be disposed on the target area T.

[0057] In some embodiments, the electrodes included in the electrode assembly 11 may be in the form of paddle, cuff, spiral, linear, fine probe, cylindrical electrodes, etc.; the electrode assembly 11 may be in the form of linear, spiral, patch, wire, or needle.

[0058] Figure 2A and Figure 2B for Figure 1 A schematic diagram of an exemplary electrical stimulation device and a schematic diagram of its use. Figure 2A and Figure 2B. In some embodiments, the electrical stimulation device 10 may be a transcutaneous electrical stimulation device 10a. An electrode assembly 11 is embedded on one surface of the electrical stimulator 12. When in use, the electrical stimulator 12 is placed on the skin of a living organism, and the surface with the electrode assembly 11 is in contact with the skin. In other words, the electrical stimulator 12 and the electrode assembly 11 of the electrical stimulation device 10a are both located outside the body. The electrical stimulation signal ES generated by the electrical stimulator 12 stimulates the superficial nerves (Superficial Nerve) under the skin through the electrode assembly 11. In this embodiment, the target area T is the superficial nerves (Superficial Nerve) under the skin. The skin may be the skin on the surface of the head, upper limbs, lower limbs, trunk or genitals, and the superficial nerves under the skin refer to nerves with a depth of approximately 1, 2, 3, or 4 centimeters under the skin.

[0059] In some embodiments, the electrode assembly 11 includes two electrodes or multiple electrodes, so that the electrical stimulation is bipolar or tripolar. In other embodiments, the electrode assembly 11 includes a working electrode and a reference electrode, so that the electrical stimulation is monopolar. Figure 2A As shown, in a bipolar example, the electrode assembly 11 includes a pair of electrode pairs 111. In the electrical stimulation device 10a, this pair of electrode pairs 111 is arranged on the surface (i.e., on the shell) of the electrical stimulator 12. When in use, the electrical stimulation device 10a is attached to the skin of the arm with the electrode pair 111, and is activated to output an electrical stimulation signal ES to the electrode pair 111, so as to electrically stimulate the skin of the arm and the superficial nerves under the skin through the electrode pair 111. In some embodiments, the superficial nerve under the skin of the arm can be the musculocutaneous nerve located in the biceps brachii, the radial nerve located in the triceps brachii, or the median nerve located near the wrist.

[0060] Figure 3 for Figure 1 Schematic diagram of another exemplary embodiment of an electrical stimulation device. Figure 3. In some embodiments, the electrical stimulation device 10 may be a minimally invasive electrical stimulation device 10b. After the electrode assembly 11 is implanted, one end thereof is wirelessly or wiredly connected to the electrical stimulator 12, and the other end is implanted in the organism. When in use, the electrical stimulator 12 is disposed on the skin of a living organism, and the electrode assembly 11 is at least partially implanted under the skin of the living organism in a minimally invasive manner. In other words, the electrical stimulator 12 of the electrical stimulation device 10b is located outside the body, and the electrode assembly 11 of the electrical stimulation device 10b is located inside the body. The electrical stimulation signal ES generated by the electrical stimulator 12 stimulates the target nerve N near the terminal of the electrode assembly 11 (the end of the electrode assembly 11 not connected to the electrical stimulator 12) wirelessly or wired via the electrode assembly 11. In this embodiment, the target area T is the target nerve N near the terminal of the electrode assembly 11.

[0061] like Figure 3 As shown, in one example, the electrical stimulation device 10b may be a peripheral nerve electrical stimulation device, and the electrode assembly 11 may be an electrode lead 112, which includes a plurality of ring electrodes 113. In other embodiments, one end of the electrode lead 112 may be implanted near the target nerve N, and the other end of the electrode lead 112 may extend from the skin surface and be connected to the electrical stimulator 12.

[0062] In some embodiments, the target area T is a nerve or a nerve structure around the ring electrode 113 on the electrode lead 112. For example, the target area T is a target nerve N around the ring electrode 113 on the electrode lead 112.

[0063] Figure 4 for Figure 1 A schematic diagram of another exemplary embodiment of an electrical stimulation device. Figure 4 In some embodiments, the electrical stimulation device 10 may be an implantable electrical stimulation device 10c, and the electrode assembly 11 is connected to the electrical stimulator 12. When in use, the electrical stimulator 12 and the electrode assembly 11 are implanted in the body. In other words, the electrical stimulator 12 and the electrode assembly 11 of the electrical stimulation device 10c are both located in the body. In this embodiment, the target area T is the nerve near the terminal of the electrode assembly 11. Figure 4 As shown, in one example, the electrical stimulation device 10c may be a spinal cord electrical stimulation device or a sacral nerve electrical stimulation device, in which the electrode wire 112 (including a plurality of ring electrodes 113) is directly connected to the electrical stimulator 12. When in use, the electrode wire 112 is implanted in the epidural space of the spine of the organism or near the sacral nerve around the buttocks.

[0064] In some embodiments, the electrical stimulation signal ES may be a biphasic electrical stimulation signal ES. In other embodiments, the electrical stimulation signal ES may also be a monophasic electrical stimulation signal ES.

[0065] Figure 5A for Figure 1 A schematic diagram of an example of an electrical stimulation signal generated by an electrical stimulator. Figure 5A In some embodiments, the waveform of the electrical stimulation signal ES generated by the electrical stimulation device 10 is a biphasic, square wave, symmetric, charge balance electrical stimulation signal ES as an example. Of course, the waveform of the electrical stimulation signal ES may also be a monophasic signal, a triangular wave, a sine wave (including a sine wave and a cosine wave), an asymmetric signal, or a charge imbalance signal.

[0066] In some embodiments, the electrical stimulation signal ES includes a plurality of burst signals B, the burst frequency of which is between 0.1 Hz (hertz) and 1000 Hz, and each burst signal B includes a plurality of pulses P, the pulse frequency of which is between 20 kHz (kilohertz) and 1000 kHz. Preferably, the burst frequency of the burst signal B is between 0.1 Hz and 500 Hz, for example, 0.1 Hz~400 Hz, 0.1 Hz~200 Hz, 0.1 Hz~100 Hz, or 0.1 Hz~20 Hz. Preferably, the pulse frequency of the pulse P is between 100 kHz and 750 kHz, for example, 400 kHz~600 kHz. The wave width Wb of the burst signal B is between 1 millisecond (ms) and 10 seconds, and the pulse width Wp of the pulse P is between 0.5 microseconds (μs) and 1 millisecond (ms). Preferably, the pulse width Wb of the burst signal B is between 2 milliseconds and 500 milliseconds, such as 20 milliseconds. Preferably, the pulse width Wp of the pulse P is between 1 microsecond and 1 millisecond, such as 1 microsecond and 100 microseconds.

[0067] In some embodiments, the current intensity of the electrical stimulation signal ES may be between 0.1 mA (milliampere) and 120 mA, and the voltage intensity V of the electrical stimulation signal ES may be between 0.05 V (volt) and 60 V. Preferably, the current intensity is between 6 mA and 40 mA. Preferably, the voltage intensity V is between 3 V and 20 V.

[0068] In some embodiments, the pulse P is a biphasic pulse, which is a continuous pulse with opposite polarities. The pulse P included in the biphasic pulse includes a positive phase pulse P1 and a negative phase pulse P2, the positive phase pulse P1 and the negative phase pulse P2 appear alternately, and preferably, the positive phase pulse P1 and the negative phase pulse P2 are charge balanced.

[0069] In some embodiments, the pulse P may be a square wave, a sine wave (including a sine wave and a cosine wave), a triangle wave or a combination thereof. In some embodiments, the burst signal B may be a square wave, a sine wave (including a sine wave and a cosine wave), a triangle wave or a combination thereof.

[0070] Figure 5B for Figure 1 Schematic diagram of another exemplary embodiment of an electrical stimulation signal generated by an electrical stimulator. Figure 5B In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 is an electrical stimulation signal ES2. The electrical stimulation signal ES2 is an example of having two interlaced burst signals B1 and B2, wherein the burst signal B1 is Figure 5A The same as the burst signal B in the figure, and its waveform is indicated by a solid square, which is not described here; and the burst frequency of the burst signal B2 is also between 0.1 Hz and 1000 Hz, preferably, the burst frequency of the burst signal B2 is less than or equal to the burst frequency of the burst signal B1. Here, the burst signals B1 and B2 appear alternately in a 1:1 ratio.

[0071] In some embodiments, the burst signal B2 includes a plurality of positive phase pulses P3 or a plurality of negative phase pulses P4. Figure 5B , the electrical stimulation signal ES2 includes two types of burst signals B2, the first type of burst signal B2 includes a plurality of positive phase pulses P3, and the second type of burst signal B2 includes a plurality of negative phase pulses P4, the two types of burst signals have the same waveform but opposite phases. The pulse frequency range of the positive phase pulse P3 and the negative phase pulse P4 is between 20 kHz and 1000 kHz, preferably, the pulse frequency range of the positive phase pulse P3 and the negative phase pulse P4 is between 20 kHz and 300 kHz. Preferably, the pulse frequency of the positive phase pulse P3 or the negative phase pulse P4 included in the burst signal B2 is less than the pulse frequency of the pulse P included in the burst signal B1. For example, the pulse frequency of the positive phase pulse P3 or the negative phase pulse P4 of the burst signal B2 is less than 1 / 3 of the pulse frequency of the pulse P of the burst signal B1.

[0072] In some embodiments, the width Wb2 of the burst signal B2 is also between 1 millisecond (ms) and 10 seconds. Preferably, the width Wb2 of the burst signal B2 is between 2 milliseconds and 500 milliseconds, such as between 5 milliseconds and 100 milliseconds.

[0073] In some embodiments, the pulse widths Wp1 and Wp2 of the positive phase pulse P3 and the negative phase pulse P4 are also between 1 microsecond (μs) and 1 millisecond (ms). Preferably, the pulse widths Wp1 and Wp2 of the positive phase pulse P3 and the negative phase pulse P4 are between 3.3 microseconds and 1 millisecond, for example, 1 microsecond. The pulse frequencies and pulse widths Wp1 and Wp2 of the positive phase pulse P3 and the negative phase pulse P4 can be the same or different. Here, the same is taken as an example. Therefore, within a unit time, the charge of the positive phase pulse P3 will be equal to the charge of the negative phase pulse P4, which can achieve delayed charge balance and reduce the phenomenon of electrode corrosion (erosion) due to polarization.

[0074] In some embodiments, when the charge accumulated in a single phase of the positive phase pulse P3 or the negative phase pulse P4 of the burst signal B2 is greater than or equal to 20 μC (microcoulomb), it can be sensed by a biological subject (a user using the electrical stimulation device 10), such as a jumping, shaking, or tingling sensation, so that the biological subject can know that electrical stimulation is in progress.

[0075] Figure 5C for Figure 1 A schematic diagram of another exemplary embodiment of an electrical stimulation signal generated by an electrical stimulator. Figure 5C . In some embodiments, the electrical stimulation device 10 has two output terminals CH1 and CH2. The two output terminals CH1 and CH2 respectively output the electrical stimulation signal ES2. In this state, the electrical stimulation signal ES2 output by the two output terminals CH1 and CH2 does not overlap in the output time of the two output terminals CH1 and CH2 during the on period (on period) of each burst signal B1, B2 or each pulse P within the cycle time t. For example, the on period of the burst signal B1 and the burst signal B2 of the output terminal CH1 does not overlap with the on period of the burst signal B1 and the burst signal B2 of the output terminal CH2. In this embodiment, the voltage or current interference of the two output terminals CH1 and CH2 when outputting the electrical stimulation signal ES2 is reduced, thereby avoiding unstable output of the two output terminals CH1 and CH2. For example, please refer to Figure 4 , the electrical stimulation device 10c may include two electrode wires 112 ( Figure 4 Only one electrode wire 112 is shown, and the other electrode wire 112 is not shown), which corresponds to two output terminals CH1 and CH2 respectively, to output the electrical stimulation signal ES2 to the multiple annular electrodes 113 on the two electrode wires 112, and output a bipolar electrical stimulation signal ES2.

[0076] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 has a voltage intensity V, and the maximum amplitude of the electrical stimulation signal ES may be ±60 volts (V). In some embodiments, the voltage intensity V is 3V to 20V. Preferably, the voltage intensity V is 3V to 10V. The electrical stimulation device 10 is activated to generate the electrical stimulation signal ES, and the accumulated electrical stimulation time per day is less than 12 hours.

[0077] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 does not induce activation of the upstream neural structure or the downstream neural structure of the target area T. In some embodiments, the upstream neural structure of the target area T is a cranial nerve or a spinal cord. In some embodiments, the downstream neural structure of the target area T is a sciatic nerve, a sacral nerve, or a peripheral nerve.

[0078] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 is transmitted to the target area T via the electrode assembly 11, but the electrical stimulation signal ES does not induce activation of the upstream neural structure of the target area T or activation of the downstream neural structure of the target area T. For example, when using the electrical stimulation device 10 for electrical stimulation, a target area T can be selected first. This target area T can be an area with symptoms (e.g., pain), a location near an area with symptoms, or on a nerve conduction path that causes nerve sensitivity or symptoms. The upstream neural structure of the target area T or the downstream neural structure of the target area T can be found through the ascending path and the descending path of the nerve conduction path of the target area T. For example, if the target area T of the electrical stimulation signal ES is in the thoracic region of the spinal cord, its upstream neural structure is the brain, cranial nerves, or the cervical region of the spinal cord, and its downstream neural structure is the sciatic nerve, the sacral nerve, or the peripheral nerves of the lower limbs. If the target area T of the electrical stimulation signal ES is the femoral nerve in the thigh, the upstream nerve structure is the brain, cranial nerves, spinal cord, sciatic nerve, or sacral nerve, and the downstream nerve structure is the peripheral nerve in the calf or foot.

[0079] Among them, the upstream neural structure is outside the range of 3 cm radius of the target area T, and the downstream neural structure is outside the range of 3 cm radius of the target area T.

[0080] In some embodiments, activation of the upstream neural structure generates an action potential for the upstream neural structure, and activation of the downstream neural structure generates an action potential for the downstream neural structure. In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 does not induce an action potential to transmit a neural signal to the upstream neural structure or the downstream neural structure. The upstream neural structure and / or the downstream neural structure include sensory nerves and motor nerves.

[0081] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 does not activate the muscle fibers in the target area T either.

[0082] In some embodiments, neurons can be divided into sensory nerves and motor nerves according to their functions, and the electrical stimulation signal ES generated by the electrical stimulation device 10 will not activate the sensory nerves and / or motor nerves of the upstream neural structure and the downstream neural structure, nor will it induce the sensory nerves and / or motor nerves of the upstream neural structure and the downstream neural structure to generate action potentials. In other words, no matter which type of neuron is activated by the electrical stimulation signal ES generated by the electrical stimulation device 10 to generate an action potential.

[0083] In some embodiments, nerve fibers can be divided into A-fibers (including Aα and Aβ), B fibers, and C-fibers according to their thickness and conduction velocity. The electrical stimulation signal ES generated by the electrical stimulation device 10 will not activate the A-fibers, B fibers, and C-fibers of the upstream and downstream nerve structures, nor will it induce the A-fibers, B fibers, and C-fibers of the upstream and downstream nerve structures to generate action potentials. In other words, no matter which type of nerve fiber is activated by the electrical stimulation signal ES generated by the electrical stimulation device 10 to generate an action potential.

[0084] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 reduces nerve sensitivity (desensitize). In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 has a voltage threshold (minimum voltage with therapeutic effect) sufficient to reduce nerve sensitivity. In some embodiments, under the voltage threshold, the electrical stimulation signal ES generated by the electrical stimulation device 10 does not induce activation of upstream neural structures or downstream neural structures of the target area T and can reduce nerve sensitivity. In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 has the effect of reducing nerve sensitivity, thereby having the effect of inhibiting and / or relieving acute pain, chronic pain, overactive bladder (OAB), premature ejaculation, or diseases or symptoms caused by nerve sensitization.

[0085] In some embodiments, when the voltage strength V of the electrical stimulation signal ES generated by the electrical stimulation device 10 is greater than 1.5 times the voltage threshold, the electrical stimulation signal ES still does not induce activation of the upstream neural structure or the downstream neural structure of the target area T. In some embodiments, when the voltage strength V of the electrical stimulation signal ES generated by the electrical stimulation device 10 is greater than 1.5 times the voltage threshold, the electrical stimulation signal ES still does not induce activation of the upstream neural structure or the downstream neural structure of the target area T, and can inhibit and / or relieve pain, relieve symptoms, and reduce nerve sensitivity.

[0086] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 suppresses and / or relieves pain. In some embodiments, the electrical stimulation signal ES suppresses and / or relieves localized pain. In some embodiments, the electrical stimulation signal ES suppresses and / or relieves chronic pain.

[0087] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 suppresses neuropathic pain, such as neuropathic pain or neuropathic pain caused by nerve damage.

[0088] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 suppresses mechanical hypersensitivity induced by nerve injury and reduces brain neuron activity.

[0089] In some embodiments, the electrical stimulation signal ES generated by the electrical stimulation device 10 is a paresthesia-free electrical stimulation signal or a subthreshold electrical stimulation signal, wherein the subthreshold electrical stimulation signal refers to an electrical stimulation signal that fails to cause a biological body (a user using the electrical stimulation device 10) to generate an action potential.

[0090] Example 1: Animal testing - mechanical hypersensitivity test

[0091] A. Test process:

[0092] (1) Brain and spinal cord electrode implantation

[0093] Electrodes were implanted in the brain and spinal cord of normal rats (Sprague Dawley, SD). The electrodes implanted in the brain were recording electrodes, while the electrodes implanted in the spinal cord were electrical stimulation electrodes. Furthermore, the rats treated with electrode implantation were divided into experimental group A, experimental group B, and experimental group C, each group having 4 to 5 rats.

[0094] The electrodes implanted in the brain were implanted in the primary somatosensory cortex (S1HL) and anterior cingulate cortex (ACC) of the hind limbs. The electrodes implanted in the spinal cord were implanted with bipolar spinal cord stimulation electrodes (GIMER Medical, Taiwan, China) into the dorsal epidural space of the spinal cord at the thoracic vertebrae (T9–T11) of rats. The electrode wires connecting the bipolar spinal cord stimulation electrodes were connected to an external electrical stimulator (ES1001, GIMER Medical, Taiwan, China). After the electrical stimulator generated an electrical stimulation signal, the electrical stimulation signal was transmitted to the bipolar spinal cord stimulation electrode through the electrode wire.

[0095] Among them, the somatosensory cortex and the anterior cingulate cortex play an important role in participating in the central nociception process. The somatosensory cortex is involved in encoding the sensory characteristics of pain, such as the nature of pain (tingling, burning, or pain), location, and duration, while the anterior cingulate cortex controls emotional and motivational responses and is more related to the emotional and situational aspects of pain.

[0096] (2) Treatment of nerve damage

[0097] 7 to 10 days after the implantation of electrodes in the brain and spinal cord, the tibial nerve and common peroneal nerve of the left hind paw of each group were ligated with 4-0 silk thread and cut approximately 2 mm away from the ligature to serve as nerve injury. Figures 6 to 8 In the literature, SNI (Spared nerve injury) is used to represent it.

[0098] (3) Mechanical hypersensitivity test after nerve injury

[0099] After nerve injury, each group was subjected to single-filament allodynia measurement (Von Frey) using Von Frey filaments (Stoelting, Wood Dale, IL) to assess mechanical hypersensitivity and calculate the withdrawal threshold of each group. Figures 6 to 8 Base) is the withdrawal threshold measured at least 2 days before nerve injury.

[0100] (4) Ultra-high frequency electrical stimulation

[0101] After 7, 9, 11, 13 and 15 days of nerve injury treatment ( Figures 6 to 8 , represented by D7, D9, D11, D13 and D15 respectively), and each group was treated with an ultra-high frequency electrical stimulation signal of different duration. The ultra-high frequency electrical stimulation signal includes at least one burst signal, and the burst signal includes pulses. The pulse is a bidirectional sine wave. The wave width of the burst signal is 25 ms, and the burst frequency of the burst signal is 2 Hz. The pulse width of the pulse is 2 μs, the pulse frequency of the pulse is 500kHz, and the voltage of the electrical stimulation signal is ±3V. Experimental Group A, Experimental Group B, and Experimental Group C all underwent 6 ultra-high frequency electrical stimulation treatments (once every two days). The difference is that the ultra-high frequency electrical stimulation treatment duration of Experimental Group A is 5 minutes each time; the ultra-high frequency electrical stimulation treatment duration of Experimental Group B is 10 minutes each time; and the ultra-high frequency electrical stimulation treatment duration of Experimental Group C is 20 minutes each time. Figures 6 to 8 , UHF1 to UHF6 represent the 1st to 6th ultra-high frequency electrical stimulation treatments, respectively.

[0102] (5) Mechanical hypersensitivity test after ultra-high frequency electrical stimulation

[0103] After ultrahigh frequency electrical stimulation, each group was subjected to single-filament tactile allodynia (Von Frey) using Von Frey filaments (Stoelting, Wood Dale, IL) to assess mechanical hypersensitivity and calculate the withdrawal threshold of each group. The analgesic effect was assessed by the allodynia induced by Von Frey filaments. Mechanical hypersensitivity is a neurosensitive response.

[0104] (6) Statistical analysis

[0105] Two-way repeated measures ANOVA was used to analyze the withdrawal threshold of each group, and post hoc analysis was performed using the Tukey method. Experimental data are presented as mean ± standard deviation (SD). All analyses were performed using two-tailed tests. P < 0.05 was considered statistically significant.

[0106] B. Test Results:

[0107] See also Figures 6 to 8 After nerve injury (SNI), the withdrawal threshold of the left hind paw (hind paw on the same side of nerve injury) of rats in each group dropped sharply from the baseline (Base) 21.9 ± 1.7 g to 1.0 ± 0.3 g, and maintained for at least one month. Among them, the mechanical hypersensitivity produced after nerve injury is a chronic neuropathic pain.

[0108] Please continue reading Figures 6 to 8 , the withdrawal thresholds of experimental groups A, B and C were significantly increased to 13.3 ± 6.5 g, 18.5 ± 3.6 g and 21.0 ± 2.8 g, respectively, 5 hours after UHF electrical stimulation. On the second day after UHF electrical stimulation, the withdrawal thresholds of experimental groups A, B and C were increased to 6.1 ± 2.5 g, 8.2 ± 2.7 g and 14.3 ± 5.9 g, respectively. In other words, after UHF electrical stimulation (pulse frequency of 500 kHz and voltage of ±3V), the withdrawal thresholds of the left hind paws of rats in each group were significantly increased, indicating that the voltage of 3V is an effective electrical stimulation intensity. UHF electrical stimulation significantly inhibited the mechanical hypersensitivity of the left hind paw induced by nerve injury. Among them, the effect of increasing the withdrawal threshold appeared 1 hour after UHF electrical stimulation, lasted for at least 5 hours, and weakened on the second day after UHF electrical stimulation.

[0109] From the above results, it can be seen that the withdrawal threshold of experimental group C (20 minutes per session) with a longer UHF electrical stimulation treatment time at 5 hours and on the second day was higher than that of experimental group A (5 minutes per session) and experimental group B (10 minutes per session). Increasing the duration from 5 minutes to 20 minutes significantly enhanced the effect of raising the withdrawal threshold. In other words, longer duration UHF electrical stimulation has a stronger pain inhibitory effect and is significantly time-dependent.

[0110] Moreover, it can be seen from the above results that repeated stimulation will produce analgesic effects of similar duration and effectiveness. Repeating the stimulation for 20 minutes every 2 days will gradually enhance the effectiveness of the analgesic effect. After 5 20-minute ultra-high frequency electrical stimulation treatments, the analgesic effect will gradually be enhanced, and the duration of analgesia will also be gradually prolonged. For example, the withdrawal threshold of experimental group C after 1 20-minute ultra-high frequency electrical stimulation treatment was 8.0±4.3 g, and the withdrawal threshold after 5 20-minute ultra-high frequency electrical stimulation treatments was 14.3±5.9 g (not shown). In other words, ultra-high frequency electrical stimulation treatment has the effect of "short stimulation time, long-term analgesia". The ultra-high frequency electrical stimulation signal generated by the electrical stimulation device inhibits the mechanical hypersensitivity induced by nerve damage.

[0111] Example 2: Animal testing - stimulus threshold test

[0112] A. Test process:

[0113] (1) Brain, spinal cord and sciatic nerve electrode implantation

[0114] Electrodes were implanted in the brain and spinal cord of normal rats (Sprague Dawley, SD). The electrodes implanted in the brain were recording electrodes, and the electrodes implanted in the spinal cord were electrical stimulation electrodes. Then, 7 days after the electrodes were implanted, recording electrodes were implanted in the sciatic nerves of the rats that had been implanted with electrodes. In addition, the rats that had been treated with electrode implantation were divided into experimental group D, experimental group E, experimental group F, experimental group G, and experimental group H, each group having 4 to 5 rats.

[0115] The electrodes implanted in the brain were implanted in the primary somatosensory cortex (S1HL) and anterior cingulate cortex (ACC) of the hindlimbs. The electrodes implanted in the sciatic nerve were implanted around the nerve in the middle third of the posterolateral sciatic nerve of the right thigh. The electrodes implanted in the spinal cord were implanted by bipolar spinal cord stimulation electrodes (GIMER Medical, Taiwan, China) into the dorsal epidural space of the spinal cord at the thoracic vertebrae (T9–T11) of rats. The electrode wires connecting the bipolar spinal cord stimulation electrodes were connected to an external electrical stimulator (ES1001, GIMER Medical, Taiwan, China). After the electrical stimulator generated the electrical stimulation signal, the electrical stimulation signal was transmitted to the bipolar spinal cord stimulation electrode through the electrode wire.

[0116] (2) Electrical stimulation test and activation threshold recording

[0117] After the electrodes were implanted, each group was given electrical stimulation signals of different frequencies through spinal cord electrical stimulation, and the local field potential (local field potential) was measured in the brain, and the compound action potential (compound action potential) was measured on the sciatic nerve to obtain the activation thresholds on the brain and sciatic nerve. As the intensity of the electrical stimulation signal gradually increased, when the electrode measured the minimum intensity (voltage) value of the electrical stimulation signal transmitted from the spinal cord, it was the activation threshold that could cause the action potential, also known as the stimulation threshold. In this way, the stimulation thresholds of the cranial nerve and sciatic nerve reactions caused by electrical stimulation signals of different frequencies were measured. Among them, the local field potential is the sum of the electrical activities of multiple neurons in the local area of ​​the electrode terminal implanted in the brain, which is often related to the action potential. The local field potential measured during the stimulated state (electrical stimulation) is also called evoked potential. The compound action potential refers to the sum of the action potentials of multiple nerves.

[0118] The electrical stimulation signal parameters used to test the stimulation threshold in each group are:

[0119] Experimental group D (0.1 Hz, single pulse): The pulse frequency of the electrical stimulation signal is 0.1 Hz, and the pulse width is 2 ms. This electrical stimulation signal only contains a 1 ms positive square wave and a 1 ms negative square wave. Among them, the positive and negative waves of experimental groups D to G are directly connected to achieve charge balance, which will not be repeated below.

[0120] Experimental group E (50 Hz, single pulse / pulse train): represents the traditional low-frequency electrical stimulation signal, the pulse frequency of the electrical stimulation signal is 50 Hz, and the pulse width is 400 μs. The single-pulse electrical stimulation signal only contains a 200 μs positive square wave and a 200 μs negative square wave. The pulse train electrical stimulation signal is a single-pulse electrical stimulation signal applied every 19.6 ms. If the stimulation threshold is not recorded after observation, the voltage is increased to continue the electrical stimulation, and it is repeated until the stimulation threshold is observed.

[0121] Experimental group F (10 kHz, single pulse / pulse train): represents high-frequency electrical stimulation signals, with a pulse frequency of 10 kHz and a pulse width of 40 μs. The single-pulse electrical stimulation signal only contains a 20 μs positive-phase sine wave and a 20 μs negative-phase sine wave. The pulse train electrical stimulation signal is a single-pulse electrical stimulation signal applied every 60 μs. If the stimulation threshold is not recorded after observation, the voltage is increased to continue the electrical stimulation, and it is repeated until the stimulation threshold is observed.

[0122] Experimental group G (500 kHz, single pulse / single pulse train): represents ultra-high frequency electrical stimulation signals, the pulse frequency of the electrical stimulation signals is 500 kHz, and the pulse width is 2 μs. The electrical stimulation signals in the form of a single pulse only contain a 1 μs positive phase sine wave and a 1 μs negative phase sine wave. The electrical stimulation signals in the form of a single pulse train are electrical stimulation signals in the form of continuous single pulses, which last for 25ms. If the stimulation threshold is not recorded after observation, the voltage is increased to continue the electrical stimulation, and it is repeated until the stimulation threshold is observed.

[0123] Experimental group H (500 kHz, continuous pulse train): represents a continuous ultra-high frequency electrical stimulation signal. The electrical stimulation signal contains multiple burst signals with a burst frequency of 5 Hz and a wave width of 25 ms. Each burst signal contains multiple pulses with a pulse frequency of 500kHz and a pulse width of 2 μs. The pulse contains a 1 μs positive phase sine wave and a 1 μs negative phase sine wave. The electrical stimulation signal in the form of a continuous pulse train is an electrical stimulation signal in the form of a single pulse train that is applied every 175 ms. If the stimulation threshold is not recorded after observation, the voltage is increased to continue the electrical stimulation and repeated until the stimulation threshold is observed.

[0124] Electrical stimulation was performed according to different parameters for each group to measure the minimum intensity (voltage) of the local field potential in the cerebral cortex and the compound action potential in the sciatic nerve to determine whether the electrical stimulation signal of each group can be transmitted anterogradely (upward) to the brain or spinal cord, or retrogradely (downward) to downstream nerves or peripheral nerves. In other words, the detectable local field potential induced in the cerebral cortex or the detectable compound action potential induced in the sciatic nerve was measured for each group as the stimulation threshold for each group to cause the response of cranial nerve and sciatic nerve neurons.

[0125] B. Test Results:

[0126] See also Fig. 9When the electrical stimulation signal was applied in the form of a single pulse, the brain nerve stimulation threshold (minimum intensity of brain activation) of experimental group D (0.1 Hz) was about 0.8 ± 0.2 V; the brain nerve stimulation threshold of experimental group E (50 Hz) was about 1.2 ± 0.3 V; the brain nerve stimulation threshold of experimental group F (10 kHz) was about 4.5 ± 1.4 V; and the brain nerve stimulation threshold of experimental group G (500kHz) was > 20 V. Fig. 9 It can be seen that when the pulse frequency of electrical stimulation is greater, the stimulation threshold of electrical stimulation on cranial nerves is also greater.

[0127] See also Fig.10 When the electrical stimulation signal was applied in the form of a single pulse, the experimental results of the sciatic nerve stimulation threshold (the minimum intensity of sciatic nerve activation) of experimental groups D to G (0.1 Hz, 50 Hz, 10 kHz, and 500 kHz, respectively) were similar to the trend of the cranial nerve stimulation threshold. Among them, the sciatic nerve stimulation thresholds were all higher than the cranial nerve stimulation thresholds.

[0128] See also Fig.11 (Cranial nerves) and Fig.12 (sciatic nerve), which respectively represent the pulse train test results of experimental group E (50 Hz) and experimental group F (10 kHz), and the test results of experimental group G (500 kHz, single pulse train) and experimental group H (500 kHz, continuous pulse train). Fig.11 As shown in the figure, when 500 kHz ultra-high frequency electrical stimulation is applied, the performance of the brain nerve stimulation threshold is roughly the same regardless of the test results of a single pulse train or a continuous pulse train. However, compared with the results of other lower frequency tests of 50 Hz and 10 kHz, there is a significant difference. The brain nerve stimulation threshold of 500 kHz ultra-high frequency electrical stimulation is significantly greater than that of the lower frequency tests of 50 Hz and 10 kHz. Fig.12 As shown in the figure, when applying 500 kHz ultra-high frequency electrical stimulation, the performance of the sciatic nerve stimulation threshold is roughly the same regardless of the test results of a single pulse train or a continuous pulse train. However, compared with the test results of other lower frequencies of 50 Hz and 10 kHz, there is a significant difference. The sciatic nerve stimulation threshold of 500 kHz ultra-high frequency electrical stimulation is significantly greater than that of the sciatic nerve stimulation threshold of the lower frequencies of 50 Hz and 10 kHz.

[0129] The minimum voltage intensity of ultra-high frequency electrical stimulation signals (20 kHz~1000 kHz) for activating the brain or sciatic nerve is much higher than that of low frequency electrical stimulation signals (1 Hz~500 Hz) and high frequency electrical stimulation signals (1 kHz~10 kHz). In this way, it can be confirmed that ultra-high frequency electrical stimulation signals are localized electrical stimulation signals, which will not activate upstream or downstream neural structures, but can still achieve the effects of pain relief, symptom relief, and desensitization of overactive nerves, which provides greater protection for the safety of the organism receiving electrical stimulation.

[0130] In addition, when the voltage of the electrical stimulation signal generated by the electrical stimulation device is greater than 1.5 times the voltage threshold (the minimum voltage with therapeutic effect), the electrical stimulation signal still does not induce activation of the upstream neural structure or the downstream neural structure of the target area, and can inhibit and / or relieve pain, relieve symptoms, and reduce nerve sensitivity. When the voltage of the electrical stimulation signal generated by the electrical stimulation device is greater than 1.5 to 5 times (1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, or 5 times) the voltage threshold, the electrical stimulation signal still does not induce activation of the upstream neural structure or the downstream neural structure of the target area, and can inhibit and / or relieve pain, relieve symptoms, and reduce nerve sensitivity. For example, when the voltage threshold is 3V, that is, the minimum voltage that has therapeutic effect is 3V (depending on the application scenario, the voltage threshold may be different), when ultra-high frequency electrical stimulation is performed, when the voltage of the electrical stimulation signal is 1.5 times the voltage threshold (4.5V), it will still not induce activation of the upstream neural structure or the downstream neural structure of the target area, but will only cause activation of the neural structure within a radius of 3 cm from the target area.

[0131] In addition, when ultra-high frequency electrical stimulation is performed at a voltage intensity with therapeutic effect (voltage greater than the voltage threshold), the daily cumulative time of using the electrical stimulation device to generate electrical stimulation signals is less than 12 hours per day. For example, each use is 5 minutes to 60 minutes, 1 time to 12 times a day. From the above results, it can be seen that the ultra-high frequency electrical stimulation generated by the electrical stimulation device will not cause orthodromic or retrograde neural signal conduction. In the case where the ultra-high frequency electrical stimulation generated by the electrical stimulation device does not cause orthodromic or retrograde neural signal conduction, the ultra-high frequency electrical stimulation generated by the electrical stimulation device will not affect the spinal cord circuit and will not cause spinal cord injury or neurological deficits.

[0132] Example 3: Clinical Trial

[0133] The clinical trial was conducted in a double-blind, double-armed manner, and the enrolled carpal tunnel syndrome subjects were randomly divided into a trial group (28 subjects) and a placebo group (30 subjects). Both the trial group and the placebo group wore a StimOn electrical stimulation device (GIMER Medical, Taiwan, China) on the median nerve of the wrist to receive transcutaneous electrical stimulation at the wrist. The median nerve of the wrist is a peripheral nerve.

[0134] The experimental group received an electrical stimulation signal generated by an electrical stimulation device. The electrical stimulation signal included multiple burst signals with a burst frequency of 2 Hz. Each burst signal included multiple pulses with a pulse frequency of 500 kHz. The voltage of the electrical stimulation signal was approximately ±3.0V. The duration of the electrical stimulation signal was 15 minutes, while the placebo group did not receive an electrical stimulation signal. During the electrical stimulation, the subjects were asked whether they had any abnormal sensations (paresthesia), including shaking, tingling, or slapping. In other words, during the electrical stimulation, the subjects were asked whether they felt that they were being electrically stimulated.

[0135] Please refer to Table 1, there is no significant difference between the two groups. In other words, the ultra-high frequency electrical stimulation signal generated by the electrical stimulation device only acts on the local area, only generates regional local potential, and does not induce action potential to be transmitted to the brain to produce perception. Therefore, the subjects cannot perceive the generation of electrical stimulation signals.

[0136] Table 1

[0137]

[0138] Traditional low-frequency electrical stimulation will exceed the nerve stimulation threshold and induce action potentials, and transmit signals to the brain, making people feel the electrical stimulation signals and thereby masking the feeling of pain. In contrast, the ultra-high frequency electrical stimulation generated by the electrical stimulation device will not induce action potentials to be transmitted to the brain and produce perception. In other words, the ultra-high frequency electrical stimulation generated by the electrical stimulation device is "paresthesia-free" electrical stimulation, which can also be called "paresthesia-independent" electrical stimulation, "subthreshold stimulation" electrical stimulation, "subthreshold stimulation" electrical stimulation or "sub-perception" electrical stimulation.

[0139] In summary, the electrical stimulation device or method will not induce activation of upstream or downstream neural structures in the target area. At a voltage intensity with therapeutic effects, the electrical stimulation device or method will not cause activation of anterograde or retrograde neural structures, will not affect the spinal loop, will not cause spinal cord injury, will not cause electromyographic signal conduction, and will not cause neurological deficits. The electrical stimulation signal of the electrical stimulation device or method is a "no paresthesia" electrical stimulation signal, a "paresthesia-independent" electrical stimulation signal, a "subthreshold stimulation" electrical stimulation signal, or a "subperceptual" electrical stimulation signal.

Claims

1. An electrical stimulation device, characterized in that: Include: Electrode assembly; as well as an electrical stimulator, generating an electrical stimulation signal and coupled to the electrode assembly; The electrical stimulation signal is transmitted to the target area via the electrode assembly, the electrical stimulation signal comprises a plurality of burst signals, the burst frequency of the plurality of burst signals ranges from 0.1 Hz to 1000 Hz, each burst signal comprises a plurality of pulses, the pulse frequency of the plurality of pulses ranges from 20 kHz to 1000 kHz, and the electrical stimulation signal does not induce activation of upstream neural structures or downstream neural structures of the target area.

2. The electrical stimulation device according to claim 1, characterized in that The activation of the upstream neural structure generates an action potential for the upstream neural structure, and the activation of the downstream neural structure generates an action potential for the downstream neural structure.

3. The electrical stimulation device according to claim 1, characterized in that The upstream neural structure of the target area is cranial nerves or spinal cord.

4. The electrical stimulation device according to claim 1, characterized in that The downstream neural structure of the target area is the sciatic nerve, the sacral nerve or a peripheral nerve.

5. The electrical stimulation device according to claim 1, characterized in that The electrical stimulation signal has a voltage threshold sufficient to reduce nerve sensitivity.

6. The electrical stimulation device according to claim 5, characterized in that When the voltage of the electrical stimulation signal is greater than 1.5 times the voltage threshold, the electrical stimulation signal still does not induce activation of the upstream neural structure or the downstream neural structure of the target area.

7. The electrical stimulation device according to claim 6, characterized in that The pulse frequency of the electrical stimulation signal ranges from 100 kHz to 750 kHz.

8. The electrical stimulation device according to claim 1, characterized in that The upstream neural structure or the downstream neural structure is outside the 3 cm radius of the target area.

9. The electrical stimulation device according to claim 1, characterized in that The cumulative time of the electrical stimulation signal is less than 12 hours per day.

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