Method for treating, improving, alleviating or preventing visual impairment due to presbyopia

Abstract

To provide a method for treating, improving, alleviating or preventing a decrease in visual function due to presbyopia. [Solution] A method for treating, improving, alleviating or preventing visual function decline due to presbyopia, comprising the steps of (A-1) administering repetitive transcranial magnetic stimulation (rTMS) or (A-2) transcranial electrical stimulation to the brain of a subject suffering from presbyopia.

Description

[Technical field]

[0001] The present invention relates to a method for treating, ameliorating, alleviating or preventing visual impairment due to presbyopia. [Background technology]

[0002] Presbyopia is a condition in which the eyes' ability to adjust focus decreases with age, making it difficult to focus on nearby objects. Presbyopia weakens the contrast of high spatial frequencies in retinal images, reducing near visual acuity (NVA) and contrast sensitivity (CS) (Non-Patent Documents 1-3). Because contrast is important in eliciting neural responses, the low-contrast, blurred retinal images caused by presbyopia weaken and slow the response of the visual cortex. This is thought to be the cause of the reduced NVA and CS observed in presbyopia (Non-Patent Document 4).

[0003] Currently, the only treatment for presbyopia is through the use of glasses or contact lenses. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2009 / 063435 [Non-patent literature]

[0005] [Non-Patent Document 1] Vision Research, 1983, 23(7), 689-699 [Non-Patent Document 2] Vision Research,2009,49(21),2566-2573 [Non-Patent Document 3] Journal of Vision,2009,9(7):18,1-15 [Non-Patent Document 4] Frontiers in Aging Neuroscience,2014,Volume6,Article163 [Non-Patent Document 5] Curr.Biol.,2007,17(6),R196-199 [Non-Patent Document 6] Proc. Natl. Acad. Sci. USA, 2008, 105(10), 4068-4073 [Non-Patent Document 7] Scientific Reports,2012,2,364 [Non-Patent Document 8] Perception & Psychophysics,1983,33(2),113-120 [Non-Patent Document 9] J. Neurosci,,2019,39(28),5551-5561 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a method for treating, ameliorating, alleviating or preventing visual function loss due to presbyopia. [Means for solving the problem]

[0007] The present inventors have obtained a novel finding that the symptoms of presbyopia can be improved by applying transcranial electrical stimulation or transcranial magnetic stimulation to the brain of a human subject with symptoms of presbyopia. Transcranial electrical stimulation or transcranial magnetic stimulation as non-invasive brain stimulation (NIBS) uses electrodes attached to the head or magnetic induction to stimulate a specific part of the brain and change the neural activity of the basal cortex (Non-Patent Document 5). It has been reported that visual function was improved by combining non-invasive brain stimulation and perceptual learning in a test on amblyopic human subjects (Patent Document 1). On the other hand, presbyopia is a symptom in which it becomes difficult to focus on nearby objects due to a decline in the focusing ability of the eyes with age, and the finding that non-invasive brain stimulation improves the symptoms of presbyopia is surprising.

[0008] The present invention based on the above-mentioned novel findings relates, in one aspect, to a method for treating, improving, alleviating, or preventing a decline in visual function due to presbyopia, the method comprising the step of (A-1) administering repetitive transcranial magnetic stimulation (rTMS) to the brain of a subject suffering from presbyopia.

[0009] In another aspect, the present invention relates to a method for treating, improving, alleviating, or preventing a decline in visual function due to presbyopia, the method comprising the step of (A-2) administering transcranial electrical stimulation to the brain of a subject suffering from presbyopia.

[0010] Each of the above methods may further include the step of (B) the subject performing a contrast detection task.

[0011] The present invention encompasses the following. [1] A method for treating, improving, alleviating, or preventing visual impairment due to presbyopia, comprising: (A-1) A method comprising a step of administering repetitive transcranial magnetic stimulation (rTMS) to the brain of a subject suffering from presbyopia. [2] The method according to [1], wherein the repetitive transcranial magnetic stimulation is continuous theta burst stimulation (cTBS). [3] The method according to [1] or [2], wherein the site to which the repetitive transcranial magnetic stimulation is administered is a site capable of perceiving phosphenes, or a site above the inion if the subject is unable to perceive phosphenes. [4] The method according to any one of [1] to [3], wherein the magnetic field strength of the repetitive transcranial magnetic stimulation is 0.05 T or more and 4.5 T or less. [5] The method according to any of [1] to [4], wherein the repetitive transcranial magnetic stimulation is administered as a pulse of at least 1 and at most 5 pulses every 200 msec. [6] The method according to any one of [1] to [5], wherein the frequency of the repetitive transcranial magnetic stimulation is 1 Hz or more and 100 Hz or less. [7] The method according to any one of [1] to [6], wherein the repetitive transcranial magnetic stimulation is administered for a period of time ranging from 1 second to 20 minutes. [8] The method according to any one of [1] to [7], wherein the repetitive transcranial magnetic stimulation is performed for a total of 100 to 1,000 pulses. [9] The method according to any of [1] to [8], wherein the coil for applying the repetitive transcranial magnetic stimulation is positioned so that the current flowing from the device body to the coil is parallel to the contact plane of the part of the subject to which the repetitive transcranial magnetic stimulation is applied, and flows from the cranial direction to the coccyx direction at that part.

[10] (B) The method according to any of [1] to [9], further comprising a step in which the subject performs a contrast detection task.

[11] The method according to

[10] , wherein the contrast detection task is training with Gabor patches.

[12] The method according to

[10] or

[11] , wherein the step (A-1) is carried out before or after the step (B).

[13] A method for treating, improving, alleviating, or preventing visual impairment due to presbyopia, comprising: (A-2) A method comprising a step of administering transcranial electrical stimulation to the brain of a subject suffering from presbyopia.

[14] The method according to

[13] , wherein the transcranial electrical stimulation is transcranial random noise stimulation (tRNS).

[15] The method according to

[13] or

[14] , wherein the site where the transcranial electrical stimulation is applied includes the occipital region.

[16] The method according to any of

[13] to

[15] , wherein the site to which the transcranial electrical stimulation is applied includes the occipital pole.

[17] The method according to any one of

[13] to

[15] , wherein the site to which the transcranial electrical stimulation is applied includes the occipital poles of the left and right brain.

[18] The method according to any one of

[13] to

[17] , wherein the current used for the transcranial electrical stimulation is 0.1 mA or more and 5 mA or less.

[19] The method according to any one of

[13] to

[18] , wherein the current used for the transcranial electrical stimulation varies in the range of 1 Hz or more and 1000 Hz or less.

[20] The method according to any one of

[13] to

[19] , wherein the electrical resistance is 0 Ω or more and 50 kΩ or less. [twenty one] The method according to any one of

[13] to

[20] , wherein the size of the electrode is a diameter of 0.5 cm or more and 10 cm or less. [twenty two] The method according to any one of

[13] to

[21] , wherein the electrodes are made of a conductive material. [twenty three] (B) A method according to any of

[13] to

[22] , further comprising a step in which the subject performs a contrast detection task. [twenty four] The method according to

[23] , wherein step (A-2) is carried out simultaneously with step (B). [twenty five] A method according to any one of [1] to

[24] , which is a method for improving the visual sensitivity of a subject suffering from presbyopia.

[0012] The present invention further includes the following: [A1] A system for treating, improving, mitigating or preventing visual function loss due to presbyopia, comprising a repetitive transcranial magnetic stimulation therapy device. [A2] A system for treating, improving, mitigating or preventing visual function loss due to presbyopia, comprising a transcranial electrical stimulation treatment device. [A3] The system according to [A1] or [A2], further comprising a contrast detection task providing device. [A4] The system described in any of [A1] to [A3] is for improving the visual sensitivity of a subject suffering from presbyopia. [B1] Use of a repetitive transcranial magnetic stimulation therapy device in the manufacture of a system for treating, improving, mitigating or preventing visual function loss due to presbyopia. [B2] Use of a transcranial electrical stimulation therapeutic device in the manufacture of a system for treating, improving, mitigating or preventing visual function loss due to presbyopia. [C1] A repetitive transcranial magnetic stimulation therapeutic device for use in a method for treating, improving, alleviating or preventing visual function decline due to presbyopia, as described in any one of [1] to

[11] and

[24] . [C2] A transcranial electrical stimulation treatment device for use in a method for treating, improving, alleviating or preventing visual function decline due to presbyopia, as described in any one of

[12] to

[24] . Effect of the Invention

[0013] According to the present invention, a method for treating, improving, alleviating or preventing a decline in visual function due to presbyopia can be provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Hereinafter, an embodiment of the present invention will be described in detail. However, the present invention is not limited to the following embodiment.

[0015] [Method for treating, improving, alleviating or preventing visual impairment due to presbyopia] The method for treating, improving, alleviating, or preventing visual function decline due to presbyopia according to this embodiment (hereinafter also simply referred to as the "method") includes at least one of the following steps (A-1) and (A-2). (A-1) A process of administering repetitive transcranial magnetic stimulation (rTMS) to the brain of a subject suffering from presbyopia (A-2) A step of applying transcranial electrical stimulation to the brain of a subject suffering from presbyopia.

[0016] The method according to the present embodiment can improve the visual impairment caused by presbyopia in subjects suffering from presbyopia. Improvement of visual impairment includes, for example, improving visual sensitivity, improving near visual acuity (NVA), improving near visual acuity under correction for distance (DCNVA), improving contrast sensitivity (CS), improving reading visual acuity, improving reading speed, reducing critical print size (the minimum print size that can maintain maximum reading speed), reducing the rate of reading glasses use in daily life, and improving satisfaction with near visual acuity.

[0017] Step (A-1) is a step of applying repetitive transcranial magnetic stimulation (rTMS) to the brain of a subject suffering from presbyopia. The repetitive transcranial magnetic stimulation can be applied to the brain of the subject using an existing repetitive transcranial magnetic stimulation treatment (e.g., treatment of depression) or a repetitive transcranial magnetic stimulation treatment device used in research.

[0018] The repetitive transcranial magnetic stimulation therapy device includes at least a coil placed on the head of a subject, and a current supply unit that supplies a predetermined current to the coil. The current supplied to the coil generates a magnetic field in the coil, and the magnetic field generates a current in the brain of the subject. The brain can be stimulated non-invasively by this current. Specific examples of repetitive transcranial magnetic stimulation therapy devices include, for example, MagPro X100 with magoption (manufactured by MagVenture A / S), MagPro Compact (manufactured by MagVenture A / S), and Rapid 2 (Magstim), MEGA-TMS (Soterix Medical), and DuoMAG XT (Deymed Diagnostic).

[0019] The site to which the repetitive transcranial magnetic stimulation is applied is preferably a site where the subject can perceive phosphenes. Phosphenes refer to the phenomenon of perceiving light in the absence of external optical stimuli. The site where the subject can perceive phosphenes can be identified as the site where the subject perceives phosphenes at the lowest intensity when a single-pulse or double-pulse magnetic stimulation is applied to a site above the inion (toward the top of the head). In this case, the site where the subject can perceive phosphenes can be identified by systematically changing the site to which the magnetic stimulation is applied and the intensity of the magnetic stimulation and screening.

[0020] If the subject is unable to sense phosphene even after screening using the above-mentioned method, an arbitrary site above the inion is used for the subject. The arbitrary site is preferably within a range of 1 cm to 10 cm above the inion and 5 cm to the left and 5 cm to the right of the inion, more preferably within a range of 1 cm to 5 cm above the inion and 3 cm to the left and 3 cm to the right of the inion, and even more preferably within a range of 3 cm above the inion. The arbitrary site may be a site slightly shifted up or down or to the left or right from the above-mentioned sites.

[0021] The repetitive transcranial magnetic stimulation in step (A-1) may be, for example, a transcranial magnetic stimulation that continuously applies regular pulses, or a transcranial magnetic stimulation that continuously applies irregularly changing pulses. From the viewpoint of more significant improvement in visual function decline, the repetitive transcranial magnetic stimulation in step (A-1) is preferably a transcranial magnetic stimulation that continuously applies irregularly changing pulses, and more preferably continuous theta burst stimulation (cTBS). The stimulation may be applied as a single pulse or double pulse, with a single pulse being preferred.

[0022] The intensity of the repetitive transcranial magnetic stimulation in step (A-1) is preferably a single pulse or double pulse, and is equal to or lower than the threshold at which the subject can perceive phosphene. From this viewpoint, the repetitive transcranial magnetic stimulation in step (A-1) may have a magnetic field intensity of, for example, 0.05 T or more and 4.5 T or less. The magnetic field intensity of the repetitive transcranial magnetic stimulation in step (A-1) can be set based on the output% of the repetitive transcranial magnetic stimulation treatment device used. From the viewpoint of more significant improvement of visual function decline, for example, when MagPro Compact (manufactured by MagVenture A / S) is used as the repetitive transcranial magnetic stimulation treatment device, the magnetic field intensity of the repetitive transcranial magnetic stimulation is preferably 10% to 100% of the output of the device, more preferably 30% to 80%, even more preferably 45% to 65%, and even more preferably 50%.

[0023] The coil for applying repetitive transcranial magnetic stimulation is preferably arranged so that the current flowing from the device body toward the coil is approximately parallel to the tangent plane of the part of the subject to which the repetitive transcranial magnetic stimulation is applied, and flows from the cranial direction to the coccygeal direction at the part. This makes the effect of improving visual function deterioration due to presbyopia more pronounced, and also increases the comfort of the subject during stimulation. Here, "approximately parallel" means that the angle between the tangent plane of the part of the subject to which the repetitive transcranial magnetic stimulation is applied and the plane containing the current flowing through the coil is -10° or more and 10° or less, and the angle is preferably -5° or more and 5° or less, more preferably -3° or more and 3° or less, even more preferably -2° or more and 2° or less, even more preferably -1° or more and 1° or less, and is particularly preferably 0° (i.e., parallel). In addition, the direction of the current flowing from the device body to the coil from the cranial direction to the coccyx direction at the site where repetitive transcranial magnetic stimulation is applied is preferably parallel to the midline of the subject, from the viewpoint of more pronounced improvement of visual function deterioration due to presbyopia and from the viewpoint of increasing the subject's comfort during stimulation. In addition, if the coil has a handle, it is more preferable to position the handle so that it points approximately in the 12 o'clock direction with respect to the occipital pole.

[0024] The repetitive transcranial magnetic stimulation in step (A-1) may have a minimum unit of 1 to 5 pulses every 200 ms, preferably 2 to 4 pulses every 200 ms, more preferably 3 pulses every 200 ms.

[0025] The frequency (pulse frequency) of the repetitive transcranial magnetic stimulation in step (A-1) may be, for example, 1 Hz or more and 100 Hz or less. From the viewpoint of more significant improvement of visual function decline, the frequency (pulse frequency) of the repetitive transcranial magnetic stimulation in step (A-1) is preferably 10 Hz or more and 90 Hz or less, 20 Hz or more and 80 Hz or less, 30 Hz or more and 70 Hz or less, 40 Hz or more and 60 Hz or less, or 50 Hz.

[0026] The time for applying the repetitive transcranial magnetic stimulation in step (A-1) may be, for example, 1 second or more and 20 minutes or less. From the viewpoint of more significant improvement in visual function decline, the time for applying the repetitive transcranial magnetic stimulation in step (A-1) is preferably 5 seconds or more and 15 minutes or less, 10 seconds or more and 10 minutes or less, 15 seconds or more and 5 minutes or less, 20 seconds or more and 3 minutes or less, 25 seconds or more and 2 minutes or less, 30 seconds or more and 1 minute or less, 35 seconds or more and 50 seconds or less, or 40 seconds.

[0027] The total number of repetitive transcranial magnetic stimulations in step (A-1) may be, for example, 100 to 1000 pulses. From the viewpoint of more significant improvement in visual function decline, the total number of repetitive transcranial magnetic stimulations in step (A-1) is preferably 200 to 900 pulses, 300 to 800 pulses, 400 to 700 pulses, 500 to 600 pulses, or 600 pulses.

[0028] In the method according to the present embodiment, it is preferable to repeat the (A-1) step, from the viewpoint of more significant improvement of visual function decline. When the (A-1) step is repeated, the interval between the (A-1) steps may be, for example, 1 day or more and 1 month or less, 1 day or more and 1 week or less, 1 day or more and 3 days or less, and is preferably 2 days. The number of times that the (A-1) step is repeated may be, for example, 2 times or more and 10 times or less, 3 times or more and 8 times or less, 4 times or more and 6 times or less, or 5 times.

[0029] Step (A-2) is a step of providing transcranial electrical stimulation to the brain of a subject suffering from presbyopia. The transcranial electrical stimulation can be provided to the brain of the subject using an existing transcranial electrical stimulation treatment device or a transcranial electrical stimulation treatment device used in research.

[0030] The transcranial electrical stimulation treatment device includes at least a pair of electrodes to be placed on the external head of the subject, and a voltage supply unit to supply a predetermined voltage to the electrodes. The pair of electrodes is placed on the external head of the subject, and the subject's brain is energized by the voltage supplied from the voltage supply unit. This current can stimulate the brain non-invasively. Specific examples of transcranial electrical stimulation treatment devices include StarSstim8 (manufactured by Neuroelectrics), neuroConn DC-stimulator Plus (manufactured by neuroConn), and 1×1 transcranial Electrical Stimulation (1×1-tES) device (manufactured by Soterix Medical).

[0031] The size of the electrode of the transcranial electrical stimulation treatment device used in step (A-2) may be, for example, 0.5 cm to 10 cm in diameter. The diameter here refers to the diameter of the surface placed on the subject's head. The smaller the diameter, the stronger the stimulation that can be given. From the viewpoint of more significant improvement in visual function decline, the size of the electrode is preferably 0.5 cm to 3 cm in diameter, more preferably 0.5 cm to 2 cm in diameter, and even more preferably 1 cm to 1.5 cm in diameter. The electrode may be made of a conductive material such as a metal, or may be made of sponge. From the viewpoint of increasing the focal point, the electrode is preferably made of a metal, and more preferably a silver / silver chloride sintered body (silver-silver chloride sintered plate electrode).

[0032] From the viewpoint of more significant improvement of visual function decline, the site to which the transcranial electrical stimulation is applied preferably includes the occipital region of the subject, more preferably includes the occipital pole of the subject, and even more preferably includes the occipital poles of the left and right brains of the subject. When the site to which the transcranial electrical stimulation is applied includes the occipital poles of the left and right brains of the subject, one of a pair of electrodes may be placed at the occipital pole of the left brain, and the other may be placed at the occipital pole of the right brain.

[0033] The transcranial electrical stimulation in step (A-2) may be, for example, transcranial direct current stimulation (tDCS) that applies a direct current, transcranial alternating current stimulation (tACS) that applies an alternating current, or transcranial random noise stimulation (tRNS). From the viewpoint of more significant improvement in visual function decline, the transcranial electrical stimulation in step (A-2) is preferably transcranial random noise stimulation (tRNS).

[0034] The current used for the transcranial electrical stimulation in step (A-2) may be, for example, 0.1 mA to 5.0 mA. From the viewpoint of more significant improvement in visual function decline, the current used for the transcranial electrical stimulation in step (A-2) is preferably 0.2 mA to 4.5 mA, 0.3 mA to 4.0 mA, 0.4 mA to 3.5 mA, 0.5 mA to 3.0 mA, 0.6 mA to 2.5 mA, 0.7 mA to 2.0 mA, 0.8 mA to 1.5 mA, 0.9 mA to 1.0 mA, or 1.0 mA.

[0035] The current used for the transcranial electrical stimulation in step (A-2) may vary within a range of, for example, 1 Hz to 1000 Hz. That is, the frequency may be 1 Hz to 1000 Hz. From the viewpoint of more significant improvement of visual function decline, the current used for the transcranial electrical stimulation in step (A-2) preferably has a frequency of 20 Hz to 950 Hz, 40 Hz to 900 Hz, 60 Hz to 850 Hz, 70 Hz to 800 Hz, 80 Hz to 750 Hz, 90 Hz to 700 Hz, 100 Hz to 650 Hz, or 101 Hz to 640 Hz.

[0036] The transcranial electrical stimulation in step (A-2) may have an electrical resistance of, for example, 0 Ω or more and 50 kΩ or less. From the viewpoint of more significant improvement in visual function decline, the transcranial electrical stimulation in step (A-2) preferably has an electrical resistance of 0 Ω or more and 20 kΩ or less, more preferably 1 kΩ or more and 20 kΩ or less, even more preferably 1 kΩ or more and 15 kΩ or less, even more preferably 1 kΩ or more and 10 kΩ or less, and particularly preferably 1 kΩ or more and 5 kΩ or less.

[0037] The time for applying the transcranial electrical stimulation in step (A-2) may be, for example, 1 minute or more and 60 minutes or less. From the viewpoint of more significant improvement in visual function decline, the time for applying the transcranial electrical stimulation in step (A-2) is preferably 5 minutes or more and 50 minutes or less, 10 minutes or more and 40 minutes or less, 15 minutes or more and 30 minutes or less, or 20 minutes.

[0038] In the method according to the present embodiment, it is preferable to repeat the (A-2) step, from the viewpoint of more significant improvement of visual function decline. When the (A-2) step is repeated, the interval between the (A-2) steps may be, for example, 1 day or more and 1 month or less, 1 day or more and 1 week or less, or 1 day or more and 3 days or less, and is preferably 2 days. The number of times that the (A-2) step is repeated may be, for example, 2 times or more and 10 times or less, 3 times or more and 8 times or less, 4 times or more and 6 times or less, or 5 times.

[0039] The method for treating, improving, alleviating or preventing visual function decline caused by presbyopia according to this embodiment preferably further comprises the following step (B) in addition to step (A-1) and / or step (A-2). By including step (B), the improvement of visual function decline becomes more remarkable. (B) Subjects perform a contrast detection task.

[0040] The contrast detection task may, for example, follow the protocols described in Non-Patent Documents 6 and 7, which have been shown to improve visual performance in normal and strabismus human populations. The contrast detection task may, for example, include presenting a grating to the subject. The contrast detection task may, for example, be training using Gabor patches. From the viewpoint of more pronounced improvement of visual function decline, the contrast detection task may include presenting a grating near the subject's cutoff spatial frequency. The subject's cutoff spatial frequency may, for example, be determined by the method described in the Examples below.

[0041] When the method according to the present embodiment includes step (A-1) and step (B), step (A-1) may be performed simultaneously with step (B), or may be performed before or after step (B). From the viewpoint of avoiding the influence of the magnetic stimulation used in step (A-1) and enabling step (B) to be performed using a computer, step (A-1) is preferably performed before or after step (B).

[0042] When the method according to the present embodiment includes the step (A-2) and the step (B), the step (A-2) may be carried out simultaneously with the step (B), or may be carried out before or after the step (B). From the viewpoint of improving the efficiency of the process, it is preferable to carry out the step (A-2) and the step (B) simultaneously.

[0043] The method for treating, improving, alleviating, or preventing a decline in visual function due to presbyopia according to this embodiment can also be reinterpreted as, for example, the following (1) to (3).

[0044] (1) A system for treating, improving, mitigating, or preventing visual impairment due to presbyopia. The system for treating, improving, mitigating, or preventing visual function decline due to presbyopia (hereinafter, also simply referred to as the "system") according to this embodiment includes at least a repetitive transcranial magnetic stimulation therapy device or a transcranial electrical stimulation therapy device.

[0045] The repetitive transcranial magnetic stimulation therapy device and the transcranial electrical stimulation therapy device included in the system according to this embodiment can be applied in the same manner as described in the method for treating, improving, alleviating, or preventing visual function decline due to presbyopia. Also, as a specific operation method of these repetitive transcranial magnetic stimulation therapy device and transcranial electrical stimulation therapy device, the same manner as described in the method for treating, improving, alleviating, or preventing visual function decline due to presbyopia can be applied.

[0046] The system according to the present embodiment may further include a contrast detection task providing device in combination with the repetitive transcranial magnetic stimulation therapy device or the transcranial electrical stimulation therapy device. The contrast detection task providing device may present a contrast detection task (e.g., present a grating) to the subject in response to an input from the subject or in accordance with a preset program. The contrast detection task providing device may be configured, for example, as a combination of a normal computer and monitor, a tablet, or the like. The contrast detection task presented to the subject by the contrast detection task providing device may be similar to that described in the method for treating, improving, mitigating, or preventing visual function deterioration due to presbyopia.

[0047] The system according to the present embodiment may be one in which a repetitive transcranial magnetic stimulation therapy device or a transcranial electrical stimulation therapy device and a contrast detection task providing device work together. Specifically, for example, the contrast detection task providing device may operate to provide a contrast detection task to a subject at a timing when the repetitive transcranial magnetic stimulation to the subject by the repetitive transcranial magnetic stimulation therapy device ends, the repetitive transcranial magnetic stimulation therapy device may operate to provide repetitive transcranial magnetic stimulation to the subject at a timing when the presentation of the contrast detection task to the subject by the contrast detection task providing device ends, or the contrast detection task providing device may operate to provide a contrast detection task to the subject at a timing when the transcranial electrical stimulation to the subject by the transcranial electrical stimulation therapy device starts.

[0048] Other specific aspects of the system according to this embodiment can be similar to those described in the method for treating, improving, mitigating, or preventing visual function deterioration due to presbyopia.

[0049] (2) Use (method) of a repetitive transcranial magnetic stimulation therapy device or a transcranial electrical stimulation therapy device The use of a repetitive transcranial magnetic stimulation therapy device or a transcranial electrical stimulation therapy device in this embodiment is the use of a repetitive transcranial magnetic stimulation therapy device or a transcranial electrical stimulation therapy device in the manufacture of a system for treating, improving, alleviating or preventing visual function decline due to presbyopia.

[0050] The system for treating, improving, mitigating or preventing visual function loss due to presbyopia is similar to that described in (1).

[0051] (3) A repetitive transcranial magnetic stimulation therapeutic device or a transcranial electrical stimulation therapeutic device for use in a method for treating, improving, mitigating, or preventing visual impairment due to presbyopia. The method for treating, improving, alleviating or preventing visual function decline due to presbyopia according to the present invention uses repetitive transcranial magnetic stimulation and transcranial electrical stimulation, which have not been used to improve presbyopia in the past, and therefore provides a new method for using a repetitive transcranial magnetic stimulation treatment device and a transcranial electrical stimulation treatment device that provide the repetitive transcranial magnetic stimulation and transcranial electrical stimulation. Therefore, the present invention can also be considered as a repetitive transcranial magnetic stimulation treatment device or a transcranial electrical stimulation treatment device for use in a method for treating, improving, alleviating or preventing visual function decline due to presbyopia. The specific aspects of the method for treating, improving, alleviating or preventing visual function decline due to presbyopia, and the specific aspects of the repetitive transcranial magnetic stimulation treatment device or the transcranial electrical stimulation treatment device can be similar to those described in the method for treating, improving, alleviating or preventing visual function decline due to presbyopia. EXAMPLES

[0052] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to the following examples.

[0053] [Test Method] (subject) The subjects were adult humans with symptoms of presbyopia, and 30 subjects were selected according to the following inclusion and exclusion criteria. <Recruitment criteria> (1) Be an adult between 40 and 55 years of age (2) Have been diagnosed with presbyopia (defined as a near prescription of +0.75DS or greater at a distance of 40cm) (3) Distance visual acuity (logMAR) of both eyes must be 0.10 or less (dispersion visual acuity (at 6m) must be 6 / 7.5 or less) (4) The difference in best corrected visual acuity (BCVA) between the two eyes must not exceed one line in logMAR. <Exclusion criteria> (5) Having an eye condition that affects vision (6) Having a history of ophthalmic surgery such as refractive surgery, cataract removal, or intraocular lens implantation. (7) Any neurological condition that affects vision or visual function. (8) Non-invasive brain stimulation therapy is contraindicated

[0054] (Study Design) The subjects were divided into the following three groups (10 subjects in each group). Group 1: Transcranial random noise stimulation (tRNS) combined with perceptual learning (PL) Group 2: Repetitive transcranial magnetic stimulation (rTMS) combined with perceptual learning (PL) Group 3: Sham (tDCS) combined with perceptual learning (PL) Note that perceptual learning (PL) is a contrast detection task.

[0055] The subjects visited the Centre for Eye and Vision Research on Day 1 (Visit 1), Day 3 (Visit 2), Day 5 (Visit 3), Day 7 (Visit 4), Day 9 (Visit 5), Day 11 (Visit 6), Day 13 (Visit 7), and Day 41 (Visit 8) to undergo the prescribed measurements and training. Details of the items performed at each visit are as follows.

[0056] (Visit 1): Day 1 [Time required: 2 hours] Eligibility assessment was performed (see inclusion and exclusion criteria above). Allocation to groups 1 to 3 was performed. Baseline measurements were performed before training. Measurements included corrected distance visual acuity (DCNVA) and contrast sensitivity function (CSF).

[0057] (Visits 2-6): Days 3, 5, 7, 9 and 11 [Time required: 2 hours each] Non-invasive brain stimulation (tRNS, rTMS or sham (tDCS)) was administered. Stimulation was constant for each subject at all visits. A contrast detection task was performed using individual subjects' cutoff spatial frequencies. -Measurements of corrected distance visual acuity (DCNVA) were performed.

[0058] (Visit 7): Day 13 [Time required: 2 hours] Post-training measurements were performed, including corrected distance and near visual acuity (DCNVA).

[0059] (Visit 8): Day 41 [Time required: 2 hours] One month after the training, measurements were conducted to examine the maintenance of the intervention effects. Measurements included corrected distance and near visual acuity (DCNVA).

[0060] A margin of error of ±1 day was allowed for scheduling at each of Visits 1 to 8. All measurements and training during the visits were performed binocularly, using the distance correction determined at Visit 1, and no additional near correction was performed.

[0061] (Contrast detection task) The contrast detection task followed the protocol described in Non-Patent Documents 6 and 7, which has been shown to improve visual performance in normal and strabismus human populations. The contrast detection task involved the presentation of a grating near each subject's cutoff spatial frequency. The cutoff spatial frequency was defined as the spatial frequency at which the contrast threshold of the contrast sensitivity function (CSF) at baseline measurement was 0.50.

[0062] (Contrast Sensitivity Function) Contrast detection thresholds at five spatial frequencies (e.g., 0.5, 1, 5, 10, and 15 cycles / degree) uniformly spaced on a logarithmic scale were determined using a Bayesian method (see non-patent literature 8). These thresholds were fitted to a contrast sensitivity function (CSF) as a function of spatial frequency.

[0063] (Non-invasive Brain Stimulation) Transcranial random noise stimulation (tRNS) was performed using a transcranial electrical stimulation treatment device (StarSstim8, manufactured by Neuroelectrics, electrode size: cylindrical with a diameter of 1.2 cm, electrode: silver-silver chloride sintered plate electrode). Referring to the conditions described in Non-Patent Document 9, electrodes were placed on both occipital poles of the subject, and a current of 1.0 mA was applied at a frequency of 101 Hz to 640 Hz. The application of stimulation consisted of 20 seconds (Ramp up) from 0 mA at the start of stimulation to 1.0 mA, 20 minutes of current application at 1.0 mA, and 20 seconds (Ramp down) from 1 mA to 0 mA. Transcranial random noise stimulation was given to the subject while he was performing a contrast detection task.

[0064] Repetitive transcranial magnetic stimulation (rTMS) was performed using a transcranial magnetic stimulation device (MagPro X100 with magoption, MagVenture A / S). Repetitive transcranial magnetic stimulation was delivered to the primary visual cortex in the form of continuous theta burst stimulation (cTBS). The site where cTBS was administered to each subject was determined as follows. Single-pulse transcranial magnetic stimulation was delivered to a 5 cm × 5 cm grid of points, with the lower edge of the grid centered on the inion. The intensity of the magnetic stimulation was systematically varied to identify the optimal stimulation site and the minimum magnetic stimulation intensity required to elicit phosphenes in 5 of 10 pulses. If the subject did not perceive phosphenes, a similar identification procedure was performed with double-pulse transcranial magnetic stimulation. Starting with a magnetic intensity of 45% of the maximum output of the device, double-pulse transcranial magnetic stimulation was applied to a 5 cm × 5 cm grid of points with the bottom edge of the grid at the center of the inion. If no location evoked phosphenes, the same procedure was repeated, increasing the magnetic intensity by 10% until it reached 65% of the maximum output of the device. Double pulses were applied with a minimum interstimulus interval of 3 s and a 40 ms stimulus onset asynchronous. If phosphenes were still not perceived at a magnetic intensity of 65% of the maximum output of the device, the magnetic intensity was increased by 5% until the subject reported perceiving phosphenes. This was repeated up to a magnetic intensity of 80% of the maximum output of the device. If perception of phosphenes still did not occur, the site for application of cTBS was set to a site 3 cm above the inion. In addition, the coil was positioned and oriented when applying magnetic stimulation so that the flat surface of the coil was parallel to the contact surface with the head, the handle was above the coil and approximately parallel to the midline (12 o'clock direction relative to the occipital pole), and current flowed from the main body of the device to the coil in the cranial-coccygeal direction. The intensity of cTBS was set at 80% of the threshold for perceiving phosphene or 50% of the maximum output of the device if phosphene was not perceived, and was reduced if subjects could not tolerate these intensities. cTBS was configured to deliver 40 s of stimulation with three 50 Hz pulses every 200 ms (600 pulses in total). The transcranial magnetic stimulation device used was equipped with neuronavigation to ensure that cTBS was delivered to the same visual cortical location at each visit. cTBS was administered to subjects immediately before performing a contrast detection task.

[0065] The sham (tDCS) stimulation was performed using the same setup as the transcranial random noise stimulation (tRNS) and under the same conditions as the tRNS except that the 20-minute 1.0 mA current was not administered (i.e., only ramp up and ramp down). The sham (tDCS) stimulation was administered to subjects while they were performing a contrast detection task.

[0066] (Data Analysis) Statistical differences between groups were verified using paired t-tests.

[0067] (result) The mean corrected-for-distance-near visual acuity (DCNVA) of the subjects before training (Visit 1), after training (Visit 7), and one month after training (Visit 8) are shown in Tables 1 and 2.

[0068] [Table 1] [Table 2]

[0069] As shown in Table 1, Group 1 (tRNS) showed an improvement in corrected-for-distance near visual acuity (DCNVA) after training (Visit 7) compared to before training (Visit 1). In addition, as shown in Table 2, both Group 1 (tRNS) and Group 2 (TMS) showed an improvement in corrected-for-distance near visual acuity (DCNVA) one month after training (Visit 8).

Claims

1. A system for treating, improving, mitigating or preventing visual function loss due to presbyopia, comprising a repetitive transcranial magnetic stimulation therapy device.

2. A contrast detection task providing device is further provided, (A) the contrast detection task providing device operates to present a contrast detection task to the subject when the repetitive transcranial magnetic stimulation to the subject by the repetitive transcranial magnetic stimulation therapy device ends, (B) the repetitive transcranial magnetic stimulation therapy device operates to provide repetitive transcranial magnetic stimulation to the subject when the presentation of the contrast detection task to the subject by the contrast detection task providing device ends, or (C) the contrast detection task providing device operates to present a contrast detection task to the subject when the repetitive transcranial electrical stimulation therapy device starts transcranial electrical stimulation to the subject, The system of claim 1 , wherein the contrast detection task is training with Gabor patches.

3. 3. The system of claim 1 or 2, wherein the repetitive transcranial magnetic stimulation is continuous Theta Burst Stimulation (cTBS).

4. 3. The system of claim 1 or 2, wherein the site at which the repetitive transcranial magnetic stimulation is administered is a site at which the subject can perceive phosphenes, or a site above the inion if the subject cannot perceive phosphenes.

5. The system of claim 1 or 2, wherein the magnetic field strength of the repetitive transcranial magnetic stimulation is greater than or equal to 0.05 T and less than or equal to 4.5 T.

6. 3. The system of claim 1 or 2, wherein the repetitive transcranial magnetic stimulation is delivered as between 1 and 5 pulses every 200 msec.

7. The system of claim 1 or 2, wherein the frequency of the repetitive transcranial magnetic stimulation is greater than or equal to 1 Hz and less than or equal to 100 Hz.

8. The system of claim 1 or 2, wherein the time for administering the repetitive transcranial magnetic stimulation is at least 1 second and not more than 20 minutes.

9. The system of claim 1 or 2, wherein the total number of repetitive transcranial magnetic stimulation pulses is between 100 and 1000 pulses.

10. The system of claim 1 or 2, wherein the coil for applying the repetitive transcranial magnetic stimulation is positioned so that the current flowing from the device body to the coil is parallel to the tangent plane of the area of ​​the subject where the repetitive transcranial magnetic stimulation is applied, and flows from the cranial direction to the coccygeal direction at the area.

11. The system of claim 2, wherein the contrast detection task providing device is operated to present a contrast detection task to the subject when the repetitive transcranial magnetic stimulation to the subject by the repetitive transcranial magnetic stimulation therapy device is completed, or the repetitive transcranial magnetic stimulation therapy device is operated to provide repetitive transcranial magnetic stimulation to the subject when the presentation of the contrast detection task to the subject by the contrast detection task providing device is completed.

12. Use of a repetitive transcranial magnetic stimulation therapy device in the manufacture of a system for treating, improving, mitigating or preventing visual function loss due to presbyopia.

Images