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

Abstract

To provide a method for treating, improving, alleviating or preventing deterioration of visual function due to presbyopia. A method for treating, improving, alleviating, or preventing visual function decline due to presbyopia, the method 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 eye's ability to focus on nearby objects decreases with age. This results in blurred images on the retina and reduced contrast at high spatial frequencies. Blurred, out-of-focus retinal images cause reduced near visual acuity (NVA) and contrast sensitivity (CS) (Non-Patent Documents 1-3). Because contrast is important in eliciting neural responses, the 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 way to deal with presbyopia is to correct it with 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 impairment due to presbyopia. [Means for solving the problem]

[0007] The present inventors have discovered the novel finding that transcranial electrical stimulation or transcranial magnetic stimulation (TMS) can improve the symptoms of presbyopia in human subjects with presbyopia. Transcranial electrical stimulation or TMS is a type of noninvasive brain stimulation (NIBS) that uses electrodes attached to the head or magnetic induction to stimulate specific brain regions, thereby altering neural activity in the basal cortex (Non-Patent Document 5). Previous research on human subjects with amblyopia has reported that combining non-invasive brain stimulation with perceptual learning improved visual function (Patent Document 1). Meanwhile, presbyopia is characterized by a decline in the ability to focus on nearby objects due to a decline in the eye's focusing ability associated with aging. The finding that non-invasive brain stimulation can improve the symptoms of presbyopia is surprising.

[0008] The present invention based on the above-described 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 visual function decline 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) having the subject perform 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 where the subject can perceive phosphene, or a site around the inion if the subject cannot perceive phosphene. [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 one of [1] to [4], wherein the repetitive transcranial magnetic stimulation is administered as pulses at least once but not more than five times 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 1 second or more and 20 minutes or less. [8] The method according to any one of [1] to [7], wherein the total number of repetitive transcranial magnetic stimulations is 100 pulses or more and 1000 pulses or less. [9] The method according to any one of [1] to [8], wherein a coil for applying the repetitive transcranial magnetic stimulation is placed above the stimulation site, and a magnetic field is applied so that a current flows from the cranial direction to the caudal direction at the stimulation site.

[10] (B) The method according to any one 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 using Gabor patches.

[12] The method according to

[10] or

[11] , wherein step (A-1) is carried out before or after 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 to which the transcranial electrical stimulation is applied includes the occipital region.

[16] The method according to any one of

[13] to

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

[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 lobes of the left and right cerebral hemispheres.

[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 within a range of 1 Hz to 1000 Hz.

[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 electrode has 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) The method according to any one 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 according to any one of [A1] to [A3], which 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 impairment due to presbyopia. [B2] Use of a transcranial electrical stimulation therapy device in the manufacture of a system for treating, improving, mitigating or preventing visual impairment due to presbyopia. [C1] A repetitive transcranial magnetic stimulation treatment device for use in a method for treating, improving, alleviating, or preventing visual function decline due to presbyopia, as set forth in any 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 set forth in any one of

[12] to

[24] . [Effects 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 INVENTION

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

[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 step of applying 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 visual impairment due to presbyopia in a subject suffering from presbyopia, including, for example, improved visual sensitivity, improved near visual acuity (NVA), improved corrected-for-distance near visual acuity (DCNVA), improved contrast sensitivity (CS), improved reading acuity, improved reading speed, reduced critical type size (the smallest type size at which maximum reading speed can be maintained), reduced use of reading glasses in daily life, and improved satisfaction with near vision.

[0017] Step (A-1) is a step of administering repetitive transcranial magnetic stimulation (rTMS) to the brain of a subject suffering from presbyopia. The repetitive transcranial magnetic stimulation can be administered 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] A repetitive transcranial magnetic stimulation therapy device includes at least a coil placed at a stimulation site on the subject's head, 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 induces a current in the subject's brain. This induced current can stimulate the brain non-invasively. Specific examples of repetitive transcranial magnetic stimulation therapy devices include the MagPro X100 with MagOption (manufactured by MagVenture A / S), MagPro Compact (manufactured by MagVenture A / S), and Rapid 2 (manufactured by Magstim), MEGA-TMS (manufactured by Soterix Medical), DuoMAG XT (manufactured by Deymed Diagnostic), etc.

[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, for example, as the site where the subject perceives phosphenes at the lowest intensity when single-pulse or double-pulse magnetic stimulation is applied to a site above the subject's inion (toward the vertex). In this case, the site where the subject can perceive phosphenes can be identified by performing calibration by systematically changing the site to which the magnetic stimulation is applied and the intensity of the magnetic stimulation.

[0020] If the subject is unable to perceive phosphene even after performing the calibration using the above-described 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 3 cm above the inion. The arbitrary site may be slightly shifted up or down or to the left or right of the above-described site.

[0021] The repetitive transcranial magnetic stimulation in step (A-1) may be, for example, transcranial magnetic stimulation in which regular pulses are applied continuously, or transcranial magnetic stimulation in which pulses are applied continuously with irregular changes. From the viewpoint of more significant improvement in visual function decline, the repetitive transcranial magnetic stimulation in step (A-1) is preferably transcranial magnetic stimulation in which pulses are applied continuously with irregular changes, and more preferably continuous theta burst stimulation (cTBS). The stimulation can 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 below the threshold at which the subject can perceive phosphene. From this perspective, 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 percentage (%) of the maximum output of the repetitive transcranial magnetic stimulation treatment device used. From the perspective of achieving a more significant improvement in visual function decline, for example, when using a MagPro X100 with MagOption (manufactured by MagVenture A / S) 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 administering repetitive transcranial magnetic stimulation is preferably positioned so that the current flowing from the device body toward the coil is substantially parallel to the tangent plane of the target site to which the repetitive transcranial magnetic stimulation is administered, and so that the induced current flows from cranial to caudal at that site. This arrangement enhances the effect of improving visual function decline due to presbyopia and increases the subject's comfort during stimulation. Here, "substantially parallel" refers to the angle between the tangent plane of the target site to which the repetitive transcranial magnetic stimulation is administered and the plane containing the current flowing through the coil being between -10° and 10°. The angle is preferably between -5° and 5°, more preferably between -3° and 3°, even more preferably between -2° and 2°, even more preferably between -1° and 1°, and particularly preferably 0° (i.e., parallel). Furthermore, the direction of the current flowing from the device body to the coil positioned at the target site to which the repetitive transcranial magnetic stimulation is administered is preferably parallel, so that the induced current flows from cranial to caudal, in order to enhance the effect of improving visual function decline due to presbyopia. Furthermore, if the coil has a handle portion that is parallel to the plane of the coil (i.e., the direction of the magnetic field), in order to increase the subject's comfort during stimulation, it is more preferable to position the coil so that the handle portion points approximately at 12 o'clock relative to the occipital lobe, so that the induced current at the stimulation site flows from the cranial direction to the caudal direction.

[0024] The repetitive transcranial magnetic stimulation in step (A-1) may have a minimum unit of one to five pulses every 200 ms, preferably two to four pulses every 200 ms, and more preferably three 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 in 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 which the repetitive transcranial magnetic stimulation is administered in step (A-1) may be, for example, 1 second or more and 20 minutes or less. From the viewpoint of achieving a more significant improvement in visual function decline, the time for which the repetitive transcranial magnetic stimulation is administered 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 achieving a 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 repeatedly perform step (A-1) from the viewpoint of achieving a more significant improvement in visual function decline. When step (A-1) is repeated, the interval between steps (A-1) may be, for example, from one day to one month, from one day to one week, or from one day to three days, with two days being preferred. The number of times step (A-1) is repeated may be, for example, from two to ten times, from three to eight times, from four to six times, or five times.

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

[0030] A transcranial electrical stimulation treatment device includes at least a pair of electrodes that are placed on the external part of the subject's head and a voltage supply unit that supplies a predetermined voltage to the electrodes. The pair of electrodes are placed on the external part of the subject's head, and the subject's brain is stimulated 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 StarStim8 (manufactured by Neuroelectrics), neuroConn DC-stimulator Plus (manufactured by neuroConn), and the 1x1 transcranial Electrical Stimulation (1x1-tES) device (manufactured by Soterix Medical).

[0031] The size of the electrodes in 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 more focused the stimulation can be. From the viewpoint of more significant improvement in visual function decline, the size of the electrodes 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 electrodes may be made of, for example, a conductive material such as metal, or may be made of sponge. From the viewpoint of improving focality, the electrodes are preferably made of metal, and more preferably a silver / silver chloride sintered body (silver-silver chloride sintered plate electrode).

[0032] From the viewpoint of achieving a more significant improvement in visual function decline, the site to which transcranial electrical stimulation is applied preferably includes the occipital lobe of the subject, more preferably includes the occipital lobe of the subject, and even more preferably includes the occipital lobes of the subject's left and right cerebral hemispheres. When the site to which transcranial electrical stimulation is applied includes the occipital lobes of the subject's left and right cerebral hemispheres, one of a pair of electrodes may be placed in the occipital lobe of the left brain, and the other may be placed in the occipital lobe 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 achieving a 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, for example, within a range of 1 Hz to 1000 Hz. That is, the frequency may be 1 Hz to 1000 Hz. From the viewpoint of achieving a more significant improvement in 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, 101 Hz to 640 Hz, or 101 Hz to 500 Hz.

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

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

[0038] In the method according to the present embodiment, it is preferable to repeatedly perform step (A-2) from the viewpoint of achieving a more significant improvement in visual function decline. When step (A-2) is repeated, the interval between steps (A-2) may be, for example, from one day to one month, from one day to one week, or from one day to three days, with two days being preferred. The number of times step (A-2) is repeated may be, for example, from two to ten times, from three to eight times, from four to six times, or five times.

[0039] The method for treating, improving, alleviating, or preventing visual function decline due to 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), improvement of visual function decline becomes more significant. (B) Subject performs 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 amblyopic 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 in visual function decline, the contrast detection task may include presenting a grating near the subject's cutoff spatial frequency, but is not limited to a specific spatial frequency. The subject's cutoff spatial frequency can be determined, for example, by the method described in the Examples below.

[0041] When the method according to the present embodiment includes steps (A-1) and (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 steps, 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 simply referred to as "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 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. Furthermore, the specific operating methods of these repetitive transcranial magnetic stimulation therapy device and transcranial electrical stimulation therapy device can be applied in the same manner as described in the method for treating, improving, alleviating, or preventing visual function decline due to presbyopia.

[0046] The system according to this 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 stimulus (e.g., presenting a grating) to the subject in response to input from the subject or according to a preset program. The contrast detection task providing device may be configured, for example, as a combination of a regular 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 in aspect to that described in the method for treating, improving, alleviating, or preventing visual function decline 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 cooperates with a contrast detection task providing device. Specifically, for example, the contrast detection task providing device may be operated to provide a contrast detection task to a subject when the repetitive transcranial magnetic stimulation therapy device has finished providing the repetitive transcranial magnetic stimulation to the subject, the repetitive transcranial magnetic stimulation therapy device may be operated to administer the 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 has finished, or the contrast detection task providing device may be operated to provide a contrast detection task to the subject when the transcranial electrical stimulation therapy device has started providing the transcranial electrical stimulation to the subject.

[0048] Other specific aspects of the system according to this embodiment can be similar to those described in the method for treating, improving, alleviating, or preventing a decline in visual function 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 the repetitive transcranial magnetic stimulation therapy device or transcranial electrical stimulation therapy device in this embodiment is the use of the repetitive transcranial magnetic stimulation therapy device or transcranial electrical stimulation therapy device in the manufacture of a system for treating, improving, alleviating or preventing visual function loss due to presbyopia.

[0050] The system for treating, improving, alleviating or preventing visual impairment 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 impairment due to presbyopia according to the present invention uses repetitive transcranial magnetic stimulation and transcranial electrical stimulation, which have not previously been used to improve presbyopia, and therefore provides a new method for using a repetitive transcranial magnetic stimulation therapeutic device and a transcranial electrical stimulation therapeutic 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 therapeutic device or a transcranial electrical stimulation therapeutic device for use in a method for treating, improving, alleviating, or preventing visual impairment due to presbyopia. Specific aspects of the method for treating, improving, alleviating, or preventing visual impairment due to presbyopia, and specific aspects of the repetitive transcranial magnetic stimulation therapeutic device or transcranial electrical stimulation therapeutic device, can be similar to those described in the method for treating, improving, alleviating, or preventing visual impairment due to presbyopia. [Example]

[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 old (2) 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 (6m notation) must be 6 / 7.5 or less) (4) The difference in distance best corrected visual acuity (BCVA) between the two eyes must not exceed one line in logMAR. <Exclusion criteria> (5) Having an eye disease that affects vision (6) Having a history of ophthalmic surgery such as refractive correction, 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 Center 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 procedures performed at each visit are as follows:

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

[0057] (Visits 2-6): Days 3, 5, 7, 9, and 11 [Duration: 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. -Measurement of corrected distance visual acuity (DCNVA) was performed.

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

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

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

[0061] (Contrast detection task) The contrast detection task followed the protocol described in Non-Patent Documents 6 and 7. This protocol has been shown to improve visual performance in normal and strabismic or anisometropic amblyopic human populations. The contrast detection task involved presenting 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) during 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 Document 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 device (StarStim8, Neuroelectrics, Inc.; electrode size: 1.2 cm diameter cylindrical; electrode: silver-silver chloride sintered plate electrode). Based on 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 frequencies ranging from 101 Hz to 500 Hz. The stimulation consisted of a 20-second ramp-up period from 0 mA at the start of stimulation to 1.0 mA, a 20-minute period of 1.0 mA current application, and a 20-second ramp-down period from 1 mA to 0 mA. Transcranial random noise stimulation was administered to the subject while he or she was performing a contrast detection task.

[0064] Repetitive transcranial magnetic stimulation (rTMS) was delivered to the primary visual cortex using a transcranial magnetic stimulation device (MagPro X100 with MagOption, manufactured by MagVenture A / S). Repetitive transcranial magnetic stimulation (rTMS) was delivered 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 applied to a 5 cm × 5 cm grid 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 stimulation intensity required to elicit phosphene activity in 5 of 10 pulses. If the subject did not perceive phosphenes, a similar identification procedure was performed with double-pulse transcranial magnetic stimulation (CTMS). Starting with a stimulation intensity of 45% of the device's maximum stimulation output (MSO), double-pulse CTMS was applied to a 5 cm x 5 cm grid with the bottom edge of the grid centered on the inion. If no location elicited phosphenes, the same procedure was repeated, increasing the stimulation intensity by 10% increments until it reached 65% of the device's maximum output. Double pulses were delivered with a minimum inter-stimulus interval of 3 s and a 40 ms stimulus onset asynchronous interval. If phosphenes were still not perceived at a stimulation intensity of 65% of the device's maximum output, the stimulation intensity was increased by 5% increments until the subject reported perceiving phosphenes. This was repeated up to a maximum stimulation intensity of 80% of the device's maximum output. If phosphenes were still not perceived, the cTBS delivery site was set to a site 3 cm above the inion. In addition, the coil (C-B70 butterfly coil, manufactured by MagVenture A / S) used for applying magnetic stimulation was positioned and oriented so that the flat surface of the coil was parallel to the tangent plane to the head, the handle (12 o'clock direction relative to the occipital lobe) was above the coil, and the center of the overlapping coils was approximately parallel to the midline, so that the induced current flowed from the cranial side to the caudal side. The cTBS intensity was set at 80% of the threshold for perceiving phosphene or 50% of the device's maximum output if phosphene was not perceived. If subjects could not tolerate these intensities, the intensity was reduced. cTBS consisted of three 50 Hz pulses delivered every 200 ms for 40 seconds (600 pulses total). The transcranial magnetic stimulation device used was equipped with neuronavigation, ensuring 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] Sham (tDCS) stimulation was performed using the same setup as transcranial random noise stimulation (tRNS) and under the same conditions as tRNS (i.e., 20-second ramp-up and ramp-down current at the start and end of stimulation, with no 1.0 mA electrical stimulation during the 20-minute stimulation period). 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 a paired t-test.

[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). Also, 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 method for treating, improving, alleviating, or preventing visual impairment due to presbyopia, comprising: (A-1) A method comprising the step of applying repetitive transcranial magnetic stimulation (rTMS) to the brain of a subject suffering from presbyopia.

2. 2. The method of claim 1, wherein the repetitive transcranial magnetic stimulation is continuous theta burst stimulation (cTBS).

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

4. 4. The method of claim 3, wherein the transcranial electrical stimulation is transcranial random noise stimulation (tRNS).

5. The method of any one of claims 1 to 4, further comprising the step of (B) the subject performing a contrast detection task.

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