Method of treating, improving, relaxing, or preventing decrease in visual function caused by presbyopia

Abstract

To provide a method of treating, improving, relaxing, or preventing a decrease in a visual function caused by presbyopia.SOLUTION: Provided is a method of treating, improving, relaxing, or preventing a decrease in a visual function caused by presbyopia, the method including a step of applying (A-1) repetitive transcranial magnetic stimulation (rTMS) or (A-2) a transcranial magnetic stimulation to the brain of a subject suffering from presbyopia.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for treating, improving, alleviating or preventing visual function decline due to presbyopia.

Background Art

[0002] Presbyopia is a symptom in which it becomes difficult to focus on nearby objects due to the decline of the eye's focusing function with aging. Presbyopia weakens the contrast of high spatial frequencies in the retinal image and reduces near visual acuity (NVA) and contrast sensitivity (CS) (Non-Patent Documents 1 to 3). Since contrast is important in eliciting a neural response, a low-contrast blurred retinal image due to presbyopia weakens and delays the response of the visual cortex. This is considered to be the cause of the NVA and CS decline observed in presbyopia (Non-Patent Document 4).

[0003] Currently, the only way to deal with presbyopia is to correct it with glasses and contact lenses.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

[0006] An object of the present invention is to provide a method for treating, improving, alleviating or preventing visual function decline due to presbyopia. [Means for Solving the Problems]

[0007] The present inventors have obtained a new finding that symptoms of presbyopia can be improved by applying transcranial electrical stimulation or transcranial magnetic stimulation to the brain of a human subject having symptoms of presbyopia. Transcranial electrical stimulation or transcranial magnetic stimulation as non-invasive brain stimulation (NIBS) uses electrodes or magnetic induction attached to the head to stimulate specific parts 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 human subject test for amblyopia (Patent Document 1). On the other hand, presbyopia is a symptom in which it becomes difficult to focus on nearby objects due to the decline of the eye's focusing function with aging, and the finding that symptoms of presbyopia are improved by non-invasive brain stimulation is unexpected.

[0008] Based on the above new findings, the present invention, in one aspect, relates to a method for treating, improving, alleviating, or preventing visual function decline due to presbyopia, which includes the step of (A-1) applying repetitive transcranial magnetic stimulation (rTMS) to the brain of a subject with presbyopia.

[0009] In another aspect, the present invention relates to a method for treating, improving, alleviating, or preventing visual function decline due to presbyopia, which includes the step of (A-2) applying transcranial electrical stimulation to the brain of a subject with 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 includes the following. [1] A method for treating, improving, alleviating, or preventing visual function decline due to presbyopia, which includes the step of (A-1) applying repetitive transcranial magnetic stimulation (rTMS) to the brain of a subject with 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 for applying the repetitive transcranial magnetic stimulation is a site where phosphenes can be perceived, or when the subject cannot perceive phosphenes, it is the site above the inion. [4] The method according to any one of [1] to [3], wherein the magnetic field intensity 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 given as pulses one or more times and five or less times every 200 milliseconds. [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 time for applying the repetitive transcranial magnetic stimulation is 1 second or more and 20 minutes or less. [8] The method according to any one of [1] to [7], wherein the total of the repetitive transcranial magnetic stimulation is 100 pulses or more and 1000 pulses or less. [9] The coil for applying the repetitive transcranial magnetic stimulation is arranged such that the current flowing from the apparatus main body toward the coil is parallel to the contact surface of the site for applying the repetitive transcranial magnetic stimulation to the subject and flows from the cranial direction to the coccyx direction at the site, according to the method of any one of [1] to [8].

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

[11] The method according to

[10] , wherein the contrast detection task is training using a Gabor patch.

[12] (B) The method according to

[10] or

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

[13] A method for treating, improving, alleviating or preventing visual function decline due to presbyopia, (A-2) comprising a step of applying 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 for applying the transcranial electrical stimulation includes the occipital region.

[16] The method according to any one of

[13] to

[15] , wherein the site for applying the transcranial electrical stimulation includes the occipital pole.

[17] The method according to any one of

[13] to

[15] , wherein the site for applying the transcranial electrical stimulation includes the occipital poles of the left and right brains.

[18] The method according to any one of

[13] to

[17] , wherein the current used for the transcranial electrical stimulation is a current of 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.

[21] The method according to any one of

[13] to

[20] , wherein the size of the electrode is 0.5 cm or more and 10 cm or less in diameter.

[22] The method according to any one of

[13] to

[21] , wherein the electrode is made of a conductive material.

[23] (B) The method according to any one of

[13] to

[22] , further comprising a step in which the subject performs a contrast detection task.

[24] (B) The method according to

[23] , wherein the step (A-2) is performed simultaneously with the step (B).

[25] The 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, alleviating or preventing visual function decline due to presbyopia, comprising a repetitive transcranial magnetic stimulation treatment device. [A2] A system for treating, improving, alleviating or preventing visual function decline 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, alleviating or preventing visual function decline due to presbyopia. [B2] Use of a transcranial electrical stimulation therapy device in the manufacture of a system for treating, improving, alleviating or preventing visual function decline due to presbyopia. [C1] A repetitive transcranial magnetic stimulation therapy device for use in the method for treating, improving, alleviating or preventing visual function decline due to presbyopia according to any one of [1] to

[11] and

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

[12] to

[24] . [Advantages of the Invention]

[0013] According to the present invention, a method for treating, improving, alleviating or preventing visual function decline due to presbyopia can be provided. [Embodiments for Carrying Out the Invention]

[0014] Hereinafter, embodiments for carrying out the present invention will be described in detail. However, the present invention is not limited to the following embodiments.

[0015] [Method for Treating, Improving, Alleviating or Preventing Visual Function Decline due to Presbyopia] The method for treating, improving, alleviating or preventing visual function decline due to presbyopia according to the present embodiment (hereinafter, also simply referred to as "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 this embodiment can improve the decline in visual function due to presbyopia in a subject suffering from presbyopia. Improving the decline in visual function includes, for example, improving visual sensitivity, improving near visual acuity (NVA), improving near visual acuity under distance correction (DCNVA), improving contrast sensitivity (CS), improving reading vision, improving reading speed, reducing the critical letter size (the smallest letter size that can maintain the maximum reading speed), reducing the usage rate of reading glasses in daily life, improving the satisfaction of near visual acuity, and the like.

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

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

[0019] The site to which 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 light stimulation. 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 inion of the subject (in the direction towards the top of the head). At this time, the site to which magnetic stimulation is applied and the intensity of the magnetic stimulation can be systematically changed and screened to identify the site where the subject can perceive phosphenes.

[0020] If the subject cannot perceive phosphenes even after screening by the above method, for such a subject, any site above the inion is adopted. The arbitrary site is preferably a site within the range of 1 cm to 10 cm above the inion and 5 cm to the left and right of the inion, more preferably a site within the range of 1 cm to 5 cm above the inion and 3 cm to the left and right of the inion, and even more preferably a site 3 cm above the inion. The arbitrary site may be a site slightly shifted up, down, left, or right from the above-described site.

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

[0022] (A-1) The intensity of repetitive transcranial magnetic stimulation in the (A-1) step is preferably a single pulse or a double pulse and below the threshold at which the subject can perceive phosphenes. From this perspective, the repetitive transcranial magnetic stimulation in the (A-1) step may have, for example, a magnetic field intensity of 0.05 T or more and 4.5 T or less. The magnetic field intensity of the repetitive transcranial magnetic stimulation in the (A-1) step can be set based on the output percentage of the repetitive transcranial magnetic stimulation treatment device used. From the perspective that the improvement of visual function decline becomes more prominent, for example, when using MagPro Compact (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% or more and 100% or less of the output of the device, more preferably 30% or more and 80% or less, still more preferably 45% or more and 65% or less, and even more preferably 50%.

[0023] The coil for applying repetitive transcranial magnetic stimulation is preferably arranged such that the current flowing from the device body towards the coil is substantially parallel to the contact surface of the site where the subject is given repetitive transcranial magnetic stimulation and flows from the cranial direction to the coccygeal direction at the site. Thereby, the improvement effect of visual function decline due to presbyopia becomes more prominent, and the comfort of the subject during stimulation can be enhanced. Here, "substantially parallel" means that the angle formed by the contact surface of the site where the subject is given repetitive transcranial magnetic stimulation and the plane including the current flowing through the coil is -10° or more and 10° or less, and this formed angle is preferably -5° or more and 5° or less, more preferably -3° or more and 3° or less, still more preferably -2° or more and 2° or less, and even more preferably -1° or more and 1° or less, and particularly preferably 0° (i.e., parallel). Also, at the site where repetitive transcranial magnetic stimulation is given, from the perspective that the improvement effect of visual function decline due to presbyopia becomes more prominent and the comfort of the subject during stimulation is enhanced, it is more preferably parallel to the midline of the subject. When the coil has a handle part, it is more preferably arranged such that the handle part points in a direction approximately at the 12 o'clock position with respect to the posterior pole of the head.

[0024] (A-1) The repetitive transcranial magnetic stimulation in the step (A-1) may be such that its minimum constituent unit is given as pulses one or more times and five or less times, for example, every 200 milliseconds. The minimum constituent unit is preferably given as pulses two or more times and four or less times every 200 milliseconds, and more preferably given as pulses three times every 200 milliseconds.

[0025] (A-1) The frequency of the repetitive transcranial magnetic stimulation in the step (A-1) (the frequency of the pulses) may be, for example, 1 Hz or more and 100 Hz or less. From the viewpoint that the improvement of visual function decline becomes more remarkable, the frequency of the repetitive transcranial magnetic stimulation in the step (A-1) (the frequency of the pulses) 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] (A-1) The time for applying the repetitive transcranial magnetic stimulation in the step (A-1) may be, for example, 1 second or more and 20 minutes or less. From the viewpoint that the improvement of visual function decline becomes more remarkable, the time for applying the repetitive transcranial magnetic stimulation in the 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] (A-1) The total of the repetitive transcranial magnetic stimulation in the step (A-1) may be, for example, 100 pulses or more and 1000 pulses or less. From the viewpoint that the improvement of visual function decline becomes more remarkable, the total of the repetitive transcranial magnetic stimulation in the step (A-1) is preferably 200 pulses or more and 900 pulses or less, 300 pulses or more and 800 pulses or less, 400 pulses or more and 700 pulses or less, 500 pulses or more and 600 pulses or less, or 600 pulses.

[0028] In the method according to this embodiment, from the viewpoint that the improvement of visual function decline becomes more remarkable, it is preferable to repeat the step (A-1). When repeating the step (A-1), the interval between the steps (A-1) 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 preferably 2 days. The number of times of repeating the step (A-1) 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] (A-2) The step is a step of applying transcranial electrical stimulation to the brain of a subject suffering from presbyopia. The transcranial electrical stimulation can be applied to the subject's brain using a transcranial electrical stimulation treatment device used in existing transcranial electrical stimulation treatments or research.

[0030] The transcranial electrical stimulation treatment device includes at least a pair of electrodes applied to the outer head of the subject and a voltage supply unit that supplies a predetermined voltage to the electrodes. The pair of electrodes is installed on the outer head of the subject, and the brain of the subject is energized by the voltage supplied from the voltage supply unit. The brain can be stimulated non-invasively by this current. Specific examples of the transcranial electrical stimulation treatment device include, for example, StarSstim8 (manufactured by Neuroelectrics), neuroConn DC-stimulator Plus (manufactured by neuroConn), 1×1 transcranial Electrical Stimulation (1×1-tES) device (manufactured by Soterix Medical), and the like.

[0031] (A-2) The transcranial electrical stimulation therapy device used in the project may have an electrode size of, for example, not less than 0.5 cm and not more than 10 cm in diameter. The diameter referred to here is the diameter of the surface placed on the subject's head. The smaller the diameter, the stronger the stimulation can be applied. From the perspective of more significant improvement in visual function decline, the electrode size is preferably not less than 0.5 cm and not more than 3 cm in diameter, more preferably not less than 0.5 cm and not more than 2 cm in diameter, and even more preferably not less than 1 cm and not more than 1.5 cm in diameter. The electrode may be composed of a conductive material such as metal, or may be made of sponge. From the perspective of enhanced focus, the electrode is preferably made of metal, and more preferably a silver / silver chloride sintered body (silver / silver chloride sintered plate electrode).

[0032] From the perspective of more significant improvement in visual function decline, the site for applying transcranial electrical stimulation preferably includes the subject's occipital region, more preferably includes the subject's occipital pole, and even more preferably includes the occipital poles of the subject's left and right brains. When the site for applying transcranial electrical stimulation includes the occipital poles of the subject's left and right brains, one of a pair of electrodes may be placed on the occipital pole of the left brain and the other on the occipital pole of the right brain.

[0033] (A-2) The transcranial electrical stimulation in the process may be, for example, transcranial direct current stimulation (tDCS) with direct current applied, transcranial alternating current stimulation (tACS) with alternating current applied, or transcranial random noise stimulation (tRNS). From the perspective of more significant improvement in visual function decline, the transcranial electrical stimulation in the (A-2) process is preferably transcranial random noise stimulation (tRNS).

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

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

[0036] (A-2) The transcranial electrical stimulation in the (A-2) step may have an electrical resistance of, for example, 0 Ω or more and 50 kΩ or less. From the viewpoint that the improvement of visual function decline becomes more remarkable, the electrical resistance of the transcranial electrical stimulation in the (A-2) step is preferably 0 Ω or more and 20 kΩ or less, more preferably 1 kΩ or more and 20 kΩ or less, still 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 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 significantly improving visual function decline, the time for applying 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 this embodiment, from the viewpoint of more significantly improving visual function decline, it is preferable to repeat step (A-2). When repeating step (A-2), the interval between step (A-2) 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 of repeating step (A-2) 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 due to presbyopia according to this embodiment preferably further includes 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 significant. (B) A step in which the subject performs a contrast detection task

[0040] The contrast detection task may be, for example, in accordance with the protocols described in Non-Patent Documents 6 and 7, which have been shown to improve visual performance in normal and oblique human populations. The contrast detection task includes, for example, presenting gratings to the subject. The contrast detection task may be, for example, training using Gabor patches. From the viewpoint of more significantly improving visual function decline, the contrast detection task may include presenting gratings near the cut-off spatial frequency of the subject. The cut-off spatial frequency of the subject can be determined, for example, by the method described in the examples below.

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

[0042] When the method according to this embodiment includes steps (A-2) and (B), step (A-2) may be performed simultaneously with step (B), or before or after step (B). From the perspective of improving process efficiency, it is preferable that steps (A-2) and (B) be performed simultaneously.

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

[0044] [(1) System for treating, improving, alleviating, or preventing visual function decline due to presbyopia] The system for treating, improving, alleviating, or preventing visual function decline due to presbyopia according to this embodiment (hereinafter also simply referred to as "system") 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 those described in the method for treating, improving, alleviating, or preventing visual function decline due to presbyopia. Also, as the specific operation methods of these repetitive transcranial magnetic stimulation therapy devices and transcranial electrical stimulation therapy devices, the same manner as that described in the method for treating, improving, alleviating, or preventing visual function decline due to presbyopia can be applied.

[0046] The system according to this embodiment may further include a contrast detection task providing device in combination with a repetitive transcranial magnetic stimulation therapy device or a transcranial electrical stimulation therapy device. The contrast detection task providing device may present a contrast detection task (for example, presenting a grating) to a subject in response to an input from the subject or according to a preset program. The contrast detection task providing device is composed of, for example, a combination of a normal computer and a monitor, a tablet, or the like. The contrast detection task presented by the contrast detection task providing device to the subject can be applied in the same manner as described in the method for treating, improving, alleviating, or preventing visual function decline due to presbyopia.

[0047] The system according to this embodiment may be such that the repetitive transcranial magnetic stimulation therapy device, or the transcranial electrical stimulation therapy device, and the contrast detection task providing device cooperate to operate. Specifically, for example, the contrast detection task providing device may operate to present a contrast detection task to the subject at the timing when the repetitive transcranial magnetic stimulation to the subject by the repetitive transcranial magnetic stimulation therapy device ends, or the repetitive transcranial magnetic stimulation therapy device may operate to apply repetitive transcranial magnetic stimulation to the subject at the timing when the presentation of the contrast detection task to the subject by the contrast detection task providing device ends. Also, the contrast detection task providing device may operate to present a contrast detection task to the subject at the timing when the transcranial electrical stimulation to the subject by the transcranial electrical stimulation therapy device is started.

[0048] Other specific aspects of 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.

[0049] 〔(2) Use (Method) of Repetitive Transcranial Magnetic Stimulation Therapy Device or Transcranial Electrical Stimulation Therapy Device〕 The use of the repetitive transcranial magnetic stimulation therapy device or transcranial electrical stimulation therapy device according to 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 decline due to presbyopia.

[0050] The system for treating, improving, alleviating or preventing visual function decline due to presbyopia is the same as that described in (1).

[0051] 〔(3) Repetitive transcranial magnetic stimulation therapy device or transcranial electrical stimulation therapy device for use in a method for treating, improving, alleviating or preventing visual function decline 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 for improving presbyopia in the past. Therefore, it can be said that the present invention provides a new method of using a repetitive transcranial magnetic stimulation therapy device and a transcranial electrical stimulation therapy device that give the repetitive transcranial magnetic stimulation and the transcranial electrical stimulation. Accordingly, the present invention can also be regarded as a repetitive transcranial magnetic stimulation therapy device or a transcranial electrical stimulation therapy device for use in a method for treating, improving, alleviating or preventing visual function decline due to presbyopia. For the specific embodiments of the method for treating, improving, alleviating or preventing visual function decline due to presbyopia, and the specific embodiments of the repetitive transcranial magnetic stimulation therapy device or the transcranial electrical stimulation therapy device, the same embodiments as those described in the method for treating, improving, alleviating or preventing visual function decline due to presbyopia can be applied.

Example

[0052] Hereinafter, the present invention will be described more specifically based on examples. However, the present invention is not limited to the following examples.

[0053] 〔Test method〕 (Subject) Thirty subjects were selected from adult humans with symptoms of presbyopia according to the following inclusion criteria and exclusion criteria. <Inclusion criteria> (1) Being an adult aged 40 or above and 55 or below (2) Diagnosed with symptoms of presbyopia (near addition prescription defined as +0.75DS or more at a distance of 40 cm). (3) The binocular distance visual acuity (logMAR) is 0.10 or less (the scattered visual acuity (notation at 6 m) is 6 / 7.5 or less). (4) The difference in the binocular distance best corrected visual acuity (BCVA) does not exceed 1 line in logMAR. <Exclusion Criteria> (5) Having eye lesions that affect vision. (6) Having a history of ophthalmic surgeries such as refractive correction, cataract extraction, and 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 3 groups (10 subjects in each group). Group 1: Combination of transcranial random noise stimulation (tRNS) and perceptual learning (PL). Group 2: Combination of repetitive transcranial magnetic stimulation (rTMS) and perceptual learning (PL). Group 3: Combination of sham (tDCS) and 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 the 1st day (Visit 1), 3rd day (Visit 2), 5th day (Visit 3), 7th day (Visit 4), 9th day (Visit 5), 11th day (Visit 6), 13th day (Visit 7), and 41st day (Visit 8) for predetermined measurements and training. The details of the matters implemented at each visit are as follows.

[0056] (Visit 1): 1st day [Required time: 2 hours] · Conducted eligibility assessment (refer to the above inclusion criteria and exclusion criteria). Assigned to Groups 1 - 3. ·Pre-training measurements (baseline measurements) were performed. The measurement items included distance-corrected near visual acuity (DCNVA) and the contrast sensitivity function (CSF).

[0057] (Visits 2 - 6): On the 3rd, 5th, 7th, 9th, and 11th days [Required time: 2 hours each] ·Non-invasive brain stimulation (tRNS, rTMS, or sham (tDCS)) was performed. The same stimulation was applied to each subject at all visits. ·A contrast detection task using the cut-off spatial frequency of each individual subject was performed. ·Measurements of distance-corrected near visual acuity (DCNVA) were performed.

[0058] (Visit 7): On the 13th day [Required time: 2 hours] ·Post-training measurements were performed. The measurement items included distance-corrected near visual acuity (DCNVA).

[0059] (Visit 8): On the 41st day [Required time: 2 hours] ·Measurements were taken one month after training to investigate the maintenance of the intervention effect. The measurement items included distance-corrected near visual acuity (DCNVA).

[0060] Note that for all of Visits 1 - 8, an error of ±1 day was allowed for scheduling. Also, 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 protocols described in Non-Patent Documents 6 and 7. This protocol has been shown to improve visual performance in normal and amblyopic human populations. The contrast detection task included presenting gratings near the cut-off spatial frequency of each subject. The cut-off spatial frequency was defined as the spatial frequency at which the contrast threshold of the contrast sensitivity function (CSF) was 0.50 during baseline measurement.

[0062] (Contrast sensitivity function) The contrast detection thresholds at five spatial frequencies (e.g., 0.5, 1, 5, 10, 15 cycles / degree) uniformly arranged on a logarithmic scale were determined using the 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 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 the posterior poles on both sides of the subject, and a current of 1.0 mA was passed at a frequency of 101 Hz to 640 Hz. The application of the stimulation consisted of 20 seconds (Ramp up) from 0 mA at the start of the stimulation to reaching 1.0 mA, 20 minutes of energization at 1.0 mA, and 20 seconds (Ramp down) from 1 mA to reaching 0 mA. Transcranial random noise stimulation was given to the subject while performing the contrast detection task.

[0064] Repetitive transcranial magnetic stimulation (rTMS) was performed using a transcranial magnetic stimulation treatment device (MagPro X100 with magoption, manufactured by MagVenture A / S). Repetitive transcranial magnetic stimulation was sent to the primary visual cortex in the form of continuous theta burst stimulation (cTBS). The site to which cTBS was given to each subject was determined as follows. Single-pulse transcranial magnetic stimulation was given to the grid-like points of a 5 cm × 5 cm grid where the lower end of the grid was at the center of the inion. The magnetic stimulation intensity was systematically changed to identify the optimal stimulation site and the minimum magnetic stimulation intensity required to induce phosphenes 5 times out of 10 pulses. When the subject did not perceive phosphenes, the same specific procedure was performed with double-pulse transcranial magnetic stimulation. Starting from a magnetic intensity of 45% of the maximum output of the device, double-pulse transcranial magnetic stimulation was applied to the grid-like points of a 5 cm × 5 cm grid where the lower end of the grid was at the center of the inion. If there was no position that caused phosphenes, the magnetic intensity was increased by 10% each time until it reached 65% of the maximum output of the device, and the same procedure was repeated. The double pulses were given with a minimum inter-stimulus interval of 3 seconds and a stimulation onset asynchrony of 40 ms. 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% each time until the subject reported perceiving phosphenes. This was repeated up to a magnetic intensity of 80% of the maximum output of the device at most. If phosphenes still did not occur, the site for applying cTBS was set at a site 3 cm above the inion. Also, the arrangement and direction of the coil when applying magnetic stimulation were set so that the flat surface of the coil was parallel to the contact surface to the head, the handle was above the coil, and it was installed almost parallel to the midline (in the 12 o'clock direction with respect to the occipital pole) in the craniocaudal direction so that the current flowed from the device body to the coil. The intensity of cTBS was set to 80% of the threshold for perceiving phosphenes, or 50% of the maximum output of the device if phosphenes were not perceived. If the subject could not tolerate these intensities, the intensity was decreased. cTBS was configured to give a stimulation of 40 seconds with three 50 Hz pulses every 200 ms (a total of 600 pulses). The transcranial magnetic stimulation treatment device used was equipped with neuronavigation, and it was guaranteed that cTBS was sent to the same position of the visual cortex at each visit. cTBS was given to the subject immediately before performing the contrast detection task.

[0065] Sham (tDCS) stimulation was performed with the same setup as transcranial random noise stimulation (tRNS), and the energization was performed under the same conditions as tRNS (i.e., only Ramp up and Ramp down) except that the energization was not performed for 20 minutes at 1.0 mA. Sham (tDCS) stimulation was given to the subject while the contrast detection task was being performed.

[0066] (Data analysis) Statistical significance between groups was verified using a paired t-test.

[0067] (Results) Table 1 and Table 2 show the mean values of the distance-corrected near visual acuity (DCNVA) of the subjects before training (visit 1), after training (visit 7), and one month after training (visit 8).

[0068] [Table 1] [Table 2]

[0069] As shown in Table 1, in group 1 (tRNS), improvement in distance-corrected near visual acuity (DCNVA) was observed after training (visit 7) compared to before training (visit 1). Also, as shown in Table 2, improvement in distance-corrected near visual acuity (DCNVA) was observed in both groups 1 (tRNS) and 2 (TMS) one month after training (visit 8).

Claims

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

2. The system according to claim 1, further comprising a contrast detection task providing device.

3. The system according to claim 1 or 2, which is for improving the visual sensitivity of a subject suffering from presbyopia.

4. The system according to claim 1 or 2, wherein the repetitive transcranial magnetic stimulation is continuous theta burst stimulation (cTBS).

5. The system according to claim 1 or 2, wherein the site for applying the repetitive transcranial magnetic stimulation is a site where the subject can perceive phosphenes, or when the subject cannot perceive phosphenes, it is a site above the inion.

6. The system according to claim 1 or 2, wherein the magnetic field intensity of the repetitive transcranial magnetic stimulation is 0.05 T or more and 4.5 T or less.

7. The system according to claim 1 or 2, wherein the repetitive transcranial magnetic stimulation is applied as pulses one or more times and five or less times every 200 msec.

8. The system according to claim 1 or 2, wherein the frequency of the repetitive transcranial magnetic stimulation is 1 Hz or more and 100 Hz or less.

9. The system according to claim 1 or 2, wherein the time for applying the repetitive transcranial magnetic stimulation is 1 second or more and 20 minutes or less.

10. The system according to claim 1 or 2, wherein the total of the repetitive transcranial magnetic stimulation is 100 pulses or more and 1000 pulses or less.

11. The system according to claim 1 or 2, wherein the coil for applying the repetitive transcranial magnetic stimulation is arranged such that the current flowing from the device body toward the coil is parallel to the contact surface of the site for applying the repetitive transcranial magnetic stimulation to the subject and flows from the cranial direction to the coccyx direction at the site.

12. The system according to claim 2, which operates such that the contrast detection task providing device presents a contrast detection task to the subject at the timing when the repetitive transcranial magnetic stimulation to the subject by the repetitive transcranial magnetic stimulation therapy device ends, or the repetitive transcranial magnetic stimulation therapy device applies repetitive transcranial magnetic stimulation to the subject at the timing when the presentation of the contrast detection task to the subject by the contrast detection task providing device ends.

13. The system according to claim 2 or 12, wherein the contrast detection task is training using a Gabor patch. **Claim 14** Use of a repetitive transcranial magnetic stimulation therapy device in the manufacture of a system for the treatment, improvement, alleviation or prevention of visual function decline due to presbyopia.

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