WO2025150430A1

WO2025150430A1 - Method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia

Info

Publication number: WO2025150430A1
Application number: PCT/JP2024/045921
Authority: WO
Inventors: Yoshihiro Takai; Hikari KUROGI; Tsuyoshi Ishii; Benjamin Thompson; Wei Sheng Ken TAN; So Yun Park
Original assignee: Centre For Eye And Vision Research Ltd; Rohto Pharmaceutical Co Ltd
Current assignee: Centre For Eye And Vision Research Ltd; Rohto Pharmaceutical Co Ltd
Priority date: 2024-01-12
Filing date: 2024-12-25
Publication date: 2025-07-17
Anticipated expiration: 2026-07-12
Also published as: JP7620751B1; JP2025109652A

Abstract

To provide a method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia. A method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the method including (A-1) a step of applying repetitive transcranial magnetic stimulation (rTMS) to a brain of a subject who has developed presbyopia or (A-2) a step of applying transcranial electric stimulation.

Description

METHOD FOR TREATING, IMPROVING, ALLEVIATING, OR PREVENTING DETERIORATION IN VISUAL FUNCTION DUE TO PRESBYOPIA

The present invention relates to a method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia.

Presbyopia is an age-related condition where the eye’s ability to focus on near objects declines. This causes the retinal image to become blurred and have reduced high spatial frequency contrast. The blurred, unfocused retinal image leads to decreased near visual acuity (NVA) and contrast sensitivity (CS) (Non Patent Literatures 1 to 3). Since contrast is important for triggering neural responses, a blurred retinal image due to presbyopia weakens and slows the response of the visual cortex. This is considered to be the cause of the decrease in NVA and CS observed in presbyopia (Non Patent Literature 4).

At present, for presbyopia, only correction with glasses and contact lenses is available.

WO 2009/063435

Vision Research, 1983, 23(7), 689-699 Vision Research, 2009, 49(21), 2566-2573 Journal of Vision, 2009, 9(7):18, 1-15 Frontiers in Aging Neuroscience, 2014, Volume 6, Article 163 Curr. Biol., 2007, 17(6), R196-199 Proc. Natl. Acad. Sci. USA, 2008, 105(10), 4068-4073 Scientific Reports, 2012, 2, 364 Perception & Psychophysics, 1983, 33(2), 113-120 J. Neurosci,, 2019, 39(28), 5551-5561

An object of the present invention is to provide a method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia.

The present inventors have obtained the novel finding that the symptoms of presbyopia can be improved by applying transcranial electric stimulation or transcranial magnetic stimulation to the brain of a human subject with symptoms of presbyopia. Transcranial electric stimulation or transcranial magnetic stimulation, which are types of non-invasive brain stimulation (NIBS), are applied to a specific site of the brain by using an electrode attached to the head region or magnetic induction so as to alter neural activity in the cortex (Non Patent Literature 5). In prior research on amblyopic human subjects, it has been reported that visual function is improved by combining non-invasive brain stimulation and perceptual learning (Patent Literature 1). Meanwhile, presbyopia is characterized by a diminished ability to focus on objects that are near due to a decline in the focus adjustment (accommodative) function of the eyes with age. The finding that the symptoms of presbyopia are improved by non-invasive brain stimulation is unexpected.

In one aspect, the present invention based on the above-described novel findings relates to a method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the method including (A-1) a step of applying repetitive transcranial magnetic stimulation (rTMS) to a brain of a subject who has developed presbyopia.

In another aspect, the present invention relates to a method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the method including (A-2) a step of applying transcranial electric stimulation to a brain of a subject who has developed presbyopia.

Each of the above-described methods may further include (B) a step of performing a contrast detection task by the subject.

The present invention includes the following.
Item 1. A method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the method including (A-1) a step of applying repetitive transcranial magnetic stimulation (rTMS) to a brain of a subject who has developed presbyopia.
Item 2. The method described in Item 1, wherein the repetitive transcranial magnetic stimulation is continuous theta burst stimulation (cTBS).
Item 3. The method described in Item 1 or Item 2, wherein a site to which the repetitive transcranial magnetic stimulation is applied is a site where the subject can perceive a phosphene, or a site around the inion when the subject cannot perceive a phosphene.
Item 4. The method described in any one of Item 1 to Item 3, wherein a magnetic field intensity of the repetitive transcranial magnetic stimulation is 0.05 T or more and 4.5 T or less.
Item 5. The method described in any one of Item 1 to Item 4, wherein the repetitive transcranial magnetic stimulation is applied as one or more and five or less pulses every 200 ms.
Item 6. The method described in any one of Item 1 to Item 5, wherein a frequency of the repetitive transcranial magnetic stimulation is 1 Hz or more and 100 Hz or less.
Item 7. The method described in any one of Item 1 to Item 6, wherein a time for applying the repetitive transcranial magnetic stimulation is 1 second or more and 20 minutes or less.
Item 8. The method described in any one of Item 1 to Item 7, wherein a total of the repetitive transcranial magnetic stimulation is 100 pulses or more and 1000 pulses or less.
Item 9. The method described in any one of Item 1 to Item 8, wherein a coil for applying the repetitive transcranial magnetic stimulation is placed over the stimulation site, such that the magnetic field generated induces a current that flows in a cranio-caudal direction at the stimulation site.
Item 10. The method described in any one of Item 1 to Item 9, further including (B) a step of performing a contrast detection task by the subject.
Item 11. The method described in Item 10, wherein the contrast detection task is training using a Gabor patch.
Item 12. The method described in Item 10 or Item 11, wherein the step (A-1) is performed before or after the step (B).
Item 13. A method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the method including (A-2) a step of applying transcranial electric stimulation to a brain of a subject who has developed presbyopia.
Item 14. The method described in Item 13, wherein the transcranial electric stimulation is transcranial random noise stimulation (tRNS).
Item 15. The method described in Item 13 or Item 14, wherein a site to which the transcranial electric stimulation is applied includes an occipital region.
Item 16. The method described in any one of Item 13 to Item 15, wherein the site to which the transcranial electric stimulation is applied includes an occipital lobe.
Item 17. The method described in any one of Item 13 to Item 15, wherein the site to which the transcranial electric stimulation is applied includes the occipital lobes of the left and right cerebral hemispheres.
Item 18. The method described in any one of Item 13 to Item 17, wherein a current used for the transcranial electric stimulation is a current of 0.1 mA or more and 5 mA or less.
Item 19. The method described in any one of Item 13 to Item 18, wherein the current used for the transcranial electric stimulation changes in a range of 1 Hz or more and 1000 Hz or less.
Item 20. The method described in any one of Item 13 to Item 19, wherein an electric resistance is 0 Ω or more and 50 kΩ or less.
Item 21. The method described in any one of Item 13 to Item 20, wherein a size of an electrode is a diameter of 0.5 cm or more and 10 cm or less.
Item 22. The method described in any one of Item 13 to Item 21, wherein the electrode is made of an electroconductive material.
Item 23. The method described in any one of Item 13 to Item 22, further including (B) a step of performing a contrast detection task by the subject.
Item 24. The method described in Item 23, wherein the step (A-2) is performed simultaneously with the step (B).
Item 25. The method described in any one of Item 1 to Item 24, which is a method for improving visual sensitivity of the subject who has developed presbyopia.

The present invention further includes the following.
Item A1. A system for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the system including a repetitive transcranial magnetic stimulation therapy device.
Item A2. A system for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the system including a transcranial electric stimulation therapy device.
Item A3. The system described in Item A1 or Item A2, further including a contrast detection task providing device.
Item A4. The system described in any one of Item A1 to Item A3, which is for improving visual sensitivity of a subject who has developed presbyopia.
Item B1. Use of a repetitive transcranial magnetic stimulation therapy device in manufacturing of a system for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia.
Item B2. Use of a transcranial electric stimulation therapy device in manufacturing of a system for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia.
Item C1. A repetitive transcranial magnetic stimulation therapy device, which is used for the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia described in any one of Item 1 to Item 11 and Item 24.
Item C2. A transcranial electric stimulation therapy device, which is used for the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia described in any one of Item 12 to Item 24.

According to the present invention, it is possible to provide a method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia.

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

Method for Treating, Improving, Alleviating, or Preventing Deterioration in Visual Function due to Presbyopia
A method for treating, improving, alleviating, or preventing deterioration in visual function 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 a brain of a subject who has developed presbyopia; and
(A-2) a step of applying transcranial electric stimulation to a brain of a subject who has developed presbyopia.

The method according to the present embodiment can improve deterioration in visual function due to presbyopia in a subject who has developed presbyopia. Examples of the improvement in deterioration in visual function include improvement in visual sensitivity, improvement in near visual acuity (NVA), improvement in distance-corrected near visual acuity (DCNVA), improvement in contrast sensitivity (CS), improvement in reading acuity, improvement in reading speed, reduction in critical type size (minimum type size capable of maintaining the maximum reading speed), reduction in usage rate of reading glasses in daily life, improvement in satisfaction level of near visual acuity.

The step (A-1) is a step of applying repetitive transcranial magnetic stimulation (rTMS) to a brain of a subject who has developed presbyopia. The repetitive transcranial magnetic stimulation can be applied to the brain of the subject using an existing repetitive transcranial magnetic stimulation therapy device used in repetitive transcranial magnetic stimulation therapies (for example, therapies for depression) or in research.

The repetitive transcranial magnetic stimulation therapy device includes at least a coil placed over the stimulation site on a head of a subject and a current supply unit supplying 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 induced in the brain of the subject by the magnetic field. This induced current can non-invasively stimulate the brain. Specific examples of the repetitive transcranial magnetic stimulation therapy device include MagPro X100 with magoption (manufactured by MagVenture A/S, MagPro Compact (manufactured by MagVenture A/S), Rapid² (manufactured by Magstim), MEGA-TMS (manufactured by Soterix Medical Inc.), and DuoMAG XT (manufactured by DEYMED Diagnostic s.r.o.).

A site to which the repetitive transcranial magnetic stimulation is applied is preferably a site where the subject can perceive a phosphene. The phosphene refers to a phenomenon where light is perceived in the absence of external light stimulus. The site where the subject can perceive a phosphene can be specified as a site where the subject perceives a phosphene with the lowest intensity, for example, when a single pulse or a double pulse of magnetic stimulation is applied to a site above the inion of the subject (in a direction toward the top of the head). At this time, calibration is performed by systematically changing the site to which the magnetic stimulation is applied and the intensity of the magnetic stimulation, whereby the site where the subject can perceive a phosphene can be specified.

When the subject cannot perceive a phosphene even if calibration is performed by the above-described method, an arbitrary site above the inion is adopted for the subject. The arbitrary site is preferably a site in a range of 1 cm to 10 cm above the inion and in a range of 5 cm on the left and 5 cm on the right of the inion, more preferably a site in a range of 1 cm to 5 cm above the inion and in a range of 3 cm on the left and 3 cm on the right of the inion, and further preferably a site 3 cm above the inion. The arbitrary site may be a site slightly shifted upward and downward or rightward and leftward from the above-described site.

The repetitive transcranial magnetic stimulation in the step (A-1) may be, for example, transcranial magnetic stimulation in which regular pulses are continuously applied, or transcranial magnetic stimulation in which pulses are irregularly changed and continuously applied. From the viewpoint that improvement in deterioration in visual function becomes more remarkable, the repetitive transcranial magnetic stimulation in the step (A-1) is preferably transcranial magnetic stimulation in which pulses are irregularly changed and continuously applied and more preferably continuous theta burst stimulation (cTBS). The stimulation can be applied in a single pulse or a double pulse, and a single pulse is preferable.

The intensity of the repetitive transcranial magnetic stimulation in the step (A-1) is preferably equal to or less than a threshold at which the subject can perceive a phosphene in a single pulse or a double pulse. From this viewpoint, in the repetitive transcranial magnetic stimulation in the step (A-1), for example, a magnetic field intensity may be 0.05 T or more and 4.5 T or less. The magnetic field intensity of the repetitive transcranial magnetic stimulation in the step (A-1) can be set based on the % of the maximum output of a repetitive transcranial magnetic stimulation therapy device to be used. From the viewpoint that improvement in deterioration in visual function becomes more remarkable, for example, in the case of using MagPro X100 with MagOption (manufactured by MagVenture A/S) as a repetitive transcranial magnetic stimulation therapy device, the magnetic field intensity of the repetitive transcranial magnetic stimulation is preferably 10% or more and 100% or less, more preferably 30% or more and 80% or less, further preferably 45% or more and 65% or less, and still more preferably 50% of the output of the device.

A coil for applying the repetitive transcranial magnetic stimulation is preferably positioned such that a current flowing into the coil from a device body is substantially parallel to the tangent plane of a site of the subject to which the repetitive transcranial magnetic stimulation is applied and the induced current flows from a cranial direction to a caudal direction at the site. As a result, the effect of improving the deterioration in visual function due to presbyopia becomes more remarkable, and the comfort of a test subject at the time of stimulation can be enhanced. Here, “substantially parallel” means that an angle formed by the tangent plane of the site of the subject to which the repetitive transcranial magnetic stimulation is applied and the surface 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, further preferably -2° or more and 2° or less, still more preferably -1° or more and 1° or less, and particularly preferably 0° (that is, parallel). The direction of the current flowing from the device body to inside the coil position over the stimulation site to which the repetitive transcranial magnetic stimulation is applied is more preferably parallel such that the direction of induced electric current flows cranio-caudal direction from the viewpoint of more remarkably improving the effect of improving deterioration in visual function due to presbyopia. When the coil has a handle portion that is parallel to the flat surface of the coil (i.e., the magnetic field direction), it is more preferable that the coil is disposed such that the handle portion is directed in the approximately 12:00 direction with respect to the occipital lobes such that the direction of induced current flows cranio-caudal direction at the stimulation site from the viewpoint of enhancing the comfort of a test subject at the time of stimulation.

In the repetitive transcranial magnetic stimulation in the step (A-1), the minimum constituent unit thereof may be applied as, for example, one or more and five or less pulses every 200 ms. The minimum constituent unit is preferably applied as two or more and four or less pulses every 200 ms, and more preferably applied as three pulses every 200 ms.

A frequency (pulse frequency) of the repetitive transcranial magnetic stimulation in the step (A-1) may be, for example, 1 Hz or more and 100 Hz or less. From the viewpoint that improvement in deterioration in visual function becomes more remarkable, the frequency (pulse frequency) of the repetitive transcranial magnetic stimulation in the 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.

A 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 improvement in deterioration in visual function 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.

A 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 improvement in deterioration in visual function 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.

In the method according to the present embodiment, from the viewpoint that improvement in deterioration in visual function becomes more remarkable, it is preferable to repeatedly perform the step (A-1). When the step (A-1) is repeated, 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 is 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.

The step (A-2) is a step of applying transcranial electric stimulation to a brain of a subject who has developed presbyopia. The transcranial electric stimulation can be applied to the brain of the subject using an existing transcranial electric stimulation therapy device used in transcranial electric stimulation therapies or in research.

The transcranial electric stimulation therapy device includes at least a pair of electrodes applied to an outer head region of a subject and a voltage supply unit supplying a predetermined voltage to the electrodes. The pair of electrodes is installed on the outer head region of the subject, and the brain of the subject is stimulated by the voltage supplied from the voltage supply unit. This current can non-invasively stimulate the brain. Specific examples of the transcranial electric stimulation therapy device include StarStim8 (manufactured by Neuroelectrics), neuroConn DC-stimulator Plus (manufactured by neuroConn), and 1×1 transcranial Electrical Stimulation (1×1-tES) device (manufactured by Soterix Medical Inc.).

In the transcranial electric stimulation therapy device used in the step (A-2), the size of the electrode may be, for example, 0.5 cm or more and 10 cm or less in diameter. The diameter described herein is a diameter of a surface of the electrode disposed on the head of the subject. The smaller the diameter, the more focal the stimulation applied. From the viewpoint that improvement in deterioration in visual function becomes more remarkable, the size of the electrode is preferably 0.5 cm or more and 3 cm or less in diameter, more preferably 0.5 cm or more and 2 cm or less in diameter, and further preferably 1 cm or more and 1.5 cm or less in diameter. The electrode may be made of, for example, a conductive material such as a metal, or may be made of sponge. From the viewpoint of enhancing the focusing, the electrode is preferably made of a metal, and is more preferably a sintered body of silver/silver chloride (silver/silver chloride sintered plate electrode).

From the viewpoint that improvement in deterioration in visual function becomes more remarkable, the site to which the transcranial electric stimulation is applied preferably includes an occipital region of the subject, more preferably an occipital lobe of the subject, and further preferably occipital lobes of the left and right cerebral hemispheres of the subject. When the site to which the transcranial electric stimulation is applied includes occipital lobes of the left and right cerebral hemispheres of the subject, one of the pair of electrodes may be disposed at the occipital lobe of the left hemisphere, and the other may be disposed at the occipital lobe of the right hemisphere.

The transcranial electric stimulation in the step (A-2) may be, for example, transcranial direct current electric stimulation (tDCS) that conducts direct current, transcranial alternating current electric stimulation (tACS) that conducts alternating current, or transcranial random noise stimulation (tRNS). From the viewpoint that improvement in deterioration in visual function becomes more remarkable, the transcranial electric stimulation in the step (A-2) is preferably transcranial random noise stimulation (tRNS).

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

The current used for the transcranial electric stimulation in the step (A-2) may change, for example, in a 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 improvement in deterioration in visual function becomes more remarkable, the current used for the transcranial electric stimulation in the step (A-2) preferably has a frequency of 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, 101 Hz or more and 640 Hz or less, or 101 Hz or more and 500 Hz or less.

In the transcranial electric stimulation in the step (A-2), an electric resistance may be, for example, 0 Ω or more and 50 kΩ or less. In the transcranial electric stimulation in the step (A-2), from the viewpoint that improvement in deterioration in visual function becomes more remarkable, the electric resistance is preferably 0 Ω or more and 20 kΩ or less, more preferably 1 kΩ or more and 20 kΩ or less, further preferably 1 kΩ or more and 15 kΩ or less, still more preferably 1 kΩ or more and 10 kΩ or less, and particularly preferably 1 kΩ or more and 5 kΩ or less.

A time for applying the transcranial electric stimulation in the step (A-2) may be, for example, 1 minute or more and 60 minutes or less. From the viewpoint that improvement in deterioration in visual function becomes more remarkable, the time for applying the transcranial electric stimulation in the 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.

In the method according to the present embodiment, from the viewpoint that improvement in deterioration in visual function becomes more remarkable, it is preferable to repeatedly perform the step (A-2). When the step (A-2) is repeated, the interval between the steps (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 the 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.

The method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia according to the present embodiment preferably includes the following step (B) in addition to the step (A-1) and/or the step (A-2). When the method includes the step (B), improvement in deterioration in visual function becomes more remarkable.
(B) Step of performing a contrast detection task by the subject

The contrast detection task may be, for example, in accordance with the protocols described in Non Patent Literatures 6 and 7 which have been shown to improve visual performance in normal and amblyopic human populations. The contrast detection task includes, for example, presenting a grating to a subject. The contrast detection task may be, for example, training using a Gabor patch. From the viewpoint that improvement in deterioration of visual function becomes more remarkable, the contrast detection task may include presenting a grating near the cut-off spatial frequency of a subject, but is not limited to a particular spatial frequency. The cut-off spatial frequency of the subject can be determined, for example, by the method described in Examples described later.

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

When the method according to the present embodiment includes the step (A-2) and the step (B), the step (A-2) may be performed simultaneously with the step (B), or may be performed before or after the step (B). From the viewpoint of process efficiency, it is preferable to perform the step (A-2) simultaneously with the step (B).

The method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia according to the present embodiment can also be reconsidered as, for example, the following (1) to (3).

(1) System for Treating, Improving, Alleviating, or Preventing Deterioration in Visual Function due to Presbyopia
A system for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia according to the present embodiment (hereinafter, also simply referred to as “system”) includes at least a repetitive transcranial magnetic stimulation therapy device or a transcranial electric stimulation therapy device.

As the repetitive transcranial magnetic stimulation therapy device and the transcranial electric stimulation therapy device included in the system according to the present embodiment, the same aspects as those described in the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia can be applied. As a specific operation method of these repetitive transcranial magnetic stimulation therapy device and transcranial electric stimulation therapy device, the same aspects as those described in the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia can be applied.

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 electric stimulation therapy device. The contrast detection task providing device may present a contrast detection task stimulus (for example, present grating) to a subject according to an input from the subject or according to a predetermined program. The contrast detection task providing device includes, for example, a combination of a normal computer and a normal monitor, a tablet, and the like. As the contrast detection task is presented to the subject by the contrast detection task providing device, the same aspects as those described in the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia can be applied.

In the system according to the present embodiment, the repetitive transcranial magnetic stimulation therapy device or the transcranial electric stimulation therapy device and the contrast detection task providing device may operate in cooperation. Specifically, for example, the contrast detection task providing device may operate to present the contrast detection task to the subject at a timing when the repetitive transcranial magnetic stimulation to the subject by the repetitive transcranial magnetic stimulation therapy device is completed, the repetitive transcranial magnetic stimulation therapy device may operate to apply the 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 is completed, and the contrast detection task providing device may operate to present the contrast detection task to the subject at a timing when the transcranial electric stimulation to the subject by the transcranial electric stimulation therapy device is started.

As other specific aspects of the system according to the present embodiment, the same aspects as those described in the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia can be applied.

(2) Use (Method) of Repetitive Transcranial Magnetic Stimulation Therapy Device or Transcranial Electric Stimulation Therapy Device
Use of the repetitive transcranial magnetic stimulation therapy device or the transcranial electric stimulation therapy device according to the present embodiment is use of the repetitive transcranial magnetic stimulation therapy device or the transcranial electric stimulation therapy device in manufacturing of a system for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia.

A system for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia is the same as that described in (1).

(3) Repetitive Transcranial Magnetic Stimulation Therapy Device or Transcranial Electric Stimulation Therapy Device for Use in Method for Treating, Improving, Alleviating, or Preventing Deterioration in Visual Function due to Presbyopia
Since the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia according to the present invention uses repetitive transcranial magnetic stimulation and transcranial electric stimulation which have not been conventionally used for improving presbyopia, it can be said that the present invention provides a new method for using a repetitive transcranial magnetic stimulation therapy device and a transcranial electric stimulation therapy device that apply the repetitive transcranial magnetic stimulation and the transcranial electric stimulation, respectively. Therefore, the present invention is also regarded as a repetitive transcranial magnetic stimulation therapy device or transcranial electric stimulation therapy device for use in a method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia. As a specific aspect of the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia and a specific aspect of the repetitive transcranial magnetic stimulation therapy device or the transcranial electric stimulation therapy device, the same aspects as those described in the method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia can be applied.

Hereinafter, the present invention will be described more specifically based on Examples. However, the present invention is not limited to the following Examples.

Test Method
(Test Subject)
Human adults with symptoms of presbyopia were targeted, and 30 test subjects were selected according to the following inclusion criteria and exclusion criteria.
<Inclusion Criteria>
(1) Adult aged 40-55 years
(2) Diagnosed as having symptoms of presbyopia (defined as the prescription of a near addition of +0.75 DS or more at 40 cm distance)
(3) Distance visual acuity (logMAR) in both eyes being 0.10 or less (distributed visual acuity (6 m notation) being 6/7.5 or less)
(4) Difference in distance-best-corrected visual acuity (BCVA) between both eyes not exceeding 1 line in logMAR
<Exclusion Criteria>
(5) Having an ocular pathology affecting vision
(6) Having a history of ophthalmic surgery such as refractive correction, cataract extraction, and intraocular lens implantation
(7) Having any neurological condition affecting visual acuity or visual function
(8) Non-invasive brain stimulation therapy being contraindicated

(Test Design)
The test subjects were divided into the following three 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)
Here, perceptual learning (PL) is a contrast detection task.

Test 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), and performed predetermined measurements and training. Details of the items implemented at each visit are as follows.

Visit 1: Day 1 (Required Time: 2 Hours)
- Eligibility assessment was performed (see the inclusion criteria and the exclusion criteria described above). Assignment to Groups 1 to 3 was performed.
- Pre-training measurement (baseline measurement) was performed. The measurement items included distance-corrected near visual acuity (DCNVA) and a contrast sensitivity function (CSF).

Visits 2 to 6: Day 3, Day 5, Day 7, Day 9, and Day 11 (Required Time: 2 Hours Each)
- Non-invasive brain stimulation (tRNS, rTMS, or sham (tDCS)) was performed. There was constant stimulation at all visits for each test subject.
- A contrast detection task using cut-off spatial frequencies of individual test subjects was performed.
- Distance-corrected near visual acuity (DCNVA) measurement was performed.

Visit 7: Day 13 (Required Time: 2 Hours)
- Post-training measurement was performed. The measurement items included distance-corrected near visual acuity (DCNVA).

Visit 8: Day 41 (Required Time: 2 Hours)
- Measurement was performed one month after training to investigate the maintenance of the intervention effect. The measurement items included distance-corrected near visual acuity (DCNVA).

In each of Visits 1 to 8, an error of ±1 day is allowed for scheduling. All measurements and trainings during the visit were performed in both eyes, the distance visual acuity correction determined in Visit 1 was used, and no additional near visual acuity correction was used.

(Contrast Detection Task)
The contrast detection task was in accordance with the protocols described in Non Patent Literatures 6 and 7. The protocols have been shown to improve visual performance in normal and strabismic or anisometropic amblyopia human populations. The contrast detection task included presenting a grating near the cut-off spatial frequency of each test subject. The cut-off spatial frequency was defined as the spatial frequency at which the contrast threshold of the contrast sensitivity function (CSF) at the baseline measurement was 0.50.

(Contrast Sensitivity Function)
Contrast detection thresholds at five spatial frequencies (for example, 0.5, 1, 5, 10, and 15 cycles/degree) uniformly arranged 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.

(Non-Invasive Brain Stimulation)
The transcranial random noise stimulation (tRNS) was performed using a transcranial electric stimulation therapy device (StarStim8, manufactured by Neuroelectrics, electrode size: cylindrical shape with a diameter of 1.2 cm, electrode: silver/silver chloride sintered plate electrode). With reference to the conditions described in Non Patent Literature 9, electrodes were respectively disposed on the occipital poles on both sides of the test subject, and a current of 1.0 mA was passed at a frequency of 101 Hz to 500 Hz. The application of stimulation consists of 20 seconds (ramp up) until the current reached 1.0 mA from 0 mA at the start of stimulation, 20 minutes where a current of 1.0 mA was passed, and 20 seconds (ramp down) until the current reached 0 mA from 1 mA. The transcranial random noise stimulation was applied to the test subject while performing a contrast detection task.

The repetitive transcranial magnetic stimulation (rTMS) was performed using a transcranial magnetic stimulation therapy device (MagPro X100 with MagOption, manufactured by MagVenture A/S). The 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 applied to each test subject was determined as follows.
A single pulse of transcranial magnetic stimulation was applied to a 5 cm × 5 cm grid-like point where the lower end of the grid is the center of the inion. An optimal stimulation site and a minimum stimulation intensity required to elicit a phosphene five times in ten pulses were specified by systematically changing the intensity of the magnetic stimulation.
When the test subject did not perceive a phosphene, the same specification procedure was performed with a double pulse of transcranial magnetic stimulation. Starting with a stimulation intensity of 45% of the maximum stimulator output (MSO) of the device, a double pulse of transcranial magnetic stimulation was applied to a 5 cm × 5 cm grid-like point where the lower end of the grid is the center of the inion. When there was no location causing a phosphene, the same procedure was repeated while increasing the stimulation intensity by 10% until the stimulation intensity reached 65% of the maximum output of the device. The double pulse was applied with a minimum stimulation interval of 3 seconds and a stimulus-onset asynchrony of 40 ms. If a phosphene was not perceived with a stimulation intensity of 65% of the maximum output of the device, the stimulation intensity was increased by 5% until the test subject reported perceiving a phosphene. This was repeated up to a stimulation intensity of 80% of the maximum output of the device. When the perception of a phosphene did not occur, the site to which cTBS was applied was set at a site 3 cm above the inion. The placement and direction of the coil (C-B70 butterfly coil, manufactured by MagVenture A/S) at the time of applying magnetic stimulation were set such that the flat plate surface of the coil was parallel to the tangent plane of the head and the handle (12:00 direction with respect to the occipital lobe) was above the coil, and the centre of the overlapping coils was aligned substantially parallel with the midline, and the coil was set such that the induced current flowed in the cranial-caudal direction.
The intensity of cTBS was 80% of the threshold at which a phosphene was perceived or 50% of the maximum output of the device when a phosphene was not perceived. When the test subject was unable to withstand these intensities, the intensity was reduced.
cTBS was configured to apply stimulation for 40 seconds with three 50 Hz pulses every 200 ms (600 pulses in total). The transcranial magnetic stimulation therapy device used included neuronavigation which ensured that cTBS was delivered to the same location of the visual cortex at each visit. cTBS was applied to the test subject immediately before the contrast detection task was performed.

Sham (tDCS) stimulation was performed with the same setup as in transcranial random noise stimulation (tRNS) and stimulation was performed under the same conditions as in tRNS (that is, only the current ramped up and ramped down over a 20 second period at the beginning and end of the 20 minute stimulation period) and that electrical stimulation delivery at 1.0 mA for 20 minutes was not performed during the stimulation period. Sham (tDCS) stimulation was applied to the test subject while performing a contrast detection task.

(Data Analysis)
Statistical differences for each group were validated using paired t-test.

(Results)
The average values of distance-corrected near visual acuity (DCNVA) of the test subjects at pre-training (Visit 1), post-training (Visit 7), and one month after post-training (Visit 8) are shown in Tables 1 and 2.

As shown in Table 1, in Group 1 (tRNS), improvement in distance-corrected near visual acuity (DCNVA) was observed in post-training (Visit 7) as compared with pre-training (Visit 1). As shown in Table 2, in both groups of Group 1 (tRNS) and Group 2 (TMS), improvement in distance-corrected near visual acuity (DCNVA) was observed one month after post-training (Visit 8).

Claims

A method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the method comprising
(A-1) a step of applying repetitive transcranial magnetic stimulation (rTMS) to a brain of a subject who has developed presbyopia.
The method according to claim 1, wherein the repetitive transcranial magnetic stimulation is continuous theta burst stimulation (cTBS).
A method for treating, improving, alleviating, or preventing deterioration in visual function due to presbyopia, the method comprising
(A-2) a step of applying transcranial electric stimulation to a brain of a subject who has developed presbyopia.
The method according to claim 3, wherein the transcranial electric stimulation is transcranial random noise stimulation (tRNS).
The method according to any one of claims 1 to 4, further comprising (B) a step of performing a contrast detection task by the subject.