Device for inducing high-frequency oscillations in brain

Abstract

An apparatus for inducing ripples in a brain of a subject includes a light source. The light source is adapted to generate light. The produced light has at least two light variations. The at least two light variations are selected from at least two of a spatial variation, a temporal variation, a wavelength spectral variation, an intensity variation, or a polarization variation. The at least two light variations are selected for inducing ripples in the brain. The produced light produces a visual stimulus in the brain at the frequency of a ripple.

Description

TECHNICAL FIELD

[0001] This application claims priority to Luxembourg Patent Application No. LU503626 and European Patent Application EP 23179351.4, filed March 13, 2023. The entire disclosure of Luxembourg Patent Application No. LU503626 and European Patent Application EP 23179351.4 is incorporated herein by reference.

[0002] The present invention includes an apparatus for inducing ripples in a brain of a subject, a system for improving memory retention of a subject, and a method for inducing ripples in a brain of a subject. BACKGROUND

[0003] U.S. Patent Application US 2023 / 0022546 Al (Cognito Therapeutics, Inc.) relates to neural stimulation via non-invasive sensory stimulation. The non-invasive stimulation can reduce neuroinflammation, improve synaptic plasticity, and stimulate neural networks. Brain injury can cause brain atrophy. The non-invasive stimulation can improve microglia-mediated clearance of brain injury, thereby arresting the progression of brain atrophy. The non-invasive stimulation induces synchronized gamma oscillations in at least one region of the brain of the subject. The non-invasive stimulation can modulate, control, or manage the frequency of the synchronized gamma oscillations (i.e., neural oscillations), thereby having an impact on one or more cognitive states or cognitive functions of the brain. The non-invasive stimulation can simultaneously mitigate or prevent adverse consequences to the cognitive states or cognitive functions due to the progression of brain atrophy.

[0004] U.S. Patent Application US 2013 / 0338738 Al (Garcia Molina et al.) relates to an apparatus for enhancing a user’s cognition and a corresponding method thereof. A user will perform a cognitive activity. The apparatus for effectively enhancing cognition includes an illumination unit for providing a barely perceptible light stimulus to the user. The apparatus also includes a control unit for controlling the illumination unit to provide the barely perceptible light stimulus within a time period of less than 5 seconds before the user performs the cognitive activity.

[0005] US patent application US 2010 / 0331912 Al (Tass et al.) discloses an apparatus and a method for providing stimulation signals that reset the phase of neural activity of neurons in a brain of a patient. The apparatus comprises a control unit and a stimulation unit. The stimulation unit has a plurality of stimulation elements. Each stimulation element generates a visual stimulation signal that, when received via the eyes of the patient, resets the phase of neural activity of the neurons. The visual stimulation signals are delivered to neurons that exhibit pathologically synchronous oscillatory neural activity in a psychiatric or neurological disease. The control unit is also able to activate the stimulation unit such that the stimulation elements generate visual stimulation signals that have a temporal offset from each other and / or have different phases and / or have different polarities.

[0006] Teeuwen et al. in “A neuronal basis of iconic memory in macaque primary visual cortex”, Current Biology 31, 5401-5414 (2021), accessible at https: / / doi.org / 10.1016 / j.cub.2021.09.052, define different types of memory. These memories include long-term memory, working memory and iconic memory. Long-term memory is stored in the brain cortex between neurons in different intensity connection patterns and is organized by the hippocampus. Working memory is stored in the sustained activity of neurons. The neural correlates of working memory are mainly located in higher cortical areas of the cerebral cortex hierarchy, such as frontal, parietal and temporal cortex. Teeuwen et al. consider iconic memory as a short-lived, high-capacity form of memory whose neural correlates are located in the primary visual cortex (V1) of the brain. This means that iconic memory can hold a large amount of information and visual details about an object for a short period of time. Iconic memory is located in the low-level visual areas of the brain and is stored in the brain for a short time. Iconic memory decays over time. This decay leads to a decrease in the storage capacity of iconic memory. Iconic memory has a short duration. Iconic memory cannot be fully stored as working memory.

[0007] Teeuwen et al. further disclose that the decay time of iconic memory is longer than the duration of activity of a single neuron in the V1 region. In other words, the preservation of an image in iconic memory does not only rely on the activity of a single neuron in the V1 region. Therefore, there must be communication between multiple brain regions in order to exchange information about the image between the V1 region and other brain structures during the duration of the image in iconic memory.

[0008] Teeuwen et al. further disclose that iconic memory is affected by the overshadowing effect of newly presented objects. Iconic memory is also affected by focusing attention to a certain object or a certain part of an object. Attention refers to a cognitive function of the brain that enhances the neural representation of an observed object or diminishes the neural representation by applying an attention weight to the observed object.

[0009] Newly presented objects erase iconic memory and erase the representation of the previous image in the primary visual cortex (V1). Attention interacts with iconic memory, thereby enhancing the associated V1 activity.

[0010] Teeuwen et al. hypothesize that the time scale of processing information and permanently storing information in the brain increases when information is transferred from iconic memory in the primary visual cortex (V1) to higher visual cortical areas of the brain (e.g. V3-V5) and to working memory (e.g. frontal, parietal and temporal cortex of the neocortical hierarchy).

[0011] Teeuwen et al. disclose that the most stable form of short-term visual memory is working memory. Objects presented to working memory are saved in working memory. Newly presented objects can be received by working memory and working memory is not overwritten by newly presented objects. However, working memory has a limited capacity for storing presented objects. The storage capacity of working memory is only in the order of seven to nine complex visual objects.

[0012] Neurons in the frontal cortex, parietal cortex and medial temporal lobe of the brain play an important role in maintaining working memory neural representations (i.e. the strength of connections between neurons in the cortex of the brain). Working memory neural representations have to be present in the brain by sustained synchronous activity of neurons. This means that the network of neurons containing working memory needs to remain continuously active for the entire duration of the memory (typically in the range of minutes).

[0013] Hence, short-term working memory requires communication between multiple brain areas. Multiple brain areas jointly organize the storage and maintenance of sensory information. Liebe et al. in “Theta coupling between V4 and prefrontal cortex predicts visual short-term memory performance” (Nat Neurosci 15, 456-462 (2012), https: / / doi.org / 10.1038 / nn.3038) have suggested that the communication between multiple brain areas is rhythmically oscillatory synchronized. According to Liebe et al. the communication between multiple brain areas is responsible for learning and the permanent formation of long-term memory.

[0014] Battaglia et al., The hippocampus: hub of brain network communication for memory, Trends in Cognitive Science 15(7), 310-318 (2011) (https: / / doi.org / 10.1016 / j.tics.2011.05.008), disclose that encoding and retrieval of long-term memories can be achieved by synchronizing collections of neurons through oscillations in neural activity. One such oscillation in neural activity is a sharp-wave ripple (SWR), which synchronizes brain structures involved in long-term memory. These brain structures include the hippocampus and the cerebral cortex.

[0015] Buzsáki, Hippocampal sharp-wave-ripple: A cognitive biomarker for episodic memory and planning, Hippocampus 25(10), 1073-1188 (2015), https: / / onlinelibrary.wiley.com / doi / 10.1002 / hipo.22488, discloses that naturally occurring SWRs are short oscillations with a duration of 40-100 ms. These short oscillations contain large-amplitude negative polarity deflections of 1-2 mV, and synchronous high-frequency oscillations of local field potentials in the CA1 region of the hippocampus. Naturally occurring SWRs most often occur during sleep or during wakeful rest.

[0016] Logothetis et al., Hippocampal-cortical interaction during periods of subcortical silence, Nature 491, 547-553 (2012), https: / / doi.org / 10.1038 / nature11618, disclose that coordinated interactions between the thalamus and the cerebral cortex can be orchestrating information exchange between the hippocampus (especially the CA1 region) and the cerebral cortex. Information exchange between the hippocampus and the cerebral cortex can be facilitated by silencing the output of subcortical centers. Subcortical centers are involved in sensory processing. Mechanisms that silence and reactivate the brain cause minimal disturbance to the brain and are able to consolidate long-term memories.

[0017] Logothetis et al. disclose that naturally occurring SWR is believed to be related to offline memory consolidation. Logothetis et al. define naturally occurring SWR as a combination of aperiodic and large deflection periodic oscillations (i.e. sharp waves) and synchronous high frequency oscillations (i.e. ripples) in the electrical activity of the hippocampus. The frequency of the high frequency oscillations is in the range of 80 to 250 Hz, depending on the anatomical location in the brain, for example in the CA1 and CA3 regions of the hippocampus, or in the entorhinal cortex. Naturally occurring SWR depends on the animal state, for example whether the animal (or human) is in an alert state or in an anesthetized state. Naturally occurring SWR also depends on the animal species.

[0018] Logothetis et al. revealed, by functional magnetic resonance imaging (fMRI), which brain areas are active or silent when naturally occurring SWR occurs in the brain. The whole cerebral cortex of the subject (except for the V1 region and subcortical areas) is active. The activation of the cortex represents communication between multiple regions in the brain.

[0019] During naturally occurring SWR, information is stored in the neural network of the hippocampus, presumably from all relevant cortical areas that are in an “active” state. However, the information in the V1 region, which is a short time (e.g. 100 ms) of iconic memory, never fully enters the more stable form of visual memory, for example working memory. The reason why the full details of the information in iconic memory are not captured by the more stable form of memory, can be that iconic memory contains too much information and / or contains sensory input noise. The information and / or sensory input noise in iconic memory can interfere with the information stored during naturally occurring SWR.

[0020] Inhibition of the V1 region during naturally occurring SWR can facilitate communication between the hippocampus and all relevant neocortical areas. This inhibition helps to consolidate long-term memory.

[0021] Behrens et al., “Induction of sharp-wave-ripple complexes in vitro and reorganization of hippocampal networks,” Nature Neuroscience, 8(11), 1560-1567 (2005), http: / / www.nature.com / articles / nn1571, disclose that SWRs can be artificially induced by various invasive stimulation methods. These artificially induced SWRs have the same temporal and spectral properties as naturally occurring SWRs. In contrast to naturally occurring SWRs, the occurrence of artificially induced SWRs can be caused by external stimulation.

[0022] The number of SWRs correlates with the number of long-term memory items that are remembered, as disclosed by Norman et al. in “Hippocampal sharp-wave-ripples linked to visual episodic recollection in humans,” Science, 365(6454), eaax1030 (2019), https: / / doi.org / 10.1126 / science.aax1030 https: / / doi.org / 10.1126 / science.aax1030. Increasing the number of SWRs can help consolidate long-term memories.

[0023] Ripples, i.e. synchronous high frequency oscillations in the frequency range of SWRs, occur throughout the brain, e.g. in the neocortex or the hippocampus. The ripples can be one of neocortical ripples or hippocampal SWRs. During wakefulness, neocortical ripples precede SWRs in the hippocampus. Thus, neocortical ripples can induce SWRs in the hippocampus. During consolidation and recall, SWRs in the hippocampus precede neocortical ripples. This reflects the information flow during encoding, consolidation and recall of long-term memories, as disclosed in Dickey et al. in “Widespread ripples synchronize human cortical activity during sleep, waking, and memory recall” (PNAS, 119 (28), e2107797119 (2022), https: / / doi.org / 10.1073 / pnas.2107797119).

[0024] Neocortical ripples in the visual area (V1) of the cerebral cortex can be produced by using visual input. The visual input is used to induce synchronous high frequency oscillations in the frequency range of SWRs in humans. The frequency range of neocortical ripples in the V1 region is higher than 80 Hz when induced by high frequency visual flicker stimuli with frequencies between 80 Hz and 250 Hz.

[0025] There are two potential problems with artificially inducing SWRs by exploiting visual input. The first problem is that high frequency visual flicker stimuli can not pass through the retina of the eye. The retina is the first stage of the visual system of the brain. The peak response latency of the cone cells of the retina is about 10 milliseconds. This creates a 100 hertz low pass filter for high frequency visual stimuli, as disclosed in Schneeweis et al. in “Photovoltage of rods and cones in the macaque retina” (Science, 268 (5213), 1053-1056, https: / / doi.org / 10.1126 / science.7754386).

[0026] The second problem is that even if the high frequency visual flicker stimuli pass through the retina, it is not certain that the V1 region of the brain is able to process the high frequency visual flicker stimuli.

[0027] Thus, there is a need to develop a system to induce SWRs in the hippocampus. There is a need to induce SWRs in the hippocampus in a non-invasive manner. There is a need to develop a system to preserve images in the primary visual cortex area of the brain. This can preserve information captured by the primary visual cortex in a form of a more stable memory, such as a working memory. The preservation of information can further proceed before the decay of the form of the memory. SUMMARY

[0028] The present disclosure teaches an apparatus for inducing ripples (i.e., neocortical ripples and / or sharp wave ripples (SWRs)) in a brain of a subject.

[0029] Ripples refer to synchronous, oscillatory neural activity of the brain, with a frequency between 80 and 250 Hz.

[0030] Neocortical ripples refer to synchronous, oscillatory neural activity of the neocortex of the brain, with a frequency between 80 and 250 Hz.

[0031] SWRs refer to synchronous, oscillatory neural activity of the hippocampus of the brain, with a frequency between 80 and 250 Hz.

[0032] The apparatus comprises a light source. The light source is configured to generate light. The generated light has at least two light variations. The at least two light variations are selected from at least two of a spatial variation, a temporal variation, a wavelength spectrum variation, an intensity variation, or a polarization variation. The at least two light variations are selected to induce ripples in the brain. The generated light generates a visual stimulus in the brain at the frequency of the ripples.

[0033] The apparatus is capable of inducing ripples in the brain of the subject non-invasively by exploiting the visual system of the brain.

[0034] In an aspect, the generated light generates a visual stimulus in the brain at the frequency of the ripples such that different cells of the retina of the subject are activated in sequence.

[0035] The induced ripples enable a breakthrough of the limitations of the retina of the subject.

[0036] The induced ripples in the V1 area of the brain enable improved communication of the large volume of the visual memory with downstream areas of the brain, such as the CA1 area. The induced ripples, i.e., oscillatory events, can trigger crosstalk between the V1 area and higher areas of the brain, thereby delivering information of the visual memory that did not have a chance to be delivered in natural circumstances.

[0037] In an aspect, the light source is one of a stroboscope, an electronic display, a light emitting diode, a panel of light emitting diodes, an electronic display comprising a plurality of light emitting diodes, a liquid crystal display, or a laser diode.

[0038] In one aspect, the at least two light variations are spatial variation and temporal variation.

[0039] In another aspect, the device comprises a piezoelectric device for vibrating the light source.

[0040] It is also taught in the present disclosure a system for improving memory retention of a subject. The subject is substantially located at the center of the field of view of the subject. The system comprises a light source adapted to produce light in the peripheral field of view of the subject. The produced light has at least two light variations. The at least two light variations are selected from at least two of spatial variation, temporal variation, wavelength spectrum variation, intensity variation, or polarization variation. The at least two light variations are selected to induce ripples in the brain of the subject. As described above, the produced light produces visual stimulation in the brain at the frequency of the ripples.

[0041] In one aspect, the device is used for at least one of: enhancing the subject’s episodic memory; improving the subject’s ability in remembering a greater number of elements in a memory image; translating episodic memory into working memory; translating working memory into hippocampal memory or long-term memory; translating hippocampal memory into long-term memory; translating spatial memory into long-term memory; preventing or treating Alzheimer’s disease; preventing or treating the effects of aging on the subject’s memory or other brain cognitive functions; preventing or treating the effects of dementia on memory or other brain cognitive functions; training the subject’s memory to retrieve lost facial identity memory; memory image pairs, word pairs, or a combination thereof.

[0042] It is further taught in the present disclosure a method of inducing ripples in the brain of a subject. The method comprises alternatingly illuminating different cells of the retina of the subject with a light source. The light source is adapted to produce light. The produced light has at least two light variations. The at least two light variations are selected from at least two of spatial variation, temporal variation, wavelength spectrum variation, intensity variation, or polarization variation. As described above, the produced light produces visual stimulation in the brain at the frequency of the ripples, thereby inducing ripples in the brain.

[0043] In one aspect, the ripples are selected from one of neocortical ripples or hippocampal SWRs.

[0044] In one aspect, the method comprises, prior to the step of alternatingly illuminating different cells of the retina, measuring brain activity of the subject, measuring brain oscillatory rhythms of the subject, and thus the step of alternatingly illuminating different cell populations based on the brain oscillatory rhythms and / or based on properties of the brain activity. The properties of the brain activity include amplitude, frequency, phase, and synchronicity.

[0045] It is also taught in the present disclosure a head-mounted device or a screen-mounted device comprising the device. The head-mounted device or the screen-mounted device is used for replacing sleep, mimicking sleep, learning during sleep, or memory consolidation during sleep. BRIEF DESCRIPTION OF DRAWINGS

[0046] Figure 1 A view of a device for artificially inducing ripples in a brain of a subject is shown.

[0047] Figure 2 A system for improving memory retention of a subject is shown.

[0048] Figure 3 A view of a head-mounted device including a device for artificially inducing ripples is shown.

[0049] Figure 4 A view of a screen-mounted device including a device for artificially inducing ripples is shown.

[0050] Figure 5 and Figure 6 A flowchart depicting a method for artificially inducing ripples in a brain of a subject is shown.

[0051] Figure 7 A combination of one or more of a spatial variation, a wavelength spectrum variation, an intensity variation, or a polarization variation with a temporal variation is shown.

[0052] Figure 8 Results from an electrophysiology experiment showing the number of artificially induced SWRs in a mouse after high frequency visual stimulation with temporal and spatial variations compared to a control condition are shown.

[0053] Figure 9 Results from an electrophysiology experiment showing the number of artificially induced SWRs in a human after high frequency visual stimulation with temporal and spatial variations compared to a control condition are shown.

[0054] Figure 10 Results from a magnetoencephalography experiment showing the number of artificially induced SWRs in a human after high frequency visual stimulation with temporal and spatial variations compared to a control condition are shown.

[0055] Figure 11 Results from a behavioral experiment showing memory recall performance after high frequency visual stimulation with temporal and spatial variations compared to a sham condition are shown.

[0056] Figure 12 A virtual reality (VR) glasses, augmented reality (AR) glasses, mixed reality (MR) glasses, extended reality (XR) glasses, or data glasses including a device for artificially inducing ripples is shown.

[0057] Figure 13 A head-mounted device is shown.

[0058] Figure 14Training and test performance of a recurrent neural network (RNN) in detecting a signal in a power spectrum of electroencephalogram signals recorded from the head surface of a subject (the signal is believed to be associated with SWRs) is shown. DETAILED DESCRIPTION

[0059] The present application will now be described with reference to the drawings. It is to be understood that the embodiments and aspects of the application described herein are by way of example only and are not limiting of the scope of the claims. The application is defined by the claims and their equivalents. It is to be understood that features of one aspect or embodiment of the application can be combined with features of a different aspect or aspects and / or embodiments of the application.

[0060] Figure 1 A view of an apparatus 10 for evoking ripples in a brain 15 of a subject 20 is shown. The apparatus 10 includes a light source 30 that produces light having at least two light variations. The at least two light variations are selected from at least two of a spatial variation, a temporal variation, a wavelength spectrum variation, an intensity variation, or a polarization variation.

[0061] In one example, the at least two light variations are a combination of one or more of a spatial variation, a wavelength spectrum variation, an intensity variation, or a polarization variation with a temporal variation.

[0062] The apparatus 10 utilizes the visual system of the brain 15 to evoke ripples in the brain 15 of the subject 20 in a non-invasive manner.

[0063] Using visual input from the visual system of the brain 15 and visual stimulation at high frequencies within the frequency range of ripples can evoke ripples.

[0064] The retina 25 of the eye 22 is the first stage of the visual system of the brain 15. Different cells of the retina, such as the cone photoreceptors of the retina 25, have a peak response latency of about 10 ms. This creates a 100 hertz low pass filter for high frequency visual stimulation. Sequential activation of different cells of the retina allows for a break through of the retina 25 limitations. The different cells of the retina can be adjacent retinal cells, different color receptor cells, or randomly selected retinal cells. In other words, evoking ripples by using visual input stimulates an area of the retina 25 in such a way that the stimulated area has enough time to reach a peak response, and then further stimulation reaches the same previously stimulated area.

[0065] The produced light creates a visual stimulation in the brain 15.

[0066] Temporal variation refers to the change in activity of the light source 30 over time. Spatial variation refers to the change in spatial position of the light source 30 or the direction of light from the light source 30 over time. Wavelength spectrum variation refers to the change in wavelength of the light source 30 over time. Intensity variation refers to the change in brightness or luminosity of the light source 30 over time. Polarization variation refers to the change in direction of light waves of the light source 30 over time.

[0067] In one aspect, the visual stimulus is generated by a temporal variation of the ripple frequency and by a light variation selected from at least one of a spatial variation, a wavelength spectrum variation, an intensity variation, or a polarization variation. The visual stimulus can stimulate different cells of the retina in sequence, i.e. different regions of the retina 25. This leads to a breakthrough of the confinement of the retina 25 to induce synchronous high frequency oscillations in the brain 15 of the subject 20.

[0068] In another aspect, the visual stimulus is generated by a temporal variation of the ripple frequency and by a light variation selected from at least one of a spatial variation, a wavelength spectrum variation, an intensity variation, or a polarization variation, which can artificially induce synchronous high frequency oscillations in the V1 region of the brain, i.e. ripples. This visual stimulus can induce SWRs in the hippocampus of the brain.

[0069] A visual stimulus generated by a temporal variation of frequencies below the frequency range of ripples and SWRs cannot artificially induce high frequency oscillations, nor can it induce ripples in the V1 region of the brain. A visual stimulus generated by a temporal variation of frequencies below the frequency range of ripples and SWRs also cannot induce SWRs in the hippocampus of the brain 15.

[0070] A visual stimulus generated by a temporal variation, and without at least one light variation selected from at least one of a spatial variation, a wavelength spectrum variation, an intensity variation, or a polarization variation, cannot stimulate different regions of the retina 25 in such an order that the different regions stimulated are given enough time to reach a peak response before a further stimulus reaches the same region of a previous stimulus.

[0071] The device 10 comprises a piezoelectric device 40, for example. The piezoelectric device 40 can vibrate the spatial position of the light source 30 or the direction of light from the light source 30, i.e. the generated light.

[0072] Most naturally occurring SWRs occur during sleep or quiet rest. The device 10 can be used to increase the number of SWRs by artificially inducing SWRs.

[0073] Imitation refers to the operation of the device 10 to increase the number of SWRs. The device 10 can replace the function of sleep to generate SWRs.

[0074] The naturally occurring SWRs in the brain 15 are very high frequency oscillations, for example, the naturally occurring SWRs have a frequency between 80 Hz and 250 Hz. The naturally occurring SWRs are short in duration, about 50 ms, and occur at most 100 times per minute. The naturally occurring SWRs occur especially during sleep and during a resting state of the brain.

[0075] The artificially induced SWRs mean that the number of SWRs is increased during and / or after the use of the device 10 compared to the time before the use of the device 10.

[0076] The produced light with at least one of a spatial variation, a wavelength spectrum variation, an intensity variation, or a polarization variation and a temporal variation of the light, results in a visual stimulus in the brain 15 in the frequency range of ripples, for example, in the frequency range between 80 and 250 Hz. The visual stimulus can result in high frequency oscillations in the V1 region, i.e. ripples. The visual stimulus can further induce SWRs in the hippocampus.

[0077] Figure 8 The number of SWRs recorded from the hippocampus of a mouse during a visual stimulus with light having a temporal variation and a spatial variation is shown on a game display with a refresh rate of 240 Hz. The number of SWRs during the visual stimulus is higher compared to during the resting baseline phase.

[0078] The frequency of the temporal variation of the visual stimulus can be chosen according to the frequency of the SWRs of the species to which the visual stimulus is applied.

[0079] The term "flickering" refers to the temporal variation of the visual stimulus. The frequency of the temporal variation of the visual stimulus is for example between 80 and 240 Hz. The temporal variation of the visual stimulus is for example combined with a spatial variation. The temporal variation of the visual stimulus combined with the spatial variation is for example the frequency of the whole visual stimulus divided by the number of spatial variations.

[0080] In one non-limiting example, the whole visual stimulus has a frequency of 180 Hz and contains 4 spatial variations. Thus, the temporal variation combined with the spatial variation is 180 Hz divided by 4, thus 45 Hz. Figure 7 The respective temporal variation (variation 1) in the 4 spatial variations (variation 2) is shown.

[0081] In certain aspects, the temporal variation of the visual stimulus is combined with a wavelength spectrum variation. The temporal variation of the visual stimulus combined with the wavelength spectrum variation is for example the frequency of the whole visual stimulus divided by the number of wavelength spectrum variations. In one non-limiting example, the whole visual stimulus has a frequency of 180 Hz and contains 2 wavelength spectrum variations. Thus, the temporal variation combined with the wavelength spectrum variation is 180 Hz divided by 2, thus 90 Hz.

[0082] In certain aspects, the temporal variation of the visual stimulus is combined with the intensity variation. The temporal variation combined with the intensity variation of the visual stimulus is the frequency of the entire visual stimulus divided by the number of intensity variations. In one non-limiting example, the entire visual stimulus has a frequency of 180 Hz and contains 2 intensity variations. Thus, the temporal variation combined with the intensity variation is 180 Hz divided by 2, thus 90 Hz.

[0083] In certain aspects, the temporal variation of the visual stimulus is combined with the polarization variation. The temporal variation combined with the polarization variation of the visual stimulus is the frequency of the entire visual stimulus divided by the number of polarization variations. In one non-limiting example, the entire visual stimulus has a frequency of 180 Hz and contains 2 polarization variations. Thus, the temporal variation combined with the polarization variation is 180 Hz divided by 2, thus 90 Hz.

[0084] It was found that the V1 region of the brain is able to process oscillations of artificially induced SWRs with a frequency of at least 80 Hz. This frequency was measured in the electrical activity of the brain after creating a flickering stimulus on a gaming display with a refresh rate of 240 Hz and combining the spatial variation.

[0085] Artificially induced SWRs contain several properties that depend on the duration, the exact frequency, the timing of naturally occurring SWRs relative to the visual stimulus (i.e. the latency) and the number of naturally occurring SWRs in the brain. For example, it was found that the frequency of artificially induced SWRs is the same as the frequency of naturally occurring SWRs.

[0086] The device 10 and the light source 30 can be stand-alone devices, i.e. the device 10 and the light source 30 can work without controlling a computer system. In one example, the light source 30 is an industrial device from Rheintacho Messtechnik GmbH. For example, the light source 30 is a stroboscope, which flashes light with a frequency of up to 20 kHz. In another example, the light source 30 is an electronic display or a light-emitting diode (LED). In another example, the light source 30 is a panel containing multiple light-emitting diodes (LEDs), a display containing multiple light-emitting diodes (LEDs), a liquid crystal display (LCD) or a laser diode. The light emitted by the light source 30 is, for example, polarized light or flickering light. The flickering light of the light source 30 flashes such that the flickering light stimulates the retina 25 of the subject 20 with a high frequency of, for example, 120 Hz.

[0087] The color of the light source 30 is, for example, red and green. Alternating the color of the light source 30 can target different types of photoreceptors in the retina 25. This different targeted way of illumination allows one cell in the retina 25 to recover while another cell in the retina 25 is stimulated. By alternating the color of the light source 30 with a frequency of, for example, 120 Hz, a high temporal frequency can be achieved.

[0088] The high frequency components of the light source 30 are usually filtered out by the low pass filter (LPF) characteristics of the retina 25. It is well known that the retina 25 removes frequencies above 100 Hz. Different cell populations in the retina 25 can be stimulated alternately in order to give rest time to one cell while stimulating another cell. Due to the above-mentioned low pass filter characteristics, the maximum temporal frequency can reach 100 Hz when stimulating the entire retina 25. In other words, this means that a higher temporal frequency than 100 Hz cannot be achieved without different types of cells (i.e. photoreceptors of the retina 25) or different areas of the retina 25 for different time points.

[0089] In one non-limiting example, the device 10 further comprises a rotating device 50 located between the light source 30 and the eye 22 of the subject 20. In one example, the rotating device 50 is a rotating disc. In another example, the rotating device 50 is a cylinder coated with a reflective surface. The cylinder can be a three-dimensional (3D) printed cylinder. In another example, the rotating device 50 is a hexagonal cylinder.

[0090] In another example, the rotating device 50 has alternating transparent shapes and non-transparent shapes, similar to a checkerboard pattern. The transparent shapes and non-transparent shapes have a specific size, dimension and shape design. In one non-limiting example, the shape is a circular wedge with an outer length of 1 cm, a side length of 13 cm and with 6 alternating transparent and non-transparent stripes, each stripe having a length of 1 cm.

[0091] In another non-limiting example, the rotating device 50 is a translucent disc, for example made of acrylic glass. In this example, the rotating device 50 has non-transparent shapes comprising black ink, called “off” fields. The remaining shapes of the rotating device 50 are transparent shapes and are called “on” fields.

[0092] In another example, the rotating device 50 has shapes of different colors. The shapes of different colors are arranged alternately to form a checkerboard pattern on the rotating device 50.

[0093] In one example, the rotating device 50 comprises at least two different colors of alternating colored filters.

[0094] In one non-limiting example, the rotating device 50 comprises alternating holes and faces. In one example, the rotating device 50 is made of wood with a thickness of 2.5 mm. In one example, the rotating device 50 is designed such that one cycle of “on” and “off” is synchronized with the “on” and “off” cycle of the stroboscopic light emitting diode (LED).

[0095] Reference will now be made toFigure 5 A method of artificially inducing SWRs is described.

[0096] The method comprises in step S1000 alternatingly illuminating different cells among the cells of the retina 25 of the subject 20 from the light source 30. This illumination thereby induces SWRs in the brain 15 in step S1202.

[0097] In one non-limiting example, the step of S1000 of alternatingly illuminating different cell populations comprises illuminating S1001 the rotating device 50 which comprises a checkerboard pattern on the surface of the rotating device 50. This checkerboard pattern creates alternating “on” fields and “off” fields.

[0098] The different cells among the cells of the retina 25 are either illuminated by an “on” field or blocked by an “off” field.

[0099] The step of S1001 of illuminating the rotating device 50 is adjacent to the step of rotating S1002 the rotating device 50. This rotation step S1002 causes the cells of the retina 25 to see “opposite” fields after the rotation S1002. For example, if a certain cell of the retina 25 is illuminated S1001 by an “on” field, this cell of the retina 25 will see an “off” field after the rotation S1002. This corresponds to one “on” and “off” stimulation cycle for this given cell in the retina.

[0100] The rotating device 50 is rotated in step S1002 in such a way that the cells of the retina 25 see this cycle in a subsequent order and this means that alternating different cell populations in the retina 25 are illuminated.

[0101] In step S1002, the rotating disc 50 is rotated in a fast manner (for example, 600-720 rotations per minute for a retina stimulated at 120 Hz), to artificially induce SWRs having the same characteristics (for example, the same frequency) as naturally occurring SWRs.

[0102] Figure 6 The method is shown, comprising the following steps: first measuring S802 the brain activity of the subject 20; then measuring in step S804 the brain oscillation rhythm 70 of the subject 20; and thereby alternatingly illuminating different cell populations in the above step S1000 based on the measured brain oscillation rhythm 70. The measuring step S804 comprises for example measuring the frequency, phase and amplitude of the brain oscillation rhythm 70.

[0103] Figure 2 A system 100 for improving memory retention of a subject 110 is shown. The system 100 comprises a rotating device 50 and a light source 30 located behind the rotating device 50. The light source 30 is located within the visual field 21 of the subject 20. The subject 110 is located substantially in the center of the visual field 21.

[0104] Figure 6 The method is shown to comprise a step S2000 of placing the object 110 at approximately the center of the visual field 21 of the subject 20 for a period of time. The step S2000 is followed by an illumination step S1000 for alternately illuminating different cell populations of the peripheral region of the retina 25 of the subject 20 for a period of time. The illumination step S1000 is followed by an induction step S1202 for artificially inducing a SWR in the brain 15 of the subject 20.

[0105] In one example, the method is used to improve the ability of the subject 20 to memorize a larger number of elements in an image. The placement step S2000 of the object 110 and the subsequent illumination step S1000 open a very short opportunity window (i.e. 100 milliseconds) for the V1 region to transfer very short-lived information located in the V1 region to higher regions of the brain 15 in the form of iconic memory. This transfer occurs during and after the SWR artificially induced in the induction step S1202. The rest of the memory process occurs naturally in the brain 15. The method is able to facilitate the transfer of information from the V1 region to higher regions of the brain shortly after the presentation of a visual image.

[0106] In one example, the method is used in a "visual mode". For example, the visual mode is a mode for memorizing elements from the object 110. In this example, the object 110 can be a visual object having a plurality of memorizable items in the object, such as a matrix of letters or a combination of icons. The method of the visual mode comprises: in the step S1000, fixating on the object 110 for a short period of time (e.g. 100 milliseconds) and actively memorizing the object 110. This means that the subject 20 will make a cognitive effort to memorize the object 110 after fixating on the object 110.

[0107] After the step S1000, in the induction step S1202, a SWR is artificially induced in the brain 15. The induction step S1202 replaces the active phase in the brain 15 during which the subject 20 starts actively memorizing the object 110.

[0108] In another example, the method is used in a "non-visual mode". For example, the non-visual mode refers to learning a foreign language vocabulary. The induction step S1202 induces a SWR and acts as a loud repetition of a word pair presented to the user to actively memorize the word pair by sending a visual image of the word pair presented to the user immediately after the presentation of the word pair to the subject 20. The presentation happens just before the decay phase of the V1 region to higher regions of the brain 15, such that the brain is directed to consolidate the word pair.

[0109] For example, the device 10 is used to enhance the visuospatial memory of the subject 20. In one example, the device 10 increases the time for which the object 110 is stored in visuospatial memory, for example, by 100 milliseconds. Thus, the memory is enhanced by providing the brain 15 with more time to transfer the information to higher brain regions and / or to a more stable form of memory, i.e. working memory, consolidating the memory. In another example, the device 10 increases the capacity of visuospatial memory by improving the performance of the subject 20 in remembering a larger number of elements in the image of the object 110.

[0110] In another example, the device 10 is used for memory conversion. The device 10 can be used to convert one form of memory, i.e. visuospatial memory, to another form of memory, i.e. hippocampal long-term memory, by inducing SWRs after presenting the image to the subject 20. This would replace the active memory of the subject 20 with the induction of SWRs in step S1202. The artificially induced SWRs convert the information from short-term visuospatial memory to a more stable long-term form of memory in the higher cortical regions of the brain 15, possibly in the hippocampus.

[0111] In another example, the device 10 is used to prevent or treat Alzheimer’s disease (AD). Zhen et al. in “Normal and Abnormal Sharp Wave Ripples in the Hippocampal-Entorhinal Cortex System: Implications for Memory Consolidation, Alzheimer’s Disease, and Temporal Lobe Epilepsy” (Frontiers in Aging Neuroscience, vol. 13, pp. 683483 (2021), https: / / doi.org / 10.3389 / fnagi.2021.683483) state that the naturally occurring SWR system is disrupted in AD patients.

[0112] Neurodegenerative diseases, such as AD, are characterized by significant loss of neural and glial cell material. Various metabolites are known to accumulate within brain cells, forming neurofibrillary tau protein tangles, and to accumulate outside brain cells, forming beta amyloid (Ab) plaques. These metabolites have neurotoxic effects, leading to further cell death, as taught by Hardy, J.A. and Higgins, G.A. in “Alzheimer’s Disease: The Amyloid Cascade Hypothesis” (Science, 256(5054), 184-185 (1992), https: / / doi.org / 10.1126 / science.1566067). Severe cognitive decline is a hallmark of AD, and patients suffer from progressive dementia, characterized by impaired spatial orientation (i.e., patients have difficulty determining their own position in space and determining spatial relationships of objects), memory loss, and learning impairment.

[0113] It is not currently known whether Ab plaques play an important role in the degenerative process after the onset of AD. The Ab cascade hypothesis is one of the first views of the physiological mechanism of the cause of AD, as disclosed by Spires-Jones et al. in “The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease” (Neuron, 82(4), 756-771 (2014), https: / / doi.org / 10.1016 / j.neuron.2014.05.004). It was originally thought that the deposition of Ab plaques in the brain of a subject would trigger a series of events that would ultimately lead to neuronal death and dementia.

[0114] Recently, the role of synaptic loss in AD pathophysiology has gained traction, as taught by Tzioras et al. in “Synaptic degeneration in Alzheimer disease” (Nature Reviews Neurology, 19(1), 19-38 (2023), https: / / doi.org / 10.1038 / s41582-022-00749-z). Synaptic loss refers to the loss of connections (i.e., synapses) between neurons in a subject’s brain. SWRs can play a central role in impaired synaptic plasticity, as taught by Caccavano et al. in “Inhibitory Parvalbumin Basket Cell Activity is Selectively Reduced during Hippocampal Sharp Wave Ripples in a Mouse Model of Familial Alzheimer’s Disease” (The Journal of Neuroscience, 40(26), 5116-5136 (2020), https: / / doi.org / 10.1523 / JNEUROSCI.0425-20.2020) and Sanchez-Aguilera et al. in “Sharp Wave Ripples in Alzheimer’s Disease: In Search of Mechanisms” (The Journal of Neuroscience, 41(7), 1366-1370 (2021), https: / / doi.org / 10.1523 / JNEUROSCI.2020-20.2020). Synaptic plasticity refers to the ability of synapses in the brain to strengthen or weaken over time.A study on glial cells described by Steadman et al. in “Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult Mice” (Neuron, 105(1), 150-164.e6, (2020), https: / / doi.org / 10.1016 / j.neuron.2019.10.013) points to a specific role of oligodendrocytes and the loss of axonal myelin and impaired SWR in AD, while Chen et al. in “Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease” (Neuron, 109(14), 2292-2307.e5 (2021), https: / / doi.org / 10.1016 / j.neuron.2021.05.012) describe that an increase in myelination can improve memory and SWR. Impaired SWR seems to play a central role in the pathophysiology of AD. Based on these observations, the inventors conclude that targeting impaired SWR by brain stimulation can help to alleviate AD symptoms in a subject.

[0115] Aβ is a neuro peptide derived from the amyloid-β precursor protein (APP). Like in humans, APP is present in 60 to 70% of vertebrates. As revealed by Tharp and Sarkar in “Origins of amyloid-β” (BMC Genomics, 14(1), 290 (2013), https: / / doi.org / 10.1186 / 1471-2164-14-290), APP has important physiological functions, but its functional role is controversial and not well understood. Accumulation of Aβ in AD patients seems to be one of the earliest biomarkers indicative of the onset of AD. It was found that accumulation of Aβ disturbs SWR and seems to impair memory formation. It was concluded that an imbalance between the synthesis and clearance of Aβ in the brain is a potential cause for the formation of Aβ plaques.

[0116] The glymphatic system has been found to play a role in Aβ plaque formation. Natale et al. have reported in “Glymphatic System as a Gateway to Connect Neurodegeneration from Periphery to CNS” (Frontiers in Neuroscience, vol. 15, 639140 (2021), https: / / www.frontiersin.org / articles / 10.3389 / fnins.2021.639140 / full) that the glymphatic system can have cleared excess Aβ from the brain to the cerebrospinal fluid (CSF). Thus, the function of the glymphatic system is thought to be the clearance of toxins into the CSF, and this clearance process mainly occurs during slow wave sleep, SWS. Furthermore, it has been found that during induction of SWR, memory consolidation also occurs, as disclosed by Branger et al. in “Relationships between sleep quality and brain volume, metabolism, and amyloid deposition in late adulthood” (Neurobiology of Aging, 41, 107-114 (2016), https: / / doi.org / 10.1016 / j.neurobiolaging.2016.02.009). For subjects with AD, an increase in SWR can be a compensatory mechanism for the decrease in SWR density in the subject’s body. Impairment of SWR seems to cause impaired encoding, impaired consolidation, and impaired retrieval of memory, as disclosed by Cushing et al. in “Impaired Hippocampal-Cortical Interactions during Sleep in a Mouse Model of Alzheimer’s Disease” (Current Biology, 30(13), 2588-2601.e5 (2020), https: / / doi.org / 10.1016 / j.cub.2020.04.087).Human experiments have shown that visual stimulation can drive the flow of CSF in the brain, as disclosed by Williams et al. in “Neural activity induced by sensory stimulation can drive large-scale cerebrospinal fluid flow during wakefulness in humans” (PLOS Biology, 21(3), e3002035 (2023), https: / / doi.org / 10.1371 / journal.pbio.3002035). By targeting impaired SWR generation with artificially induced SWRs, the clearance of Abeta can be increased by activating the colloidal lymphatic system, while increasing the SWR density. The inventors concluded that increasing the SWR density would further alleviate AD memory pathology, i.e. the observed decrease in memory function by subjects suffering from AD.

[0117] In addition to the above-mentioned degeneration of neural tissue, there is also white matter damage in AD, i.e. alterations in central nervous axon myelination. Myelination is related to the structure that supports the axons of the brain. Axons are the elongated projections of neurons in the brain that are responsible for transmitting electrical impulses within the brain. Degeneration of myelin leads to a decrease in the speed of electrical signal transmission along the central nervous axon.

[0118] Experimental studies have shown that changes in myelination are experience-dependent, indicating that changes in myelination play an important role in neural plasticity and memory, as disclosed by Xin and Chan in “Myelin plasticity: Sculpting circuits in learning and memory” (Nature Reviews Neuroscience, 21(12), 682-694 (2020), https: / / doi.org / 10.1038 / s41583-020-00379-8).

[0119] Studies have also found that myelin is necessary for promoting SWR generation. Loss of glial cells impairs the renewal of axon myelin and impairs SWRs and their associated memory formation.

[0120] The inventors conclude that an increase in myelination will improve memory and enhance SWR function, countering AD pathology. Chen et al. in “Enhancing myelin renewal reverses cognitive dysfunction in a murine model of Alzheimer’s disease” (Neuron, 109, 2292-2307 (2021)) show that stimulating myelin renewal in mice can improve memory and increase SWR density and frequency in a mouse model of AD. Increasing SWR density can promote the activity of glial cells and axonal remyelination, thus improving neural network function and memory formation.

[0121] Molecular changes and cellular degeneration are central to current AD models, but synaptic dysfunction can be detected before, for example, clinically relevant Aβ plaque deposition is observed. Cellular changes cause changes in synaptic activity. Synaptic activity changes molecular structure and function, leading to cellular changes, as revealed in Iaccarino et al. in “Gamma frequency entrainment attenuates amyloid load and modifies microglia” (Nature, 540(7632), 230-235 (2016), https: / / doi.org / 10.1038 / nature20587). Deficits in neural plasticity are evident in early stages of AD and link Aβ and Tau to cognitive decline. Considering the early changes in synaptic activity in AD and synaptic loss in different molecular pathologies in AD, the inventors conclude that dysfunction of synapses can be the link between neuropathology and cognitive symptoms. Experimental evidence shows that SWR plays a key role in triggering and regulating synaptic plasticity. Therefore, the inventors conclude that artificially inducing synaptic plasticity by artificially inducing SWR can counteract early pathological synaptic loss in AD. Countering early pathological synaptic loss in AD can prolong normal function and prevent neurodegenerative progression of AD, considering neuropathological changes.

[0122] The device 10 can artificially induce SWR of the required rhythm and temporal pattern of the cortical network to compensate for the lack of naturally occurring SWR in the brain 15 of a person suffering from AD. The device 10 can also be used in a “pacemaker” fashion, similar to the concept of a cardiac pacemaker.

[0123] The apparatus 10 can be used to prevent or treat the effects of dementia on memory or other cognitive functions of the brain. The presence of SWRs does decrease with age.

[0124] In another example, the apparatus 10 can be used to train the memory of the subject 20 to retrieve lost facial identity memories, pairs of images, pairs of words, or combinations thereof.

[0125] In this example, the apparatus 10 can be used to help the subject 20 remember pairs of images. During a training phase, the subject 20 is presented with several pairs of images. The training phase is the phase in which the subject 20 learns the information. The pairs of images are divided into a first subset of pairs of images and a second subset of pairs of images. For the first subset of pairs of images, SWRs are induced after the pair of images is displayed. For the second subset of pairs of images, SWRs are not induced after the pair of images is displayed. The subject 20 answers "yes" or "no" to a test pair during a testing phase. The test pair indicates whether the test pair contains two images that were displayed during the training phase. The subject 20 is expected to be able to remember the images better if the test pair belongs to the first subset of pairs of images during which artificial SWRs were induced. The subject should then be able to give more correct answers to the first subset of pairs of images for which artificial SWRs were presented than to the second subset of pairs of images for which artificial SWRs were not presented. This improvement is due to the better memory of the first subset of pairs of images with artificial SWRs.

[0126] SWRs occur naturally during the resting state of the brain 15, especially during sleep. The apparatus 10 can increase the number of SWRs by artificially inducing SWRs. "Mimic" means that the apparatus 10 can be used to increase the number of SWRs. Thus, the apparatus 10 can replace the function of sleep to produce SWRs.

[0127] In one example, SWRs are artificially induced in the brain 15 in any state (e.g., a wakeful state or a sleep state) to enable people who are sleep deprived or have poor sleep quality to benefit from memory consolidation during sleep. The head-mounted apparatus 200 can also act as a memory enhancer or a memory consolidator. The head-mounted apparatus 200 can replace sleep, mimic sleep, and learn in sleep.

[0128] In another example, the head-mounted device 200 is implemented as a virtual reality (VR) glasses, an augmented reality (AR) glasses, a mixed reality (MR) glasses, an extended reality (XR) glasses, or a data glasses. In one example, the VR glasses, the AR glasses, the MR glasses, the XR glasses, or the data glasses are implemented as a standalone wearable device with a dedicated processing unit, or a standalone wearable device with a power source. Other implementations include, but are not limited to, a housing capable of housing a standalone device or a light source, such as a smartphone. The head-mounted device 200 can also be connected to an external processing unit or to a power source unit, such as a computer.

[0129] In one example, the head-mounted device 200 further comprises an optical-mechanical assembly for projecting light into the visual field 21, for example, to the peripheral area of the retina 25 of the visual field 21. The optical-mechanical assembly is, for example, a micro-electro-mechanical system (MEMS), a light projection assembly, or an integrated light source in a glass lens, such as micro-LEDs and pico-LEDs.

[0130] In one example, the smartphone is placed at the center of the rotating device 50.

[0131] Figure 3 A head-mounted device 200 comprising the device 10 is shown. In one example, the device 10 is light-sealed with the head-mounted device 200.

[0132] In one aspect, the head-mounted device 200 is worn by the subject 20 to improve memory and learning capacity. Visual or auditory content to be learned is presented to the subject 20 in a time relationship with the time at which the light source 30 produces the visual stimulus. The time relationship is, for example, a time window in the range of 1000 milliseconds to 3000 milliseconds after the presentation of the visual or auditory content to the subject 20. The head-mounted device should be worn for a time between 1 minute and 60 minutes, the time of wearing being a time of the day when the subject 20 is relaxing or resting.

[0133] In another aspect, the head-mounted device 200 is worn by the subject 20 to prevent AD, or at least to stop the progression of AD. The head-mounted device 200 is worn by the subject 20 for a defined time of the day for a defined time, while the high-frequency visual stimulus is not necessarily paired with learning visual or auditory content.

[0134] Figure 4 A screen-mounted device 201 comprising the device 10 is shown. In one example, the screen-mounted device 201 is used to enhance memory.

[0135] Figure 7 A combination of one or more of a spatial variation, a wavelength spectrum variation, an intensity variation, or a polarization variation applied with the device 10 with a temporal variation is shown.

[0136] An example is provided below. Flickering visual stimuli for the entire visual field 21 can elicit steady-state visual evoked potentials (SSVEP) of up to about 100 Hz, as revealed in Herrmann, C.S., “Human EEG responses to 1-100 Hz flicker: resonance phenomena in visual cortex and their potential correlation to cognitive phenomena,” Experimental Brain Research, 137 (3-4), 346-353 (2001), accessible at https: / / doi.org / 10.1007 / s002210100682.

[0137] Artificially enhancing these oscillations can artificially induce SWRs and possibly enhance perception and information uptake.

[0138] A stroboscope (as light source 30) was built in combination with a rotating disc (as rotating device 50) with opaque and transparent sections. The stroboscope is an industrial device by Rheintacho Messtechnik GmbH. The combination made it possible to selectively and sequentially target different cells of the retina 25 with high frequency flickering light at 120 Hz, 165 Hz, 180 Hz, or 190 Hz.

[0139] Every 10 milliseconds, multiple cells in the retina 25 were stimulated. Different cell groups were stimulated at a later time (i.e., lag) of 8.33 milliseconds, 6.06 milliseconds, 5.55 milliseconds, or 5.26 milliseconds (i.e., 120 Hz, 165 Hz, 180 Hz, and 190 Hz), respectively. 60 trials of two seconds of the above stimulation frequency were performed (i.e., 240 trials in total). 64-channel EEGs from 10 participants were recorded over 240 trials. Spatially selective SSVEPs for 120 Hz and 180 Hz stimulation were successfully recorded with a parieto-occipital topography.

[0140] On the other hand, 64-channel EEGs from six participants were recorded over four additional trials of thirty seconds, and high-frequency SSVEP responses to 180 Hz vs. 180 Hz stimulation were successfully measured.

[0141] Electrophysiological experiments in humans and mice have shown that high-frequency visual flicker stimulation above 80 Hz, combined with spatial variations, can induce SWRs in the hippocampus, as Figure 8 ,Figure 9 and Figure 10 As disclosed in U.S. Patent No. 9, 1 12, 1 12, the problem of eliciting high frequency oscillations in the visual cortex and SWRs in the hippocampus by passing through the retina 25 can be solved by combining high frequency visual flicker stimulation with one or a combination of spatial variation, wavelength spectrum variation, intensity variation, or polarization variation.

[0142] In one example, a light emitting diode display produces light that projects a spatial pattern on the retina 25 of a mouse. The light emitting diode display used is an industrial device by ASUS. The light emitting diode display produces high frequency flicker light at frequencies of 144 Hz, 180 Hz, and 240 Hz, enabling selective and alternating illumination of different cell populations in the retina 25 of the mouse.

[0143] Cells in the retina 25 of the mouse are stimulated every 22.22 milliseconds. Different cell populations in the retina 25 are stimulated with a lag time of 6.94 milliseconds, 5.55 milliseconds, or 4.16 milliseconds (i.e., 144 Hz, 180 Hz, or 240 Hz), respectively, for a total of 50 times, 2 seconds each. Signals from intracranial electrodes implanted in the right hippocampus of six mice are recorded.

[0144] Figure 8 An increase in SWRs of the hippocampal local field potentials of the mice is recorded for 144 Hz stimulation compared to the resting state condition before stimulation.

[0145] In another example, a light emitting diode display produces light that projects a spatial pattern on the retina 25 of a human. The light emitting diode display used is an industrial device by Samsung. The device produces high frequency flicker light at 120 Hz, 144 Hz, and 180 Hz, enabling selective and alternating illumination of different cell populations in the retina 25.

[0146] Cells in the retina 25 are stimulated every 22.22 milliseconds. Different cell populations in the retina 25 are stimulated with a lag time of 8.33 milliseconds, 6.94 milliseconds, or 5.55 milliseconds (i.e., 120 Hz, 144 Hz, or 180 Hz), respectively, for a total of 70 times, 2 seconds each. Electrical activity of the brain is recorded from intracranial electrodes implanted in the left hippocampus of two human participants.

[0147] Figure 9 An increase in SWRs of the electrical activity of the hippocampus of the two human participants is recorded for 120 Hz stimulation compared to the resting state condition before stimulation.

[0148] In another example, the light produced by the light emitting diode display projects a spatial pattern on the human retina 25. The light emitting diode display used is an industrial device by ViewPixx Technologies. The device 10 produces high frequency flickering light at 120 Hz and 180 Hz, enabling selective and alternating illumination of different cells in the retina 25.

[0149] The cells in the retina 25 are stimulated once every 22.22 milliseconds. Different ones of the different cells in the retina 25 are stimulated with a lag time of 8.33 milliseconds or 5.55 milliseconds (i.e. 120 Hz or 180 Hz) for 100 times, two seconds each. The 306 channel magnetoencephalography (MEG) of six participants is recorded. Using the occipital topography, the spatial selectivity SSVEP for 120 Hz and 180 Hz stimulation is successfully recorded.

[0150] Figure 10 An increase in the SWR in the magnetic field of the electrical activity of the hippocampus of six human participants is recorded for 120 Hz stimulation compared to the resting state condition before stimulation.

[0151] In another example, the light produced by the light emitting diode display projects a spatial pattern on the retina 25. The light emitting diode display used is an industrial device by ASUS. The light emitting diode display produces high frequency flickering light at 120 Hz, enabling selective and alternating illumination of different cells in the human retina 25.

[0152] The cells in the retina 25 are stimulated once every 22.22 milliseconds. Different ones of the different cells in the retina 25 are stimulated with a lag time of 8.33 milliseconds (i.e. 120 Hz) for 5 times, 60 seconds each. Before the stimulation, 17 participants learn a list of words. After the stimulation, the participants recall the previously learned words in the order in which they were presented.

[0153] Figure 11 An increase in the correct recall of the word order by the participants after receiving the stimulation is shown compared to the sham stimulation control condition of the same participants.

[0154] The spatially selective non-invasive visual stimulation is used as a tool to artificially enhance the processing of the stimulation, the selection of attention information and the naturally occurring high frequency oscillations during memory. Targeted therapeutic interventions based on the device 10 are expected to be possible, for example, visual stimulation for specific times.

[0155] Figure 12A view of a virtual reality (VR) glasses, augmented reality (AR) glasses, mixed reality (MR) glasses, extended reality (XR) glasses or data glasses comprising a device 10 for artificially inducing ripples in the brain is shown. The device 10 is composed of two lenses 220. The device 10 further comprises a projector 210. The projector 210 comprises a light source 30. The light generated from the light source 30 is projected onto or inside the lenses 220. The generated light is shown as a square on the lenses 220 in a non-limiting manner.

[0156] Figure 13 A view of a head-mounted device 200 selected from one of virtual reality (VR) glasses, augmented reality (AR) glasses, mixed reality (MR) glasses, extended reality (XR) glasses or data glasses is shown. The head-mounted device 200 comprises a device 10 for artificially inducing ripples in the head of a subject 20. The head-mounted device 200 further comprises a screen 230 for generating a stimulus to the retina 25 of the subject 20.

[0157] In one aspect, the step of measuring S802 the brain activity of the subject 20 comprises measuring a signal in the brain oscillatory rhythm that is considered a correlate of SWR. The correlate of SWR is recorded from the surface of the head of the subject 20 by electroencephalography. The alternate illumination of different cells of the retina 25 can be adjusted so as to increase the number of measured correlates of SWR.

[0158] In another aspect, the correlate of SWR is recorded from the surface of the head of the subject 20 by electroencephalography by computing the power spectrum of the recorded signal.

[0159] In another non-limiting aspect, the detection of the correlate of SWR can be achieved by training a recurrent neural network (RNN) that implements the computation of the power spectrum of the recorded signal. Figure 14 The experimental results shown above indicate that training a RNN on the power spectrum of the electroencephalographic signal can achieve a detection of SWR with more than 80% accuracy.

[0160] Reference numerals 10 device 15 brain 20 subject 21 visual field 22 eye 25 retina 26 cell 30 light source 31 first light source 32 second light source 40 piezoelectric device 50 rotating device 70 motor 80 microcontroller 100 system 110 object 200 head-mounted device 201 screen-mounted device 210 projector 220 lens 230 screen

Claims

1. A device (10) for inducing ripples in a brain (15) of a subject (20), the device (10) comprising a light source (30), wherein the light source (30) is adapted to produce light, the produced light has at least two light variations, the at least two light variations being selected from at least two of a spatial variation, a temporal variation, a wavelength spectrum variation, an intensity variation or a polarization variation; wherein the at least two light variations are selected to induce the ripples in the brain (15); and the produced light produces a visual stimulus in the brain (15) at a frequency of the ripples.

2. The apparatus (10) of claim 1, wherein, the ripples are selected from one of neocortical ripples or hippocampal sharp wave ripples, SWRs.

3. The apparatus (10) according to claim 1 or 2, wherein the produced light produces the visual stimulus in the brain (15) at a frequency of the ripples, thereby sequentially activating different cells of the retina (25) of the subject (20).

4. The apparatus (10) according to any one of the preceding claims, wherein the at least two light variations are selected from at least one of a spatial variation, a wavelength spectrum variation, an intensity variation or a polarization variation and a temporal variation.

5. The apparatus (10) according to any one of the preceding claims, wherein the produced light produces the visual stimulus in a frequency range between 80 and 250 Hz.

6. The apparatus (10) according to any one of the preceding claims, wherein the light source (30) is any one of a stroboscope, an electronic display, a light emitting diode, LED, a panel of light emitting diodes, an electronic display comprising a plurality of light emitting diodes, a liquid crystal display, LCD, or a laser.

7. The apparatus (10) according to any one of the preceding claims, wherein the at least two light variations are a spatial variation and a temporal variation.

8. The device (10) according to any one of the preceding claims, further comprising a piezoelectric device (40) for vibrating the light source (30).

9. A system (100) for improving memory retention of a subject (110), the subject (110) being substantially located in the center of a field of view (21) of a subject (20); the system (100) comprising a light source (30) adapted to produce light in a peripheral field of the subject (20), the produced light having at least two light variations; the at least two light variations being selected from at least two of a spatial variation, a temporal variation, a wavelength spectrum variation, an intensity variation or a polarization variation; wherein the at least two light variations being selected to induce ripples in a brain (15) of the subject (110); and the produced light producing a visual stimulus in the brain (15) at a frequency of the ripples.

10. The device (10) according to any one of claims 1 to 8, for at least one of: enhancing episodic memory of the subject (20), improving performance of the subject (20) in remembering a greater number of elements in a memory image, translating episodic memory into working memory, translating working memory into hippocampal memory or long-term memory, translating hippocampal memory into long-term memory, translating spatial memory into long-term memory, preventing or treating Alzheimer’s disease, AD, preventing or treating the effects of aging on memory or other cognitive functions of the brain (15) of the subject (20), preventing or treating the effects of dementia on memory or other cognitive functions of the brain, training memory of the subject (20) to learn lost identity face memory, memory image pairs, word pairs or combinations thereof.

11. Use of the device (10) of any one of claims 1 to 8 for at least one of: enhancing episodic memory of the subject (20), improving performance of the subject (20) in remembering a greater number of elements in a picture, translating episodic memory into working memory, translating working memory into hippocampal memory or long-term memory, translating hippocampal memory into long-term memory, translating spatial memory into long-term memory, preventing or treating Alzheimer’s disease AD, preventing or treating the effects of aging on memory or other cognitive functions of the brain (15) of the subject (20), preventing or treating the effects of dementia on memory or other cognitive functions of the brain, training memory of the subject (20) to learn lost identity face memory, memory picture pairs, word pairs or combinations thereof.

12. A method for inducing ripples in a brain (15) of a subject (20), the method comprising: alternately illuminating (S1000) different cells of a retina (25) of the subject (20) from a light source (30), wherein the light source (30) is adapted to produce light, the produced light having at least two light variations, the at least two light variations being selected from at least two of a spatial variation, a temporal variation, a wavelength spectrum variation, an intensity variation or a polarization variation; wherein the at least two light variations are selected to induce the ripples in the brain (15); the produced light producing a visual stimulus in the brain (15) at a frequency of the ripples; thereby inducing (S1202) the ripples in the brain (15).

13. The method of claim 12, wherein, the ripples being selected from one of neocortical ripples or hippocampal sharp wave ripples SWRs.

14. The method of claim 12 or 13, wherein, the produced light producing the visual stimulus in the brain (15) at a frequency of the ripples, thereby sequentially activating different cells of the retina (25) of the subject (20).

15. The method of any one of claims 12 to 14, wherein, the at least two light variations being selected from at least one of a spatial variation, a wavelength spectrum variation, an intensity variation or a polarization variation and a temporal variation.

16. The method of any one of claims 12 to 15, wherein, prior to the step of alternately illuminating (S1000) the different cells of the retina (25), the method comprising: measuring (S802) brain activity of the subject (20); measuring (S804) a brain oscillation rhythm (70) of the subject (20); and thereby alternately illuminating (S1000) the different cells of the retina (25) based on the brain oscillation rhythm (70) and / or based on a characteristic of the brain activity.

17. The method of any one of claims 12 to 16, further comprising placing (S2000) an object (110) at a center of a field of view (21) of the subject (20) for a time period t; and alternately illuminating (S1000) the different cells of the retina (25) in a peripheral retina (25) of the subject (20) for the time period t.

18. A head-mounted device (200) or a screen-mounted device (201) comprising the device (10) of any one of claims 1 to 8 or the system (100) of claim 9.

19. The head-mounted device (200) of claim 18, for use in one or more of replacement sleep, mimetic sleep, learning during sleep, memory consolidation during sleep, or a combination thereof.

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