Method and system of neural stimulation via music and synchronized rhythmic stimulation

Abstract

The present invention provides a method and system for neural stimulation via suitable music and synchronized rhythmic stimulation. [Solution] A system and method for treating cognitive impairment are disclosed. The system may include a sound source, a light source, an input device, and a neural stimulation system for extracting or selecting a stimulus profile. The stimulus profile may include one or more musical pieces for playback, one or more rhythmic stimulus patterns having variable parameters, and time-varying signal characteristics that can be adjusted in accordance with the music. The system may select the signal characteristics of the rhythmic stimulus based on the analysis of the music, measure the physiological state of the subject, and further adjust the rhythmic stimulus based on the neural response. The neural stimulation system may play the selected musical piece and direct the sound towards the ear, or respond to ambient musical sounds detected by a microphone, set the values ​​of the variable parameters and the characteristics of the rhythmic pattern, construct an output signal, and provide an output signal.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This invention claims priority to U.S. Provisional Patent Application No. 63 / 075,516, filed on September 8, 2020, the entire disclosure of which is incorporated herein by reference.

[0002] (Field of the Invention) The present invention generally relates to methods and systems for neural stimulation. In particular, the methods and systems of the present disclosure can provide a stimulation signal including a music stimulation signal and a visual stimulation signal to induce synchronous oscillations in the brain of a subject.

Background Art

[0003] Neural oscillations occur in humans and animals and include rhythmic or repetitive neural activity in the central nervous system. Neural tissue can generate oscillatory activity either by mechanisms within individual neurons or by interactions between neurons. Oscillations can appear either as periodic fluctuations in membrane potential or as rhythmic patterns of action potentials, which can lead to oscillatory activation of postsynaptic neurons. Synchronized activity of neuron groups can give rise to macroscopic oscillations, which can be observed by sensing the electric or magnetic fields within the brain using techniques such as electroencephalography (EEG), intracranial EEG (iEEG), also known as electrocorticogram (ECoG), and magnetoencephalography (MEG).

[0004] Nerve oscillations can be characterized by their frequency, amplitude, and phase. These signal characteristics can be observed from neural recordings using time-frequency analysis. For example, EEG can measure oscillatory activity between groups of neurons, and the measured oscillatory activity can be classified into frequency bands as follows: delta activity corresponds to the frequency band of 0.5–4 Hz, theta activity corresponds to the frequency band of 4–8 Hz, alpha activity corresponds to the frequency band of 8–13 Hz, beta activity corresponds to the frequency band of 13–30 Hz, and gamma activity corresponds to the frequency band of 30 Hz or higher.

[0005] Neuronal oscillations in different frequency bands can be associated with cognitive states or functions such as perception, activity, attention, reward, learning, and memory. Depending on the cognitive state or function, one or more neuronal oscillations in one or more frequency bands may be involved. Furthermore, neuronal oscillations in one or more frequency bands may have beneficial or harmful effects on one or more cognitive states or functions.

[0006] Neural synchronization occurs when an external stimulus of a specific frequency or combination of frequencies is perceived by the brain, triggering neural activity within the brain, resulting in neurons vibrating at frequencies associated with the specific frequency of the external stimulus. Therefore, neural synchronization can refer to synchronizing neural oscillations within the brain using an external stimulus so that the oscillations occur at frequencies corresponding to a specific frequency of the external stimulus. Neural synchronization can also refer to synchronizing neural oscillations within the brain using an external stimulus so that the oscillations occur at frequencies corresponding to the harmonics, subharmonics, integer ratios, and specific frequency combinations of the external stimulus. Specific neural oscillation frequencies that can be observed in response to a set of external stimulus frequencies are predicted by models of neural oscillation and neural synchronization.

[0007] Cognitive functions such as learning and memory involve coordinated activity distributed across subcortical and cortical brain regions, including the hippocampus, cortical and subcortical association areas, sensory areas, and the prefrontal cortex. Across different brain regions, behavior-related information is encoded, maintained, and retrieved through transient increases in the power and synchronization of neural oscillations, reflecting multiple frequencies of activity.

[0008] In particular, oscillatory neural activity in the theta and gamma frequency bands is associated with encoding, maintenance, and retrieval processes between short-term, working, and long-term memory. Evoked gamma activity is involved in working memory and is accompanied by increased scalp recording gamma-band activity and intracranial gamma-band activity during working memory maintenance. Increases in gamma activity power dynamically track the number of items maintained in working memory. Using cortical electroencephalography (ECoG), one study found that increases in gamma power tracked working memory load in the hippocampus and medial temporal lobe as participants maintained sequences of letters or faces in working memory. Finally, other evidence suggests that hippocampal gamma activity assists episodic memory, and distinct sub-gamma frequency bands correspond to encoding and retrieval stages.

[0009] Theta oscillations (4–8 Hz) are associated with working memory processing and episodic memory processing. Intracranial EEG (iEEG) recordings demonstrate that during working memory, theta oscillations gate on and off (i.e., amplitude increases and sustains before rapidly decreasing) across the encoding, maintenance, and retrieval phases. Other studies have observed increased scalp recording theta activity during working memory maintenance. A recent systematic review concluded that scalp recording theta activity emerging from frontal midline electrodes is the most robust neural correlation for verbal working memory maintenance. Furthermore, frontal midline theta activity tracks working memory load, increasing and sustaining power as a function of the number of items maintained in working memory.

[0010] Prior art research has found that gamma frequency auditory-visual stimulation can improve dementia or Alzheimer's disease (AD)-related biomarkers and pathophysiology, and can provide neuroprotection when administered during the early stages of disease progression.

[0011] However, auditory stimuli at gamma frequencies are perceived as crude and unpleasant by human listeners. In a prior art study by Malchano and Williams, the physiological and attentional states of subjects were monitored while an "orchestration policy" switched between stimulus modalities within a treatment session. This study found that gamma frequency auditory stimuli may be poorly tolerated by patients and could be problematic when administered over the long periods required to deliver clinical benefit.

[0012] To address the crude and unpleasant nature of auditory stimuli at gamma frequencies, conventional solutions attempt to embed gamma frequency auditory stimuli within the music signal, for reasons similar to how a spoonful of sugar can make medicine easier to swallow. This approach has several problems. Firstly, most music contains bass frequencies that vary within the gamma range, and bass frequencies are the most important cues for harmonic perception. Therefore, incorporating additional gamma frequency sounds to harmonize with existing music can be difficult or impossible. In other words, this approach does not cover aversive auditory gamma stimuli, which simply makes the music sound worse.

[0013] Another problem with embedding gamma frequency auditory stimuli within music signals is that the brain's natural response to music already includes a gamma frequency response. This natural neural gamma frequency response to music can interfere with additional auditory gamma stimuli, potentially neutralizing the therapeutic stimulus. Furthermore, conventional systems stimulate only one specific frequency. A common consequence of such stimulation is neural adaptation, which leads to a decrease in the neural response over time.

[0014] U.S. Patents 10,293,177, 10,279,192, and 10,307,611, all assigned to Cognito Therapeutics, Inc., are examples of this type of prior art gamma-frequency auditory stimulation. The techniques disclosed therein include methods for reproducing musical audio signals in addition to auditory stimulation pulses at specific gamma frequencies. However, as stated above, the pure superposition of gamma-frequency audio stimulation to existing audio signals reduces patient tolerance to the treatment and diminishes the effectiveness of the treatment. [Overview of the Initiative] [Means for solving the problem]

[0015] To solve these and other prior art problems, in preferred embodiments, the systems and methods of the present disclosure relate to neural stimulation by rhythmic light stimulation presented simultaneously with auditory stimulation by music. The combination of music and light stimulation can induce a neural oscillatory effect or stimulation. The combined stimulation can be tuned, controlled, or otherwise influenced to provide beneficial effects on one or more cognitive states, cognitive functions, the immune system, or inflammation, while mitigating or preventing adverse consequences on cognitive states or cognitive functions. For example, the systems and methods of the present invention can treat, prevent, protect against, or otherwise influence Alzheimer's disease. The present invention provides, for example, the following: (Item 1) Auditory analysis system, A tuning simulator operably connected to the aforementioned auditory analysis system, A vibration selection module operably connected to the aforementioned tuning simulator, A brain rhythm stimulator operably connected to the vibration selection module, A nerve stimulation system comprising an output device operably connected to the aforementioned brain rhythm stimulator. (Item 2) The neural stimulation system according to item 1, wherein the auditory analysis system comprises a filtering module having means for filtering an input audio signal, an onset detection module having means for detecting the onset of an acoustic event in the input audio signal, and a gain control module having means for adjusting the gain of the input audio signal. (Item 3) The neural stimulation system according to item 2, wherein the auditory analysis system provides an output to the tuning simulator in the form of a start signal. (Item 4) The tuning simulator includes means for predicting the frequency, phase, and amplitude of a human neural response to music. The neural stimulation system according to item 1, wherein the synchronization simulator provides an output to the vibration selection module in the form of one or more network states. (Item 5) The neural stimulation system described in item 4, wherein the one or more frequency ranges include a delta frequency band, a theta frequency band, and a gamma frequency band. (Item 6) The vibration selection module includes means for selecting the most prominent vibration in one or more frequency ranges and coupling gamma frequencies to the beat and rhythmic structure of music via theta-gamma and delta-theta PACs. The neural stimulation system according to item 1, wherein the vibration selection module provides output to the brain rhythm stimulator in the form of one or more selected vibration states. (Item 7) The neural stimulation system according to item 1, wherein the brain rhythm stimulation device comprises a light pattern buffer, a light generation module, a light adjustment module, and a filtering component. (Item 8) The neurostimulation system according to item 7, wherein the output device includes a device selected from the group including LED lights, computer monitors, TV monitors, goggles, virtual reality headsets, augmented reality glasses, and smart glasses. (Item 9) The output device is a visual stimulation ring, the visual stimulation ring includes a cylindrical body having one or more LED lights arranged around the inner surface in the circumferential direction, and the one or more LED lights are operably connected to the brain rhythm stimulation device. The nerve stimulation system according to item 7. (Item 10) The brain rhythm stimulation device provides an output to the output device in the form of a control signal, and the control signal includes an instruction to cause the output device to display a rhythmic light pattern corresponding to one or more selected vibration states selected by the vibration selection module. The nerve stimulation system according to item 9. (Item 11) The nerve stimulation system according to item 1, wherein the output device includes one or more stimulation devices for generating an electromagnetic field and / or an electric current to deliver a tactile stimulation, a vibration stimulation, a thermal stimulation, an electrocutaneous stimulation, or a transcranial stimulation. (Item 12) The nerve stimulation system according to item 11, wherein the output device is selected from the group including a wearable device, a glove, a smartwatch, a mobile device, or an array of electromagnets or electrodes. (Item 13) The nerve stimulation system according to item 1, further comprising a brain vibration monitor operably connected to the synchronization simulator and having one or more means for sensing an electric field or a magnetic field in the brain. (Item 14) The one or more means for sensing an electric field or a magnetic field in the brain includes one or more devices selected from the group including an electroencephalogram (EEG), an intracranial EEG (iEEG), electrocorticogram (ECoG), or magnetoencephalography (MEG). The nerve stimulation system according to item 13. (Item 15) The auditory analysis system includes one or more means for receiving an auditory input selected from the group including a built-in voice reproduction system, an auxiliary voice input, or a microphone, and the one or more means receive an auditory input operably coupled to the auditory analysis system. The nerve stimulation system according to item 1. (Item 16) The nerve stimulation system according to item 15, further comprising an auditory output means. (Item 17) A profile manager further comprising a processor or an Internet-compatible software application that accesses a non-temporary and / or random access memory storing data regarding one or more users, the data being selected from a list comprising identification information, stored information from previous treatments, a library of audio files, and / or one or more user preferences, the nerve stimulation system according to item 1. (Item 18) The nerve stimulation system according to item 17, wherein the profile manager is operably connected to the tuning simulator, the auditory analysis system, and the brain rhythm stimulation device. (Item 19) Selecting one or more vibrations within one or more predetermined frequency ranges; Generating a stimulation pattern using the one or more vibrations; Outputting the stimulation pattern to an output device, a method of nerve stimulation. (Item 20) The method of nerve stimulation according to item 19, wherein the stimulation pattern includes a type of stimulation selected from the group comprising a light pattern, a vibrotactile pattern, or a pattern of electrical or magnetic pulses. (Item 21) Receiving an auditory input including an acoustic signal; Filtering the acoustic signal; Detecting the start of one or more acoustic events included in the acoustic signal and simulating neural synchronization to the acoustic signal using a tuning simulator; Generating one or more coupling parameters for combining the one or more vibrations; Adjusting the one or more coupling parameters or intrinsic parameters using an adaptive learning algorithm; Selecting one or more vibrations within one or more predetermined frequency ranges for display; Generating a light pattern using the one or more vibrations; A method of nerve stimulation, comprising displaying the aforementioned light pattern on a visual output device. (Item 22) Prior to the step of generating the light pattern, the step further includes reading the patient profile from the profile manager, The method of nerve stimulation according to item 21, wherein the step of generating a light pattern further comprises the steps of selecting a light pattern based on the patient profile and adjusting the light pattern based on the patient profile. (Item 23) Receiving input from a brain vibration monitor, The input is provided to one or more multi-frequency neural networks, The inputs are combined using one or more combination parameters, The method further includes using an adaptive learning algorithm to adjust one or more parameters to optimize the frequency, amplitude, and phase of one or more transmitted vibration signals. The method of nerve stimulation according to item 21, wherein one or more emitting vibration signals are used to generate the light pattern and display it on the visual output device. (Item 24) The method of nerve stimulation according to item 23, wherein the brain vibration monitor includes one or more means of sensing an electric or magnetic field in the brain, selected from the group including electroencephalography (EEG), intracranial EEG (iEEG), cortical electroencephalography (ECoG), or magnetoencephalography (MEG). (Item 25) The method of nerve stimulation according to item 21, wherein the auditory input is a musical piece, and the musical piece is played in synchronization with the light pattern. [Brief explanation of the drawing]

[0016] The drawing is as follows:

[0017] [Figure 1]In a preferred embodiment of the present invention, a breakdown of frequencies selected by OSM is provided with respect to specific underlying musical stimuli and the range of frequencies present in each frequency band, as in one exemplary embodiment of the present invention. [Figure 2] On the left is a MEG recording of the human auditory cortex recorded while a subject listened to rhythmic auditory stimuli of two different tempos, and on the right is a highlight of some of the brain regions that showed this response. [Figure 3] This is a schematic diagram showing various components / modules of the present invention system in one embodiment of the present invention. [Figure 4] This is a schematic diagram illustrating the high level of interoperability of the components of the present invention coupled with the resulting brain stimulation in one embodiment of the present invention. [Figure 5] The panel shows the stimulation provided by a song in one embodiment of the present invention. Panel A compares the auditory rhythmic frequency (i.e., the onset spectrum) of the music to the frequency of an auditory 40 Hz pulse train. Panel B compares the visual frequency stimulated by the present invention to the frequency of a visual 40 Hz pulse train. [Figure 6] The panel shows the stimulation provided by a second song in one embodiment of the present invention. Panel A compares the auditory rhythmic frequency (i.e., the onset spectrum) of the music with the frequency of an auditory 40 Hz pulse train. Panel B compares the visual frequency stimulated by the present invention with the frequency of a visual 40 Hz pulse train. [Figure 7] This is a diagram of a device for delivering visual stimuli according to one embodiment of the present invention. [Modes for carrying out the invention]

[0018] The inventors have discovered that music can synchronize and drive neural activity across multiple frequency ranges, and therefore, musical stimuli themselves can synchronize and drive oscillatory neural activity involved in learning, memory, and cognition. In a preferred embodiment, the present invention relies on the brain's natural delta, theta, and gamma frequency responses to music by providing music as the sole auditory stimulus in systems and methods for treating, preventing, protecting against, or otherwise influencing Alzheimer's disease and dementia. In a preferred embodiment of the present invention, auditory stimuli are coupled with visual stimuli in the delta, theta, and / or gamma frequency bands, which are tuned by a synchronization simulator to synchronize with the delta, theta, and / or gamma frequency bands of the brain's response to auditory stimuli for improved therapeutic effects. In other embodiments of the present invention, additional frequencies and frequency bands may be targeted for stimulation to treat, prevent, and / or protect against other diseases such as Alzheimer's disease, dementia, and / or Parkinson's disease.

[0019] The inventors have observed that musical rhythms are organized into well-structured combinations of frequencies. For example, musical rhythms synchronize neural activity in delta and theta frequency ranges by directly stimulating the brain in these frequency ranges. The frequency of the fundamental beat typically corresponds to neural activity in the delta frequency band. Subdivisions of the beat typically correspond to neural activity in the theta frequency band. It has also been found that, because musical rhythms involve structured combinations of frequencies, they can drive activity at delta and theta frequencies that are not explicitly present in the rhythm. The frequencies observed in brain activity can include harmonics, subharmonics, integer ratios, and combinations of frequencies present in musical rhythms, and can be predicted by simulations of neural oscillations and neural synchronization.

[0020] The inventors also observed that musical rhythms can drive gamma neural activity in the brain in a manner distinct from the synchronization of delta and theta activity. The amplitude of endogenous gamma neural oscillations is modulated so that the amplitude peaks synchronize with musical events (see Figure 2). Amplitude modulation of gamma neural activity reflects phase-amplitude coupling to lower frequency (e.g., delta and theta) neural activity. Phase-amplitude coupling (PAC) is defined as the statistical dependence between the amplitude of an oscillation in one frequency band and the phase of an oscillation in another frequency band. For example, in a theta-gamma phase-amplitude coupling, the peak of the gamma amplitude corresponds to a specific phase of synchronized theta activity. Thus, gamma activity is driven by synchronized theta and delta activity.

[0021] The system and corresponding methods of the present invention work by activating the brain's natural delta, theta, and gamma responses to music in a way that does not interfere with the enjoyment of music. Since enjoyment is important for patient tolerance and protocol completion, the present invention overcomes the shortcomings of prior art methods that reduce patient compliance with treatment by including jarring and unpleasant sounds of added sound waves in the gamma frequency band.

[0022] In preferred embodiments, the present invention also uses visual stimuli in the delta frequency band, theta frequency band, and / or gamma frequency band to enhance frequencies important in musical enjoyment (as opposed to competing frequencies as in the prior art). The inventors believe that this additional aspect of the present invention enhances the effectiveness of the method of the present invention because visual stimuli in the gamma band are less aversive than auditory stimuli in the gamma band. In some embodiments, gamma stimuli can be combined with delta and theta stimuli to generate visual stimuli that mimic the brain's natural response to musical rhythm. In the systems and methods of the present invention, gamma stimuli can be amplitude-modulated through phase-amplitude coupling to theta frequency oscillations and / or delta frequency oscillations to mimic auditory processing (see Figure 1), thereby increasing the effectiveness and degree of the neural stimulation. Furthermore, specific stimulation frequencies are determined by the musical stimulation, and therefore the stimulation frequencies provided by the present invention vary within a stimulation session, reducing the possibility of neural adaptation and thus increasing stimulation effectiveness. Therefore, in these embodiments, the present invention combines music listening with delta frequency visual stimuli, theta frequency visual stimuli, and / or gamma frequency visual stimuli to generate an attractive and effective audiovisual stimulus for the patient.

[0023] In other embodiments, additional frequency bands may be used via both auditory and visual stimuli, as described above.

[0024] In a preferred embodiment, the solution of the present invention outputs an improved set of stimuli that amplify the brain's natural delta, theta, and gamma responses to music in a manner that does not produce neural interference between the brain's natural vibrational response to music and an additional vibrational auditory stimulus within the same frequency band. Specifically, in one embodiment, the system and method of the present invention uses a simulation of neural synchronization to determine the frequencies of the brain's natural delta, theta, and gamma responses to music. The system of the present invention then enhances and amplifies the natural response to music by delivering the same delta, theta, and / or gamma frequencies in a visual stimulus. The simulation may include delta-theta-gamma phase-amplitude coupling to faithfully mimic the brain's auditory response and amplify the effect. Thus, the visual stimulus amplifies the brain's natural vibrational response to music rather than interfering with or canceling it out (as in the methods of the prior art).

[0025] The present invention relates to a system and method for outputting a stimulus that induces neural stimulation via a rhythmic light stimulus presented simultaneously with a musical stimulus. The present invention's combination of music and rhythmic light pulses can induce electroencephalogram (EEG) effects or stimulation. The combined stimulus can adjust, control, or otherwise influence the frequency of neural oscillations to provide beneficial effects on one or more cognitive states, cognitive functions, the immune system, or inflammation (or other conditions), mitigating or preventing adverse consequences to cognitive states or cognitive functions, and maximizing enjoyment, treatment tolerance, and completion of treatment protocols. For example, the system and method of this technology can treat, prevent, protect against, or otherwise influence Alzheimer's disease.

[0026] The frequencies of nerve oscillations observed in a patient may be influenced by, or correspond to, the frequencies of musical rhythms and rhythmic light pulses. Therefore, the system and method of the present invention can induce neuronal synchronization by outputting multimodal stimuli, such as musical rhythms and light pulses, emitted at frequencies determined by analysis of the musical rhythms. This combined multimodal stimulus can synchronize electrical activity among groups of neurons based on one or more frequencies synchronized and driven by the musical rhythms. Neuronal synchronization can be observed based on the total frequency of oscillations generated by synchronized electrical activity in a collection of neurons throughout the brain.

[0027] In other embodiments, additional outputs from the system may also include one or more stimulators for generating tactile, vibratory, thermal and / or electrotranscutaneous stimulation. Such stimulators may include mobile devices, smartwatches, gloves, or other devices capable of vibrating. In other embodiments, the output device may include stimulators for generating electromagnetic fields or currents, such as electromagnets or arrays of electrodes, to deliver transcranial stimulation.

[0028] To achieve the method of the present invention, the system according to the present invention includes an auditory analysis system (AAS) having means for receiving auditory input, filtering acoustic signals, detecting the onset of an acoustic event (e.g., a musical note or drum strike), and adjusting the gain of the resulting signal. In embodiments, the main function of the AAS is to preprocess auditory stimuli to provide multi-channel rhythmic input (e.g., the starting point of a musical note). In some embodiments of the present invention, the auditory input is provided by the system, such as a built-in audio playback system having access to a library of songs and / or other musical pieces. In such embodiments, the system may further include a graphical display and input means accessible to the user (e.g., a patient or therapist) to enable the user to make selections from the library for playback. In other embodiments, in addition to, or as an alternative to, the built-in audio playback system, the system of the present invention includes an auxiliary audio input to enable the system to receive input from a secondary playback system, such as a personal music playback device (e.g., an iPod®, MP3 player, smartphone, etc.). In further embodiments, in addition to or as an alternative to the auditory input means, the system includes a microphone or similar means that enables the system to receive auditory input from ambient sounds such as live music performances or music broadcast from secondary speakers, such as the user's home stereo system. To facilitate one or more of the auditory input means, in some embodiments, the AAS interfaces with a profile manager that includes a processor or internet-enabled software application that accesses non-temporary and / or random-access memory that stores data about one or more users or patients, such as various user preferences, such as song selection, as well as identification information (e.g., name or patient ID number), memory information from previous treatments, and / or a library of audio files.

[0029] In embodiments where the audio signal is received by the system via an auxiliary input such as a built-in playback system or an MP3 player, the system may further include headphones or an integrated speaker to enable the listener to hear the audio signal in real time.

[0030] As described above, the AAS further comprises a filtering module, an onset detection module, and an optional gain control module, respectively, for filtering signals, detecting the onset of acoustic events, and adjusting the gain of the resulting signal.

[0031] In some preferred embodiments, the system of the present invention utilizes a tuned simulator (ES) that receives and processes one or more received audio signals, enhances the received audio signals to simulate processing in the human brain, and outputs an oscillatory signal, thereby improving the therapeutic effect of the treatment of the present invention. In some embodiments, the AAS is operably connected to the ES and provides data to the ES in the form of a start signal. In some embodiments, the ES also interfaces with a profile manager to retrieve patient data, for example, from a previous treatment. In some embodiments, the main function of the ES is to simulate tuned neural oscillatory to predict the frequency, phase, and amplitude of a human neural response to music.

[0032] In some preferred embodiments, the system of the present invention includes a vibration selection module (OSM). In these embodiments, the OSM receives input from the ES and outputs one or more selected vibration states as frequency, amplitude, and phase for visual stimuli.

[0033] Collectively, the components described above enable the system of the present invention to (1) receive auditory input through one or more means for receiving the above-described audio signals; (2) simulate neural tuning to the pre-processed auditory signals using one or more tuning simulators, which may include a multi-frequency artificial neural oscillator network; (3) couple the vibrations in the network using phase-amplitude or phase-phase coupling; (4) adjust the coupling parameters and / or intrinsic parameters using an adaptive learning algorithm; and / or (5) select the most prominent vibrations in one or more frequency bands for display as visual stimuli via a brain rhythm stimulator as described below.

[0034] As described above, in some embodiments, the ES includes one or more oscillatory neural networks designed to simulate neural synchronization. In embodiments, the artificial oscillatory neural network receives a pre-processed auditory stimulus (music) and synchronizes simulated neural oscillators to predict the frequency, phase, and relative amplitude of a human neural response to the music. The OSM then selects the most prominent oscillators within one or more predetermined frequency ranges (preferably delta frequency bands, theta frequency bands, and gamma frequency bands) for a visual stimulus. Using the simulated neural oscillators via a brain rhythm stimulator (described below), the visual stimulus in the selected frequency range is synchronized to the rhythm of the music via a device such as an LED light ring, as described below.

[0035] In some embodiments, the ES may comprise, but is not limited to, any other means of mimicking an oscillatory neural network, including, but not limited to, a deep neural network, an oscillator network, a set of formulas, algorithms, or any other sufficient means. Sufficient for these purposes means that the simulator should be able to accurately predict the frequency, phase, and relative amplitude of oscillatory vibrations in a typical human brain that are tuned and driven by any given musical stimulus. It should be able to accurately predict responses in at least the delta (1–4 Hz), theta (4–8 Hz), and lower gamma (30–50 Hz) frequency bands.

[0036] In some embodiments, the OSM according to the present invention couples visual gamma frequency stimuli to the beat and rhythmic structure of music via phase-amplitude coupling (for example, as described in Lakatos et al., An Oscillatory Hierarchy Controlling Neuronal Excitability and Stimulus Processing in the Auditory Cortex, J Neurophysiol 94:1904-1911, 2005, first published on 18 May 2005, the content of which is incorporated herein by reference in its entirety). In preferred embodiments, the OSM selects variable music-based frequencies within the delta, theta, and gamma ranges for visual stimulation to the user, which is generated by a Brain Rhythmic Stimulator (BRS) as described below. Figure 1 shows a breakdown of four frequencies selected by the OSM in one exemplary embodiment, relating to the underlying music and the range of frequencies present. In some embodiments, the OSM selects one or more harmonically related frequencies within the delta frequency range, theta frequency range, and a lower gamma (30-50 Hz) frequency range. In some embodiments, the gamma amplitude is modulated by a theta frequency to simulate a theta-gamma phase-amplitude coupling. In other embodiments, the theta amplitude is modulated by one or more delta frequencies to simulate a delta-theta phase-amplitude coupling. Collectively, the above simulates a delta-theta-gamma oscillation hierarchy in the auditory cortex.

[0037] Continuing with Figure 1, an exemplary protocol for visual stimulus frequencies generated by the system of the present invention in the gamma, theta, and delta frequency bands according to one aspect of the present invention is shown. Panel A shows the time-domain waveform of the musical stimulus over a 4-beat time interval and the start point calculated during preprocessing. Panel B shows the delta-theta-gamma coupled change in luminance provided by OSM, and Panel C shows the same change in each frequency band. For comparison, Figure 2 shows MEG recordings of the human auditory cortex recorded while a subject listened to two rhythms with different tempos. Panel A of Figure 2 is a time-frequency map of signal power changes associated with rhythmic stimuli presented every 390 ms (2.6 Hz), showing a periodic pattern of signal increase and decrease in the gamma frequency band. Panel B shows the same measurements for rhythmic stimuli presented every 585 ms (1.7 Hz). In the auditory cortex, gamma is amplitude-modulated by delta and theta, and this pattern is simulated by the apparatus of the present invention. Panel D of Figure 1 shows the stimuli generated by the apparatus of the present invention in the frequency domain. Collectively, these figures show that gamma oscillations are effectively stimulated by the output provided by the apparatus of the present invention in a frequency range around the principal frequency. These additional frequencies are called sidebands, and they are caused by amplitude modulation of the apparatus and method of the present invention from theta and delta frequencies. Furthermore, each song reproduced by the apparatus of the present invention results in a different selection of frequencies within the delta, theta, and gamma ranges. Thus, while reproducing several songs with the apparatus of the present invention, the output provided by the apparatus stimulates many gamma frequencies. In contrast, apparatuses of the prior art stimulate only a single gamma frequency.

[0038] Therefore, the device simulates amplitude modulation of stimuli provided in the gamma frequency band by the phase of stimuli provided in the delta and theta frequency bands, which mimics the brain's natural gamma-delta-theta phase-amplitude coupled response, thereby improving both the tolerability and efficacy of the treatment. As described above, panel D in Figure 1 shows that gamma oscillations are effectively stimulated in a range of frequencies (sidebands) around the principal frequency. These sidebands are caused by amplitude modulation from theta and delta frequencies provided by the system of the present invention.

[0039] Furthermore, each piece of music played by the system results in a different selection of frequencies within the delta, theta, and gamma ranges. Thus, different gamma frequencies are stimulated during a single session. In contrast, conventional systems stimulate only one frequency, and a common outcome is neural adaptation, resulting in reduced neural response. In a preferred embodiment of this system, varying the frequency avoids neural adaptation and promotes a robust neural response.

[0040] Therefore, in embodiments, the rhythmic visual stimuli (described later) selected for output to the user include delta frequencies, theta frequencies, and / or gamma frequencies, as well as theta-gamma and / or delta-gamma phase amplitude couplings to enhance the naturally occurring oscillatory response to musical rhythms. Sensory cortices in the brain (e.g., the primary visual cortex and primary auditory cortex) are functionally connected to the hippocampus, as well as areas important for learning and memory, such as the medial and lateral prefrontal cortex. Therefore, coupling complex rhythmic visual stimuli, including delta frequency visual stimuli, theta frequency visual stimuli, and gamma frequency visual stimuli, to musical rhythms can drive theta, gamma, and theta-gamma couplings in the brain, activating neural circuits involved in learning, memory, and cognition. This can drive learning and memory circuits involved in music. In some embodiments, the system incorporates means to prompt the user to select their own individualized musical preferences as auditory stimuli, which can maximize the effectiveness of a given system by stimulating the auditory and reward systems in patients in the early stages of dementia and cognitive decline.

[0041] Figures 5 and 6 show a comparison between the auditory and visual stimuli provided by the present invention and those provided by exemplary prior art devices. Both figures show the diverse frequencies of the auditory and visual stimuli provided by both the present invention and the prior art devices. Figures 5 and 6, respectively, show the stimuli provided by different songs. As can be seen from the figures, the prior art devices provide both auditory and visual stimuli at a single frequency, which can be easily contrasted with the wide range of frequencies at which the device of the present invention provides both auditory and visual stimuli.

[0042] In a preferred embodiment, rhythmic visual stimuli are output to the user via a brain rhythm stimulator (BRS) operably connected to the ES and optional OSM within the system of the present invention. The BRS may include a pattern buffer, a generation module, a tuning module, and filtering components, and may be operably connected to an output device having means for displaying rhythmic visual stimuli. The output device may include an LED light, a computer monitor, a TV monitor, goggles, a virtual reality headset, augmented reality glasses, smart glasses, or other suitable stimulus output device. In some embodiments, the output device may be a stimulator for generating tactile, vibration, heat, and / or electrotranscutaneous stimulation in a wearable device, smartwatch, or mobile device, etc. In some embodiments, the output device may include a stimulator for generating an electromagnetic field or current, such as an electromagnet or array of electrodes, to deliver transcranial stimulation. The BRS may also interface with a profile manager, which has a processor or internet-enabled software application that accesses non-temporary and / or random-access memory storing data about one or more users or patients, as described above. Therefore, in some preferred embodiments, the information stored by the profile manager may also include previously captured or user-selected preferences for other parameters of the stimulus, such as patterns, waveforms, or colors, which are preferred by the user / patient.

[0043] Collectively, these components enable the BRS to (1) read the patient's profile from the profile manager, (2) select a pattern based on the profile, (3) extract one or more selected vibration signals and / or vibration states from the ES / OSM, (4) generate a pattern, (5) adjust the pattern based on the profile, and (6) display or output rhythmic stimuli to an output device. In some embodiments, the pattern refers to a light pattern and the output device refers to a visual output device.

[0044] In some embodiments, the visual output device according to the present invention may include an integrated or connected LED light, a computer monitor, a TV monitor, goggles, a virtual reality headset, augmented reality glasses, smart glasses, or other suitable light output device. In some embodiments, the output device may be a stimulator for generating tactile, vibratory, thermal, and / or electrotranscutaneous stimulation in a glove, smartwatch, or other wearable device or mobile device. In some embodiments, the output device may be a stimulator for generating an electromagnetic field or current, such as an electromagnet or an array of electrodes, to deliver transcranial stimulation.

[0045] In one preferred embodiment, referring to Figure 7, the visual stimulus is provided via a visual stimulation ring 100 comprising an LED light 102 operably connected to the rest of the apparatus of the present invention and / or the BRS component. In some embodiments, the visual stimulation ring 100 is placed in front of the participant seeking the fovea at the center indicated by reference numeral 101. In some embodiments, the visual stimulation ring 100 is positioned at an appropriate distance to stimulate the retina at a particular visual angle. For example, the ring may be positioned at an appropriate distance to stimulate the retina at visual angles of 0–15 degrees, 10–60 degrees, 15–50 degrees, 15–25 degrees, 18–22 degrees, or 19–21 degrees. In some embodiments, the visual stimulation ring 100 may be positioned at an appropriate distance to stimulate the retina at a visual angle of 20 degrees, where the maximum density of rods in the retina is observed.

[0046] Finally, in a preferred embodiment, the system of the present invention includes a brain oscillatory monitor (BOM) that provides neural feedback which can be used to optimize the frequency, amplitude, and phase of a visually presented oscillatory signal to optimize the frequency, phase, and amplitude of the oscillatory signal in the brain. In an embodiment, the BOM provides feedback to the system so that it can adjust the parameters to optimize the phase of the emitting oscillatory signal. The BOM includes electrodes, a magnetometer, or other means for sensing brain activity, a signal amplifier, filtering components, and feedback interface components which can interface with or otherwise communicate with them. In a preferred embodiment, the feedback is provided to the ES in the form of an EEG signal.

[0047] Collectively, these components enable the BOM to identify the frequency, phase, and amplitude of brain oscillations synchronized by the stimulus. The brain oscillation monitor senses an electric or magnetic field in the brain, amplifies brain signals, filters the signals to identify specific nerve frequencies, and provides input to the ES as described above. The means by which the BOM senses an electric or magnetic field in the brain may include electrodes connected to an electroencephalogram (EEG), intracranial EEG (iEEG), also known as cortical electroencephalography (ECoG), magnetoencephalography (MEG), and other means known in the art.

[0048] Figure 3 shows a schematic diagram illustrating the various components / modules of the system of the present invention.

[0049] In some embodiments, a schematic diagram illustrating the high level of interoperability of the components of the present invention coupled with the resulting brain stimulation is shown in Figure 4.

[0050] Therefore, in the method according to one embodiment of the present invention, the system is (A) Receiving auditory input, (B) Filter the acoustic signal, (C) Detect the start of an acoustic event, (D) Simulate neural synchronization to a pre-processed auditory signal using one or more multi-frequency neural oscillator networks. (E) Couple vibrations in the network using phase-amplitude coupling or phase-phase coupling, (F) Using an adaptive learning algorithm, adjust the coupling parameters and / or eigenparameters. (G) Select the most prominent oscillations within the delta frequency band, theta frequency band, and / or gamma frequency band for display. (H) Generate a light pattern, (I) Display rhythmic light on the visual output device.

[0051] In some preferred embodiments, before receiving voice input, the system also performs a step of prompting the user to select a source for voice input and / or to make a selection from a library of songs or musical pieces stored by the system.

[0052] In particular, the inventors discovered that self-selected music—that is, music chosen by individual patients and familiar to them—is more effective in engaging a larger network of brain activity in brain regions including the hippocampus, auditory cortex, and frontal lobe, which are important for long-term memory, compared to music selected by others or music unfamiliar to the patient. They also found that listening to familiar music is more effective in driving brain activity in older adults and activating more brain regions. Importantly, familiar music drives greater activation in the hippocampus, a critical region for memory.

[0053] Data developed by the inventors indicate that music selected by listeners is far more likely to be preferred and familiar to the listeners, and is far more effective in engaging brain activity than music selected by researchers. In particular, the inventors found that, in relation to the invention, self-selected music, in addition to activating the auditory system, increases activity in the dopaminergic reward system, the default mode network, and the brain's predictive processing. While not bound by any particular theory, the inventors observed that prolonged music listening increases the brain's functional connectivity from the sensory cortex to the dopaminergic reward system, which is the cause of various motivated behaviors.

[0054] Therefore, in a preferred embodiment of the present invention, the auditory stimulation includes music self-selected by the patient, which has the practical effect of maximizing whole-brain engagement. Thus, the present invention enables patients to listen to their favorite music recordings while viewing an engaging audiovisual display including delta frequency stimulation, theta frequency stimulation, and gamma frequency stimulation, further improving patient compliance to one or more disclosed treatment protocols.

[0055] In yet another preferred embodiment, prior to the step of generating and displaying a light pattern, the system further performs the steps of (G2) reading a patient profile from a profile manager, (G3) selecting a light pattern based on the profile, (G4) taking one or more vibration signals from the ES, (H) generating a light pattern, and (H2) adjusting the light pattern based on the profile.

[0056] In one preferred embodiment, the system also optimizes the frequency, phase, and / or amplitude of the emitted vibration signal based on data received from the BOM. Thus, the system performs the additional steps of optimizing the frequency, phase, and amplitude of the emitted vibration signal by (J) intermittently or continuously receiving input from the BOM, (K) providing input to the ES, (L) coupling the inputs via phase-phase coupling, and (M) adjusting the coupling parameters and / or eigenparameters using an adaptive learning algorithm.

[0057] Therefore, the method according to the present invention provides neural stimulation to the user by presenting rhythmic visual stimuli simultaneously, synchronously, and in harmony with musical stimuli.

[0058] For example, in another embodiment of the present invention, the system generates and displays light patterns based on system self-selection or based on profile data stored for individual users that are displayed simultaneously with musical stimuli. In such embodiments, the system (A) Select one or more vibrations in the delta frequency band, theta frequency band, and / or gamma frequency band, (B) Generate a light pattern using one or more selected vibrations, (C) Display the light pattern on a visual output device.

[0059] The system in this embodiment may also examine the user's profile and select a light pattern based on the profile. The system may first prompt the user to select a profile from an input device and / or user interface integrated or coupled to the system, and then read the patient's profile from a profile manager to determine the appropriate light pattern to display.

[0060] As described herein in relation to various embodiments, the auditory analysis system receives auditory input through a microphone or auxiliary audio input, filters the acoustic signal, detects the onset of an acoustic event (e.g., a musical note or drum strike), and adjusts the gain of the resulting signal.

[0061] As described herein with respect to various embodiments, the ES receives auditory input from an auditory analysis system, uses the input to simulate neural synchronization to a preprocessed auditory signal using one or more multi-frequency neural oscillator networks, couples oscillations within the network using phase-amplitude or phase-phase coupling, adjusts coupling parameters and / or eigenparameters using an adaptive learning algorithm, and selects oscillations to be displayed within a given frequency range based on the extracted profile. It also receives input from a brain oscillator monitor, provides input to one or more multi-frequency neural networks, couples neural inputs through phase-phase coupling, and optimizes the amplitude and phase of the emitted oscillatory signal by adjusting coupling parameters using an adaptive learning algorithm.

[0062] As described herein in relation to various embodiments, the BRS reads a patient profile from a profile manager, selects a light pattern based on the profile, reads one or more vibration signals from the ES, selects at least one of delta frequencies, theta frequencies, gamma frequencies, and / or frequency combinations whose frequencies, amplitudes, and phases are determined by a tuning simulator, generates a rhythmic light pattern based on the selected frequencies, adjusts the light pattern based on the profile, and displays the rhythmic visual stimulus on an LED, computer monitor, TV monitor, or other suitable light output device directed towards the eye.

[0063] Therefore, the result of the method of the present invention is that the system senses an electric or magnetic field in the brain, amplifies brain signals, and filters the signals to identify specific nerve frequencies. In some embodiments, the system then collects output from the user's brain based on the brain's reception of visual and auditory stimuli and returns this feedback to the ES to further optimize the visual and auditory stimuli.

[0064] The inventors have found that the systems and methods of this disclosure can synchronize and drive oscillatory neural activity involved in learning, memory, and cognition. By providing music as the sole auditory stimulus in addition to visual stimuli in the delta frequency band, theta frequency band, and / or gamma frequency band, the systems and methods of the present invention can play a role as a method for treating, preventing, protecting against, or otherwise influencing Alzheimer's disease and dementia. [Industrial applicability]

[0065] The present invention relates to an apparatus and method for treating and improving the symptoms of Alzheimer's disease and dementia. By providing music as the sole auditory stimulus in addition to visual stimuli in the delta frequency band, theta frequency band, and / or gamma frequency band, the system and method of the present invention can play a role as a method for treating, preventing, protecting, or otherwise influencing Alzheimer's disease and dementia. Since Alzheimer's disease and dementia affect a large and growing portion of the world's population, the innovative apparatus and method has immediate applicability for the treatment of current patients and patients who have not yet experienced the full onset of symptoms.

Claims

1. A nerve stimulation system, wherein the nerve stimulation system is An auditory analysis system configured to receive acoustic input, A tuning simulator operably connected to the auditory analysis system, wherein the tuning simulator is configured to simulate neural tuning to the acoustic input, A vibration selection module operably connected to the aforementioned tuning simulator, wherein the vibration selection module is configured to select one or more vibrations within one or more frequency ranges for simulation, A brain rhythm stimulator operably connected to the vibration selection module, wherein the brain rhythm stimulator is configured to generate a stimulation pattern according to one or more vibrations, and the stimulation pattern is synchronized with the acoustic input, An output device operably connected to the brain rhythm stimulator, wherein the output device is configured to provide the stimulation pattern, and Equipped with, The vibration selection module is Selecting the most prominent vibration in one or more frequency ranges of the processed stimulus signal, The gamma frequency of the processed stimulus signal is coupled to the beat and rhythmic structure of the music via theta-gamma and delta-theta phase amplitude coupling (PAC), To provide output to the brain rhythm stimulator in one or more of the aforementioned vibration modes. A neural stimulation system further configured to perform the following actions.

2. The neural stimulation system according to claim 1, wherein the auditory analysis system comprises a filtering module configured to filter an input audio signal, an onset detection module configured to detect the onset of an acoustic event in the input audio signal, and a gain control module configured to adjust the gain of the input audio signal.

3. The neural stimulation system according to claim 2, wherein the auditory analysis system provides an output to the tuning simulator in the form of a start signal.

4. The tuning simulator is further configured to predict the frequency, phase, and amplitude of a human neural response to music within one or more frequency ranges. The neural stimulation system according to any one of claims 1 to 3, wherein the synchronization simulator provides an output to the vibration selection module in the form of one or more vibration states.

5. The nerve stimulation system according to claim 4, wherein the one or more frequency ranges include a delta frequency band, a theta frequency band, and a gamma frequency band.

6. The brain rhythm stimulation device comprises a light pattern buffer, a light generation module, a light adjustment module, and a filtering component, according to any one of claims 1 to 5.

7. The neural stimulation system according to claim 6, wherein the output device includes at least one of an LED light, a computer monitor, a TV monitor, goggles, a virtual reality headset, augmented reality glasses, and smart glasses.

8. The neural stimulation system according to claim 6, wherein the output device is a visual stimulation ring, the visual stimulation ring comprises a cylindrical body having one or more LED lights arranged around its circumferential inner surface, and the one or more LED lights are operably connected to the brain rhythm stimulation device.

9. The neurostimulation system according to claim 8, wherein the brain rhythmic stimulator provides an output to the output device in the form of a control signal, and the control signal includes a command to cause the output device to display a rhythmic light pattern corresponding to one or more selected vibration states selected by the vibration selection module.

10. The nerve stimulation system according to any one of claims 1 to 9, wherein the output device comprises one or more stimulators for generating an electromagnetic field and / or electric current to deliver tactile stimulation, vibration stimulation, thermal stimulation, electrotranscutaneous stimulation, or transcranial stimulation.

11. The nerve stimulation system according to claim 10, wherein the output device is at least one of a wearable device, a glove, a smartwatch, a mobile device, or an array of electromagnets or an array of electrodes.

12. The neural stimulation system according to any one of claims 1 to 11, further comprising a brain vibration monitor operably connected to the synchronization simulator and having one or more means for sensing an electric or magnetic field in the brain.

13. The neurostimulation system according to claim 12, wherein the one or more means for sensing an electric or magnetic field in the brain includes at least one of electroencephalography (EEG), intracranial EEG (iEEG), cortical electroencephalography (ECoG), or magnetoencephalography (MEG).

14. The auditory analysis system includes at least one of a built-in voice playback system, an auxiliary voice input, or a microphone, according to any one of claims 1 to 13.

15. The neural stimulation system according to claim 14, further comprising auditory output means.

16. The neurostimulation system according to any one of claims 1 to 15, further comprising a profile manager including a processor or internet-enabled software application that accesses non-temporary and random-access memory storing data relating to one or more users, wherein the data includes at least one of identification information, stored information from previous treatments, a library of audio files, and / or one or more user preferences.

17. The neural stimulation system according to claim 16, wherein the profile manager is operably connected to the synchronization simulator, the auditory analysis system, and the brain rhythm stimulation device.

18. A method for operating a nerve stimulation system, wherein the nerve stimulation system comprises an auditory analysis system, a vibration selection module, and a brain rhythm stimulation device, and the method for operating the system is: The aforementioned auditory analysis system receives acoustic input, The vibration selection module selects one or more vibrations within one or more predetermined frequency ranges, The vibration selection module selects the most prominent vibration within one or more frequency ranges of the processed stimulus signal. The vibration selection module couples the gamma frequency of the processed stimulus signal to the beat and rhythmic structure of the music via theta-gamma and delta-theta phase amplitude coupling (PAC), The vibration selection module provides output in one or more vibration modes, The brain rhythmic stimulation device determines a stimulation pattern using one or more vibrations, The brain rhythm stimulation device synchronizes the stimulation pattern with the acoustic input. A method of operation, including the method of operation.

19. The method of operation according to claim 18, wherein the stimulation pattern includes a type of stimulation that includes at least one of a light pattern, a vibratory tactile pattern, or a pattern of electrical pulses or magnetic pulses.

20. A method for operating a neural stimulation system, wherein the neural stimulation system comprises an auditory analysis system, a synchronization simulator, a vibration selection module, and a brain rhythm stimulation device, and the method for operating the system is: The aforementioned auditory analysis system receives auditory input including acoustic signals, The auditory analysis system filters the acoustic signal, The auditory analysis system detects the start of one or more acoustic events contained within the acoustic signal, The aforementioned tuning simulator simulates neural tuning to the acoustic signal, The vibration selection module selects one or more vibrations within one or more predetermined frequency ranges for display, The vibration selection module selects the most prominent vibration within one or more frequency ranges of the processed stimulus signal. The vibration selection module couples the gamma frequency of the processed stimulus signal to the beat and rhythmic structure of the music via theta-gamma and delta-theta phase amplitude coupling (PAC), The vibration selection module provides output in one or more vibration modes, The tuning simulator generates one or more coupling parameters to couple one or more vibrations, The synchronization simulator adjusts one or more coupling parameters using an adaptive learning algorithm, The brain rhythm stimulation device determines a light pattern using one or more vibrations, The brain rhythm stimulation device synchronizes the light pattern with the auditory input. A method of operation, including the method of operation.

21. The aforementioned operating method further includes, prior to the step of determining the light pattern, the brain rhythm stimulator reading the patient profile from the profile manager, The operating method according to claim 20, wherein the step of determining a light pattern includes selecting a light pattern based on the patient profile and adjusting the light pattern based on the patient profile.

22. The aforementioned operating method is The aforementioned synchronization simulator receives input from the brain vibration monitor, The tuning simulator provides the input to one or more multi-frequency neural networks, The tuning simulator combines the inputs using one or more coupling parameters, The tuning simulator uses an adaptive learning algorithm to adjust one or more coupling parameters to optimize the frequency, amplitude, and phase of one or more transmitted vibration signals. It further includes, The operating method according to claim 20 or 21, wherein the one or more transmitted vibration signals are used to determine the light pattern.

23. The method of operation according to claim 22, wherein the brain vibration monitor includes a device configured to sense an electric or magnetic field in the brain, the device being at least one of electroencephalography (EEG), intracranial EEG (iEEG), cortical electroencephalography (ECoG), or magnetoencephalography (MEG).

24. The operating method according to any one of claims 20 to 23, wherein the auditory input is a musical piece, and the musical piece is played in synchronization with the light pattern.

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