A method and system to stimulating entrainment of alpha waves and gamma waves using 10 HZ and 40 HZ stimulation for neurodegenerative diseases

Abstract

A method of treatment for improving cognitive or mental functions and neural activity in an individual comprising the step of subjecting a body of the individual to a combination of 10 Hz stimulation and 40 Hz stimulation, wherein the 10 Hz simulation and 40 Hz stimulation induce respective alpha and gamma waves in the individual.

Description

A METHOD AND SYSTEM TO STIMULATING ENTRAINMENT OF ALPHA WAVES AND GAMMA WAVES USING 10 HZ AND 40 HZ STIMULATION FOR NEURODEGENERATIVE DISEASESCROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of and priority to US patent application Serial No. 63 / 675,497, filed July 25, 2024, which is hereby expressly incorporated by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to neural stimulation, and more particularly, relates to a method and system for stimulating entrainment of alpha waves and gamma waves for cognitive impairment and Alzheimer’s disease.BACKGROUND OF THE DISCLOSURE

[0003] Individuals with mild cognitive impairment (MCI) and mild Alzheimer’ s disease (AD) exhibit subtle impairments in working memory (WM) compared to healthy controls, and these impairments manifest as difficulties in holding information over short period of times, correctly retaining information without making errors (accuracy), and responding with slower speed to stimuli (reaction time). These are tested parameters of WM that are affected in individuals with MCI and AD, reflecting underlying deficits in WM and cognitive processing. While previous studies have demonstrated that combining light and sound can enhance cognitive and memory functions, such as the impairments observed in AD and MCI patients, recent research has raised questions about the consistency and reliability of these findings in animal models.

[0004] By 2050, it is expected that one new' case of AD will develop every 33 seconds (as compared with the present figure of every 67 seconds), resulting in nearly 1 million new' cases per year. AD progresses on a three-stage spectrum: an early asymptomatic stage (preclinical); a middle stage, often referred to as mild cognitive impairment (MCI); and a final stage marked by symptoms of dementia. The incidence increases with age, with age-specific rates ranging from 0.1 % at age 60 to 8.6% at age 95. In the MCI stage, cognitive difficulties are usually prominent and depressive symptoms are frequently experienced. Although general cognitive function is preserved, individuals with MCI have memory impairment that is greater than what one would expect for normal progression of age. These subjects do not meet criteria for AD, but tend to progress clinically to AD at a rate of 10-15% per year. This is in contrast to normalelderly subjects who will develop AD at a rate of 1-2% per year. Cognitive changes tire apparent early during AD and MCI pathogenesis. Studies have shown that patients with MCI, exhibit amyloid plaques and neurofibrillary tau tangles in AD-vulnerable regions of the brain involved in memory formation, specifically, in the olfactory cortex, subiculum, and the parahippocampal gyrus in the medial temporal lobes. Recall accuracy and reaction time (RT) tend to be particularly compromised in AD / MCI in tasks that require involvement of working memory, often exhibited as difficulties when responding or in processing information. Studies suggest that providing cues can improve recall accuracy and reaction times in patients with AD / MCI, further suggesting that memory retrieval benefits from external stimulus.

[0005] The networks governing WM are distributed over a large part of the brain. In particular, the visuospatial aspect of WM activates areas of the prefrontal cortex and is often reported to be lateralized to the right hemisphere. Findings from imaging studies show that integration of regional neuronal activity is required for the complex processing of WM. A variety of cognitive functions, including WM. involve frequency dependent brain oscillation, or brainwaves. Studies have found that sensory stimulation approaches, such as those involving binaural beat (BB), which is a ’‘phantom” sound illusion that occurs when tones of two slightly different frequencies are presented separately to each ear and the brain perceives the difference between the frequencies as a “middle” frequency, can increase response accuracy and modify the strength of the brain networks during task performance. When BB is perceived, there are two standing tones in each hemisphere; the hemispheres work together to synthesize the two distinct standing tones into a single tone. This single tone “beat,” having an overall frequency equal to the difference between the two constituent tones, entrains both hemispheres to the same frequency and maximizes interhemispheric neural communication. This process involves internal processing within the nervous system and suggests thatBB might entrain the brain and enhance certain cognitive functions such as WM and attention. Application of BBs have the potential to impact cognition and have been effective in enhancing gait function in Parkinson’s disease, as well as cognition and pain perception and memory.

[0006] BB in certain frequency bands, e.g., 8-12 Hz, are in the same frequency range as alpha brain waves. Stimulation using Alpha BB of 10 Hz showed improvement in the Stroop task. Others have reported that BB in the alpha range may improve both attention and WM in healthy older subjects. While 5 min of alpha stimulation provided no significant effect on visuospatial or verbal WM, 30 min of alpha BB was found to influence visuospatial working memory. Studies have also shown that an increase in alpha oscillation shifts visual attention and improves perceptual facilitation. Enhancement of alpha oscillation is often viewed as an indexof recovery of memory disorders and cognitive function, observed as an enhancement in alpha peak oscillation that is linked to improved performance.

[0007] Furthermore, gamma-band (30-100 Hz) brain oscillation has received increased attention as a potential treatment option for modulating memory function in MCI and AD patients. Human AD patients’ models showed reduced power of oscillatory activity in the gamma range, which mediates a range of essential neural functions including cortical arousal, sensory processing, working memory, attention dependent stimulus, and higher order cognition. Slow gamma oscillations (-30-50 Hz) are observed in CAI and coupled with inputs from the CA3 region of the hippocampus that are essential for memory retrieval, whereas fast gamma oscillations (-55-140 Hz) recorded in the medial entorhinal cortex are thought to play a role in memory encoding. Research has shown that enhancing gamma stimulation using 40 Hz rhythmic light (RL) affected synaptic plasticity, reduced neurodegeneration and brain atrophy, increased synaptic density, and improved cognitive function.

[0008] Gamma oscillation has been shown to be dominant in tasks requiring memory and can be induced in the brain by sensory input. Specifically, 40 Hz gamma frequency has been found to have a superior impact on cognitive functions compared to other frequencies. Brain imaging studies demonstrated that 40 Hz RL can functionally reorganize brain regions and regulate the coherence (functional connectivity) of related brain netw'orks. A study inducing 40 Hz RL stimulation reported increased coherence of alpha-gamma in left prefrontal brain regions during light stimulation, and between the dorsolateral prefrontal cortex and the visual cortex. The synchronicity of 40 Hz RL has been demonstrated in a recent study that aimed to determine brain responses in cohorts of healthy young adults. Furthermore, 40 Hz RL seems to be neuroprotective, as it has been found to enhance presynaptic excitatory neurotransmission.SUMMARY OF THE DISCLOSURE

[0009] A method of treatment for improving cognitive functions and neural activity in an individual with mild cognitive impairment and / or Alzheimer’s disease comprising the step of subjecting a body of the individual to a combination of 10 Hz stimulation and 40 Hz stimulation, wherein the 10 Hz simulation and 40 Hz stimulation induce respective alpha and gamma waves in the individual.

[0010] A system for improving cognitive functions and neural activity in an individual with mild cognitive impairment and / or Alzheimer’s disease comprises one or more stimulusemitting devices that are configured to apply to a body of the individual a combination of 10Hz stimulation and 40 Hz stimulation, wherein the 10 Hz simulation and 40 Hz stimulation induce respective alpha and gamma waves in the individual.

[0011] These and other aspects, features, and advantages can be appreciated from the following description of certain embodiments and the accompanying drawing figures and claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG, 1 A shows a graph of an exemplary alpha wave.

[0013] FIG. IB is a schematic illustration of a subject receiving BB stimulation via a device which provides audio output.

[0014] FIG. 2 is a schematic diagram that illustrates three such implementations of the method of stimulation according to the present disclosure.

[0015] FIG. 3 is a schematic diagram illustrating the synergetic effect of combining 10 Hz binaural beat (BB) and 40 Hz rhythmic light (RL) simulation.

[0016] FIG. 4A is a graph of a 10 Hz alpha wave; FIG. 4B is a graph of a 40 Hz gamma wave; FIG. 4C is a graph of a 40 Hz gamma wave amplitude modulated by a 10 Hz alpha wave phase; FIG. 4D is a graph of samples of signal generated showing the impeded amplitude of 40 Hz gamma wave by the phase of 10 Hz alpha wave; FIG. 4E is a graph of power spectrum versus frequency for the samples shown in FIG. 4D; and FIG. 4F is a graph of spectrogram which demonstrates the frequency content of the signal over time, illustrating the distribution of signal energy across frequencies.

[0017] FIG. 5 is an illustration showing the benefits of combined 10 Hz (alpha) and 40 Hz (gamma) stimulation as analogs of traffic signals, highlighting the differences between the two types of brain waves.

[0018] FIG. 6A is a graph of power density received on electrodes for subjects in the healthy control group exposed to 40 Hz RL flicker (dark line) and placebo (light line) conditions; FIG. 6B is a topographic map (topo-plots) which provides visual representation of the spatial distribution of electroencephalogram (EEG), activity across the scalp for the healthy group exposed to the 40 Hz RL flicker; FIG. 6C is a graph of power density received on electrodes for subjects in a MCI group exposed to 40 Hz RL flicker (dark line) and placebo (light line) conditions; and FIG. 6D is a topographic map (topo-plots) provides visual representation of the spatial distribution of EEG activity across the scalp for the MCI group exposed to the 40 Hz RL flicker.

[0019] FIG. 7A shows alpha-gamma coupling for healthy group exposed to 40 Hz RL (light grey) and placebo conditions (dark grey) in different regions of the brain. FIG. 7B shows thetagamma coupling for healthy group exposed to 40 Hz RL (light grey) and placebo conditions (dark grey) in different regions of the brain; FIG. 7C shows alpha-gamma coupling for MCI group exposed to 40 Hz RL (light grey) and placebo conditions (dark grey) in different regions of the brain; and FIG. 7D shows theta-gamma coupling for MCI group exposed to 40 Hz RL (light grey) and placebo conditions (dark grey) in different regions of the brain.

[0020] FIGS. 8A-8G include data graphs and power spectrum vs frequency graphs which show responses to random light flickering at placebo, 20 Hz, 30 Hz and 50 Hz on mildly cognitively impaired subjects (FIGS. 8A-8D) and healthy control subjects (FIGS. 8E-8G).

[0021] FIG. 9 is a schematic diagram illustrating the parts and length of one exemplary study for testing the effects of 10 Hz and 40 Hz (and derivatives) on subjects with Alzheimer’s disease, MCI and healthy controls.DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE

[0022] The present disclosure describes a method of combining 10 Hz (alpha) stimulation with 40 Hz (gamma) stimulation on cognitive functions in individuals with Mild Cognitive Impairment (MCI) and / or Alzheimer’s disease (AD). The 10 Hz and 40 Hz stimulation can be presented using a variety of modalities. In certain implementations, the 10 Hz stimulation comprises alpha binaural (BB) sounds, and the 40 Hz stimulation comprises rhythmic light (RL) in the visible spectrum that flickers at 40 Hz. As noted above, a binaural beat (BB is a ■‘phantom” sound illusion that occurs when tones of two slightly different frequencies are presented separately to each ear and the brain perceives the difference between the frequencies as a “middle” frequency). BB stimulation has been found to increase response accuracy and modify the strength of the brain networks during task performance. When BB is perceived, there are two standing tones in each hemisphere, which work together to synthesize the tones into a single tone. This single tone “beat,” having overall frequency equal to the difference between the two constituent tones, entrains both hemispheres to the same frequency and maximizes interhemispheric neural communication. FIG. 1A shows a graph of an exemplary alpha wave. FIG. IB is a schematic illustration of a subject 110 receiving BB stimulation via device 120 which provides audio output. As shown, the subject actually receives two different tones, a first tone 130 of 420 Hz via one side of the device, and second tone of 430 Hz 140 at a second side of the device. The difference between the first tone 130 and the second tone 140, of 10 Hz, matches the range of alpha wave frequency. It will be appreciated that the aboveexample of using 420 Hz and 430 Hz is merely exemplary and any number of other tone (frequency) combinations can be used so long as the difference is 10 Hz. In other words, the first tone is of a first frequency (X Hz) and the second tone is of a second frequency (Y Hz) and X Hz - Y Hz - 10 Hz.

[0023] In other implementations, both the 10 Hz and 40 Hz stimulation are delivered using binaural sound stimulation. In still other implementations, both the 10 Hz and 40 Hz stimulation are delivered using flickering RL in the two different frequency ranges. The stimulation in the two frequency ranges can be provided simultaneously or sequentially. For example, subjects can be presented with a 10 Hz stimulation before bed and 40 Hz stimulation upon waking. It has been observed that combined stimulation within these two frequency ranges, which synchronizes with neural alpha and gamma brain waves, unexpectedly enhances the effects of each range employed alone, in influencing cognitive functions and neural activity.

[0024] FIG. 2 is a schematic diagram that illustrates three such implementations of the method of stimulation according to the present disclosure. In a first implementation 210, subjects are provided wdth separate presentations 215. The first presentation 220 is of BB sounds in the 10 Hz range associated with alpha waves, while the second presentation 225 is of RL in the visible spectrum that flickers at 40 Hz, associated with gamma waves. In a second implementation 230, there is only a single presentation 235 in that it only employs a single sensory mode. In the depicted example, the single sensory mode is RL, but the presentation 240 flickers at tW'O distinct frequencies of 10 Hz and 40 Hz, or equivalently, a 40 Hz amplitude can be nested w'ithin a 10 Hz phase. In the third implementation 250, the single presentation 255 only employs a sound sensory mode. In the depicted example, binaural stimulation 260 is provided at both 10 Hz and 40 Hz which can be achieved by nesting a 40 Hz amplitude in a 10 Hz phase, AH of the different combinations in w'hich 10 Hz and 40 Hz stimulation are applied are found to provide synergistic combined effect.

[0025] While the synergistic effects of the combined stimuli have been shown in early studies to determine the effects of the stimulation with greater precision and accuracy, an additional phase 1 longitudinal at-home study of individuals having MCI and / or AD is performed. Participants in the study are randomly assigned to one of four experimental groups: Group A: constituting of participants subjected to 10 Hz binaural beat (BB) audio track for 30 minutes each night before going to sleep (e.g., via headphones or other device having sound output); Group B: consisting of participants subjected to combined 10 Hz BB before bed and 40 Hz RL after waking up; Group C: consisting of participants subjected to both 10 Hz binaural beats and 40 Hz rhythmic light stimulation simultaneously via a single wearable device,separate devices, one which has sound output the other light output (Group C participants are subject to the combined stimulation either before bed or after waking up based on their preference); and Group D: consisting of participants subjected to a control condition that is a combined approach but without 10 Hz BB and with light flickering at random.

[0026] The study assesses with particularity the impact of 10 Hz alpha binaural beat (BB) stimulation on working memory (WM) performance and neural activity in individuals with MCI and / or mild AD. It is hypothesized that 10 Hz alpha BB stimulation before bed enhances WM performance, evidenced by improved accuracy and faster reaction times, and results in measurable changes in neural activity, particularly in brain regions associated with WM, such as the prefrontal cortex. Participants in Group A listen to a 10 Hz alpha BB audio track for 30 minutes each night before sleep. WM performance and neural activity using baseline, midstudy, and post-study evaluations are assessed, including EEG and WM tasks.

[0027] Another aim of the study is to evaluate with particularity the combined effect of 10 Hz alpha BB before bed and 40 Hz gamma flicker rhythmic light (RL) stimulation after w'aking up on cognitive functions in individuals with MCI and / or mild AD. It is hypothesized that the combined use of 10 Hz alpha BB before bed and 40 Hz gamma RL after waking up produce greater improvements in WM performance and neural activity than either stimulation alone. Participants in Group B receive 10 Hz alpha BB before bed and 40 Hz gamma RL after waking up. Cognitive performance and neural activity of Group B are compared to the other groups, assessing changes through EEG and WM tasks.

[0028] The effects of simultaneous 10 Hz alpha BB and 40 Hz gamma RL stimulation on cognitive functions and neural activity in individuals with MCI and / or mild AD are also investigated. It is hypothesized that simultaneous 10 Hz alpha BB and 40 Hz gamma RL stimulation, whether used before bed or after waking up, yield significant improvements in cognitive functions and neural activity, potentially offering a more efficient intervention. Participants in Group C use a device, (e.g., a wearable device, headset, or other tabletop apparatus) that delivers 10 Hz alpha BB and 40 Hz gamma RL simultaneously. The effectiveness of this combined approach in enhancing WM performance and neural activity are evaluated using baseline, mid-study, and post-study assessments.

[0029] The efficacy of each stimulation approach and the control condition in enhancing cognitive functions and neural activity in individuals with MCI and / or mild AD are compared. It is hypothesized that all active intervention groups (Groups A, B, and C) show greater improvements in cognitive functions and neural activity compared to the sham control group (Group D), with the combined approaches (Groups B and C) showing the most significantbenefits. Participants in Group D receive a sham control condition, with random light flickering and without BB.

[0030] The combination of two sensory modalities providing synergistic effect has a superior chance to improve measures of cognitive and motor functions in MCI patients. The unique nature of the gamma frequency band in particular provides a promising avenue to measure subtle and complex relationships within neural activity that may readily influence brain function and structure, which is significant for understanding individual differences in cognitive processes, responses to stimuli, in health and disease. Combining alpha and gamma stimulation provides a powerful and versatile toolkit for understanding the complexities of the human brain, enabling discoveries that might not be achievable through conventional methods. Audio and Visual Implementation

[0031] As noted, the integration of a 10 Hz and 40 Hz stimulation can induce complex neural entrainment effects in the human brain. Some implementations of this approach leverage auditory and visual stimuli to modulate brainwave activity, potentially enhancing cognitive functions and therapeutic outcomes. FIG. 3 is a schematic illustration showing the synergistic effect of combining 10 Hz binaural beat (BB) and 40 Hz rhythmic light (RL) stimulation. The BB is processed in the brainstem’s superior Olivary complex (SOC) 305, where the frequency difference is detected and transmitted to the auditory cortex 310. More specifically, the SOC cortex 305 detects the frequency difference between the two auditory inputs received from each ear and transmits this difference to the auditory cortex 310. Since the difference is transmitted to the auditory cortex 310, the brain perceives a single beat frequency, known as the binaural beat, even though no physical beat is present in the auditory input.

[0032] When exposed to a 10 Hz binaural beat, the brain entrains this frequency, meaning that the brain synchronizes its neural oscillations to match the frequency of the external stimulus. This entrainment can enhance alpha wave activity 320 of a similar frequency range, which is associated with relaxation, creativity, and improved cognitive processes such as memory 325. Studies have also demonstrated that 40 Hz gamma rhythmic light (visible radiation) can induce gamma oscillations 350 in the visual cortex, which then propagate to other brain regions involved in cognitive functions 355. These gamma oscillations are also entrained, and the brain synchronizes neural oscillations 360 to match the frequency believed to enhance synaptic plasticity, improve neural communication, and potentially reduce amyloidbeta levels, which are implicated in Alzheimer’s disease pathology. When combining 10 Hz BB with 40 Hz RL 370. the brain benefits synergistically 375 from both alpha wave entrainment and enhanced gamma oscillations. Alpha waves can improve relaxation andcognitive processes, while gamma oscillations support higher-order cognitive functions and neural synchronization. This dual approach targets multiple neural mechanisms, potentially offering a more comprehensive intervention for individuals with MCI and AD. The synergistic effects of alpha and gamma oscillations 375 can be employed by modulating the amplitude of a 40 Hz gamma with the phase of a 10 Hz alpha wave, effectively embedding the amplitude of the gamma wave within the alpha wave. For instance, a 10 Hz sine wave can modulate the amplitude of a 40 Hz flicker, creating an envelope that oscillates at the 10 Hz frequency. This integration can be achieved manually using techniques such as Pulse Width Modulation I'PWM ) to ensure precise control of the stimulus, such as light or sound.

[0033] As noted, the 10 Hz BB and 40 Hz RL can be presented either simultaneously (concurrently) or sequentially. In one promising sequential application, 10 Hz BB is presented before bedtime, 40 and Hz RL is presented after waking. Using 10 Hz BB before bedtime can promote relaxation and enhance sleep quality, which is critical for cognitive function and memory consolidation. A good night's sleep facilitated by binaural beats could create an optimal cognitive state for the next day. Upon waking, 40 Hz RL can further stimulate gamma oscillations, enhancing cognitive function and providing a synergistic effect. This sequential application can leverage the benefits of both sleep enhancement and gamma entrainment. In effect, the application of the 10 Hz stimulation provides an augmentation of the application of the 40 Hz stimulation leading advantageously to the synergistic effects described herein.

[0034] Alternatively, using 10 Hz BB and 40 Hz RL separately (i.e., in a relatively less exact sequence) can still provide significant cognitive benefits. Binaural beats before bedtime can improve sleep and relaxation, while 40 Hz flicker light during waking hours can stimulate brain activity related to cognition. Separate application allows for flexibility in integrating these interventions into daily routines without the need for simultaneous use. The optimal duration for the BB stimulation varies depending on the intended effect. For improving sleep and relaxation, sessions lasting between 30-60 minutes before bedtime are commonly recommended. Some studies suggest that listening to BB for 20-30 minutes can be effective in promoting relaxation. Similarly, exposure to 40 Hz RL flicker light for cognitive enhancement typically involves shorter durations compared to BB. Sessions lasting 20-30 minutes during waking hours are often used in research. The specific duration can depend on the individual and the desired cognitive effect.

[0035] The BB / RL approach, which provides multimodal sensory stimulation, can be ad vantageous for a range of health conditions beyond MCI and AD, extending to ADHD, pain management, and stress-related disorders such as anxiety and depression. In these conditions,gamma activity is often deficient, and alpha activity can aid in relaxation. By leveraging these natural brain rhythms, the approach offers a non-invasive avenue for cognitive enhancement and therapeutic intervention. Furthermore, different approaches to presenting auditory and visual stimuli can potentially lead to similar cognitive enhancements by targeting specific neural oscillations associated with cognitive functions. The use of 10 Hz binaural beats and 40 Hz flicker light, either separately or in combination, represents a versatile toolkit for modulating brain activity in ways that could benefit cognitive performance, particularly in individuals with mild cognitive impairment (MCI) and Alzheimer’s disease (AD).Audio and Visual-Only Implementations

[0036] Another approach to enhancing cognitive functions using auditory stimuli involves the use of a 10 Hz BB with a 40 Hz gamma flicker. In this implementation, the amplitude of the 40 Hz gamma oscillations is nested within the phase of the 10 Hz alpha waves. This dualfrequency stimulation targets different aspects of neural activity, aiming to provide a synergistic effect on cognitive enhancement. This can be done using software such as MATLAB, as will be appreciated by those of skill in the art. The same approach can be employed to present 40Hz RL in combination with 10 Hz. in either audio or visual signal-only form. In one implementation, 40 Hz RL can be presented alongside the 10 Hz. The amplitude of the 40 Hz gamma oscillations is nested within the phase of the 10 Hz alpha waves, producing a modulated signal in which the 40 Hz gamma wave's amplitude varies according to the phase of the 10 Hz alpha wave. This combined approach aims to leverage the cognitive benefits of both frequency bands by enhancing neural synchronization and connectivity across different brain regions.

[0037] The visual system processes this modulated flicker, entraining both alpha and gamma oscillations in the brain simultaneously. The modulation of 40 Hz gamma activity by a 10 Hz alpha wave can enhance cross-frequency coupling (CFC), which is essential for cognitive processes such as attention and memory encoding. FIGS. 4A-4F are graphs that collectively illustrate the synergistic effect of alpha and gamma cross-frequency coupling. FIG. 4A is a graph of a 10 Hz alpha wave; FIG. 4B is a graph of a 40 Hz gamma wave; FIG. 4C is a graph of a 40 Hz gamma wave amplitude modulated by a 10 Hz alpha wave phase; FIG. 4D is a graph of samples of signal generated showing the impeded amplitude of 40 Hz gamma waves by the phase of 10 Hz alpha waves; FIG. 4E is a graph of power spectrum versus frequency for the samples shown in FIG. 4D; and FIG. 4F is a graph of spectrogram which demonstrates the frequency content of the signal over time, illustrating the distribution of signal energy across frequencies.

[0036] Evidence suggests that external modulation of brain rhythms can have a significant impact on cognitive processes, and further suggests that manually modulating alpha and gamma oscillations through external stimuli, such as light or sound flicker at specific frequencies can enhance cognitive function and potentially mitigating the effects of neurodegenerative diseases. The current approach leverages the natural mechanisms of crossfrequency coupling to improve neural synchronization and communication, offering a novel avenue for therapeutic intervention.

[0038] The balance between excitation and inhibition is essential for cortical information processing. The opposing actions of pyramidal cells and interneurons produce membrane and network oscillations, which synchronize neural signals. Neocortical interneurons, due to their strategic positioning, play a pivotal role in controlling circuit dynamics and contributing to the cortex's morphological diversity. This control is crucial for regulating the scope and timing of neural network activities, including the modulation of alpha oscillations. Alpha oscillations, typically observed in the frequency range of 8-12 Hz, are linked to various cognitive functions and are influenced by the inhibitory actions of interneurons. Moreover, the interaction between alpha and gamma oscillations is critical for cognitive processes such as attention and memory. Thus, alpha-gamma coupling is essential for the coordination of neural activities across different brain regions. Disruptions in this cross-frequency coupling have been implicated in neurodegenerative conditions, highlighting the importance of maintaining proper inhibitory control for preserving cognitive function. This coupling is believed to facilitate attention, working memory, and information encoding. Furthermore, enhanced alpha-gamma coupling can improve functional connectivity between brain regions, leading to better cognitive performance and reduced symptoms of cognitive impairment.

[0039] FIG. 5 is an illustration showing the benefits of combined 10 Hz (alpha) and 40 Hz (gamma) stimulation as analogs of traffic signals, highlighting the differences between the two types of brain waves. As indicated in FIG. 5. alpha waves 510 are generally associated with calming traffic noise, smoother movement of neural signals, reduced congestion (mental noise), optimization of the “traffic’' management system and an upgrading of communication channels. Gamma waves 520 are generally associated with rapid signals at intersections, enhancing the responsiveness and coordination (neural networks). Gamma signaling ensures that critical information is processed quickly and efficiently, akin to emergency vehicles moving swiftly through intersections.

[0040] By capitalizing on the benefits of alpha wave entrainment and gamma oscillatory activity, this method offers a promising avenue for early detection and intervention, aiming atslowing the progression of disease and easing of symptoms. This approach can improve cognitive outcomes and quality of life for affected individuals, ultimately contributing to more effective management of MCI and AD.Test Data

[0041] Tests were performed to assess regional specific response in source level 40 Hz power spectral density, and alterations in theta, alpha, and gamma responses in older adults with AD / ADRD. In a randomized, cross over-subjects controlled clinical trial, subjective measures of sleepiness, along w'ith working memory, electroencephalography (EEG) sensor and source level analyses were utilized to explore the potential beneficial effects of 40 Hz rhythmic light (RL) on sleepiness, cognition, and neural activity in 20 individuals with mild cognitive impairment (MCI, indicated by Montreal Cognitive Assessment scores between 17 and 25) compared to 16 age-matched healthy controls. All participants were exposed to both a 40 Hz RL intervention and a placebo RL condition.

[0042] FIG. 6A is a graph of power density received on electrodes for subjects in the healthy control group exposed to 40 Hz RL flicker 605 and placebo conditions 610. FIG. 6B is a topographic map (topo-plots) provides visual representation of the spatial distribution of EEG activity across the scalp for the healthy group exposed to the 40 Hz RL flicker; FIG. 6C is a graph of power density received on electrodes for subjects in an MCI group exposed to 40 Hz RL flicker 615 and placebo conditions 620 during the tests. FIG. 6D is a topographic map (topo-plots) provides visual representation of the spatial distribution of EEG activity across the scalp for the MCI group exposed to the 40 Hz RL flicker.

[0043] The tests showed a statistically significant difference (p=0.02) in power spectral density between the two lighting conditions (40 Hz RL, placebo RL) in the control group. In the 40 Hz RL condition, occipital electrode O1 (M=4.05, SD-2.92) yielded a greater increase in 40 Hz gamma power compared to placebo RL condition (M=2.93, SD=1 .89) (FIG. 6B). For the MCI group, a statistically significant increase in 40 Hz gamma power was measured for midline occipital electrode OZ, midline parietal electrode PZ, and POZ (p=0.03, / ?=0.04, and p=0.027 respectively) (FIG. 6D).

[0044] FIG. 7A-7D are histograms that illustrate phase-amplitude cross frequency coupling. FIG. 7A show's alpha-gamma coupling for healthy group exposed to 40 Hz RL (light grey) and placebo conditions (dark grey) in different regions of the brain. FIG. 7B shows theta-gamma coupling for healthy group exposed to 40 Hz RL (light grey ) and placebo conditions (dark grey) in different regions of the brain. FIG. 7C shows alpha-gamma coupling for MCI group exposed to 40 Hz RL (light grey) and placebo conditions (dark grey) in different regions of the brain.FIG. 7D shows theta-gamma coupling for MCI group exposed to 40 Hz RL (light grey) and placebo conditions (dark grey) in different regions of the brain.

[0045] Results for control participants showed a significant increase in coupling under the 40 Hz RL was evident for the right posterior cingulate cortex in both alpha-gamma (F-4.25, p=0.002). (FIG. 7A) and theta-gamma (F=4.11, p=0.003) (FIG. 7B). On the other hand, an opposite pattern developed for the MCI participants. Phase-amplitude coupling of the alphagamma in participants with MCI showed a significant decrease in coupling for the right posterior cingulate cortex (F=3.13,p=0.01 ) (FIG. 7C). Likewise, results of the phase-amplitude coupling of the theta-gamma in participants with MCI, show a significant effect for the right posterior cingulate cortex (F=3.35, p=0.005), with a significant decrease in coupling for participants with MCI under the 40 Hz RL (FIG. 7D).

[0046] Tests were also performed using random light flickering at 20, 30 and 50 Hz that produced 40 Hz gamma waves. During preliminary data analysis, it was observed that a recurrent 40 Hz peak occurred in electrodes readings when a placebo light flickering at random frequencies of 20, 30, and 50 Hz was used. This 40 Hz peak was evident in both the MCI and healthy control groups, suggesting a biological origin of this phenomenon. This peak is shown in FIGS. 8A-8G which shows results tests on MCI and control subjects on distinct selected frontal, parietal and occipital channels [Fz, 01, 02, Oz, and Pz] This can be explained by the concept of frequency harmonics and intermodulation. When multiple frequencies are combined in a nonlinear system such as the brain, the frequencies interact in complex ways to produce new frequencies through a process known as intermodulation. The newly-generated frequencies can be the sums or differences of the original frequencies. For example, if 20 Hz and 30 Hz stimuli are present, their mathematical interactions can yield, difference frequency: 30 Hz - 20 Hz = 10 Hz, or sum frequency: 30 Hz + 20 Hz = 50 Hz. For the test performed, it is hypothesized that when frequencies of 20 Hz, 30 Hz, and 50 Hz interacted, that they generated further harmonics and intermodulation products. These interactions included:- Interaction of 20 Hz and 50 Hz: 50 Hz - 20 Hz = 30 Hz- Interaction of 30 Hz and 50 Hz: 50 Hz - 30 Hz = 20 Hz- Second harmonic of 20 Hz: 2 x 20 Hz = 40 Hz- Second harmonic of 30 Hz: 2 x 30 Hz = 60 Hz

[0047] Studies have shown that brain activity can produce harmonics and intermodulation frequencies when exposed to multiple stimuli. For instance, Herrmann demonstrated that the brain's response to mixed auditory stimuli involves intermodulation products, supporting the notion that complex frequency interactions can generate new oscillatory components(Herrmann CS. Human EEG responses to 1-100 Hz flicker: resonance phenomena in visual cortex and their potential correlation to cognitive phenomena. Exp Brain Res 2001; 137). Additionally. Picton et al., also discussed how auditory steady-state responses at different frequencies can lead to the emergence of harmonic and intermodulation components in the EEG, further illustrating this principle (Picton TW, John MS, Dimitrijevic A, et al. Human auditory steady-state responses. Int J Audi ol 2003; 42: 177-219). The gamma oscillations in the brain are typically within the 30-100 Hz range, with 40 Hz being a significant and commonly studied gamma frequency associated with cognitive functions. It is hypothesized that when the brain is exposed to stimuli at 20, 30, and 50 Hz, the nonlinear neural dynamics can result in the emergence of 40 Hz oscillations due to frequency interactions and second harmonics principles as shown in FIGS. 8A-8G and described above.

[0048] In summary, the random flickering of light at 20, 30, and 50 Hz can produce a peak at 40 Hz gamma frequency through the mechanisms of frequency harmonics, intermodulation, and neural entrainment. This phenomenon leverages the brain's natural ability to synchronize with rhythmic stimuli, making it a potential method for inducing gamma oscillations and investigating their cognitive and therapeutic benefits. These findings align the observation of a 40 Hz peak arising from the interaction of 20 Hz, 30 Hz, and 50 Hz stimuli. This finding reinforces the biological basis of frequency harmonics and highlights the potential of producing a 40 Hz peak indirectly by introducing different oscillations. This method leverages intrinsic brain interactions, emphasizing the efficacy of targeted oscillatory stimulation in modulating brain activity. This indirect approach opens new avenues for neuromodulation and cognitive enhancement strategies by utilizing harmonic interactions to achieve desired neural effects.Expanded Study

[0049] FIG. 9 is a schematic diagram illustrating the parts and length of the study fortesting the effects of 10 Hz and 40 Hz (and derivatives) on subjects with Alzheimer’s disease, MCI and healthy controls. As indicated in FIG. 2B, the study investigates the impact of a combined intervention approach (10 Hz BB + 40 Hz RL) on alpha-gamma spectral power density performance, working memory tasks, and sleep in AD and MCI patients. The study has a double blinded, randomized, between-subjects’ design, in which 80 patients are with MCI and mild AD. The patients are exposed to one of four intervention arms: 1) BB + RL (combined condition), 2) RL+ sham BB (RL only condition), 3) arrhythmic light + alpha BB (BB condition only), and 4) arrhythmic light + sham BB (control condition). Participants take part in a 12- week long intervention, once per day for 30 minutes (12 weeks x 6 days per week x 30 minper day), followed by a 6-week washout period. Assessment measures are eollected at baseline, midpoint (week 6), end of intervention (week 12), and post intervention (week 18-19).

[0050] The study investigates several particular features and parameters including how the interventions impact alpha-gamma power spectral density (PSD). Resting state EEG measures of changes in alpha and gamma PSD activity are computed. It is hypothesized that the combined intervention is associated with greater changes in PSD activity within the alpha (decrease in high alpha and increase in low alpha oscillations) and gamma (increase in 40 Hz oscillations) frequencies. The study also investigates how the interventions impact working memory tasks. Working memory that involves visuospatial information is assessed using the Trail Making Test (TMT) A and B, Brook’s Spatial Memory Test, and the Benson Complex Figure Test (BCFT). It is hypothesized that the combined intervention results in improvement in test scores in all working memory tests and that aspects of the EEG data, such as functional connectivity and changes in gamma power correlate positively with changes in working memory task scores. The study further investigates interventions impact sleep quality. Sleep quality is assessed through changes in actigraphy and PSQI. It is hypothesized that the combined intervention results in lower PSQI scores and greater sleep regularity index and sleep duration, and that aspects of the EEG data, such changes in alpha power are positively correlated with changes in PSQI scores and quality of sleep.

[0051] Participants are randomly assigned to one of the four stimulation conditions. The research coordinator (RC) who conducts the study assessments is blinded to study group membership. Patients and caregivers are also blinded to study group membership. 80 participants are recruited for the study. Eligible participants are MCI (mild cognitive impairment) or mild AD patients and reside in their own homes, in independent living facilities, or in assisted living facilities. The providers perform the diagnosis according to the following pre-selection criteria: Participants are 50 years or older and are diagnosed with amnestic MCI or mild AD, as defined by their physician, and have a Montreal Cognitive Assessment (MoCA) score between 17 and 25. Inclusion criteria: those taking sleep medication are included unless they agree to stop the medication for 4 weeks prior to starting the study. Those taking antidepressants are included, but the type of medicine and dosage intake are monitored. There is no exclusion based on gender, race, and ethnicity. Other exclusion criteria for the study include: presence of another brain disease that fully explains the dementia (extensive brain vascular disease, Parkinson’s disease, dementia with Lew'y bodies, traumatic brain injury, or multiple sclerosis); indication of psychiatric hospitalization or acute suicidality in the opinion of the physician; recent major organ failure (e.g., kidney failure); uncontrolled generalizeddisorders such as hypertension, epilepsy, or diabetes; uncontrolled obstructive sleep apnea; a diagnosis of hearing loss, cochlear implant, or hearing aids. The exclusion criteria also include obstructing cataracts, macular degeneration, and blindness. Participants’ ophthalmologic tests are reviewed during selection. Those who have undergone cataract surgery and received an intraocular lens coated with ultraviolet- and blue-blocking filters (400-440 / 440-500 nm) are also excluded. Exclusion criteria also include a history of severe epilepsy, photosensitivity dermatitis, severe progressive retinal disease (e.g., macular degeneration), or a permanently dilated pupil (e.g., after certain types of cataract surgery). While there is no supportive evidence that these conditions are associated with adverse responses to light therapy, they are theoretical risks and study participants are screened by interview' with the physicians’ collaborators, who can exclude potential participants for any reason.

[0052] Participants are recruited from the Mount Sinai Health System (MSHS) in conjunction with physicians who have access to the clinical population. Community centers and assisted living facilities around New York, New Jersey, and Connecticut area are also targeted. The Institute for Health Equity Research (IHER) provides the ability to expand recruitment to minority communities. Recruitment methods include: (1) provider referral, (2) on-site (in assisted living or senior centers) by research staff, (3) flyers placed in participating sites or through advertising in the community, and (4) social media. Equal numbers of participants in winter and summer are collected to account for a possible effect of season and equal number of women and men. Participant can also be recruited from a satellite lab in Menands, NY.

[0053] Clinical assessments are conducted at baseline, mid-intervention (w'eek 6), end of intervention (week 12) and 6 weeks after completion of the intervention (week 18). All assessments are administrated by a trained research coordinator who is blinded to intervention allocation and not involved in data analysis. A 5 min of resting state EEG with eyes closed is recorded with each participant seated upright in a comfortable chair. The EEG signal is sampled using a 32-electrode array (ACTi Champ 32). Impedance is checked to remain below 5kQ (sampling rate = 2500 Hz, band-passed 0.15-200Hz). Resting state EEG data is processed offline using a custom MATLAB script, and EEGLAB toolbox. The EEG Lab is used off-line to resample data and band-pass filter the data in the range of 0.1 - 55 Hz. Resampled, filtered data is plotted and inspected visually for manual artifact-rejection by an experienced examiner. Average Fourier cross-spectral matrices are computed for brain oscillation bands (delta 2-3.5 Hz, theta 4-7.5 Hz, alpha 8-12 Hz, beta 13-30 Hz, and gamma 30.5-44 Hz). An independent component analysis (ICA) is performed to remove ocular, muscle artifacts, and other noisefrom the rs-EEG data. Further visual artifact detection is administered to remove any remaining artifact(s).

[0054] The initial power spectrum (PSD) (signal distribution along the range of frequencies) of the brain activity is computed using the Spectopo function as implemented in EEGLAB, using Welch’s method (with a window length of 512 points, (f) length of 1024 points, nonoverlap). The power is calculated for each channel and each frequency band: Delta (2-3.5) Hz, Theta (4-7.5) Hz, Alpha (8-12) Hz, Beta (13-30) Hz and Gamma (30.5-44) Hz. Differences in power spectrum over all electrodes are statistically assessed using a permutation test that identifies clusters of electrodes with significant changes, while correcting for multiple comparisons. Standardized low-resolution brain electromagnetic tomography (sLORETA) images are obtained using nonparametric statistical analyses (SnPM) at subject and group level. These tests show changing in brain network activity.

[0055] Further tests are performed to determine changes in brain network functional connectivity (FC). Source localization is used to estimate the intracerebral electrical sources. The log-transformed electric current density is computed for regions of interests (ROIs), and lagged phase synchronization / coherence or functional connectivity contrast maps are calculated between all the ROIs. FC is computed for the following ROIs: medial prefrontal cortex, dorsal prefrontal cortex, and posterior cingulate cortex.

[0056] Changes in theta-gamm a and alpha-gamma coupling are also determined. The changes are calculated by computing the time series for the x, y, and z components of the source localized current, which is filtered in the alpha (8-12Hz), theta (4-7.5 Hz) and gamma (30-44 Hz) frequency ranges. ICA analysis is computed, and the first component is retained for theta and gamma. The Hilbert transform is applied on the gamma component and the signal envelope retained. Finally, a Pearson correlation between the theta component and the gamma, as well as alpha and gamma envelope, are computed. Differences in power spectrum over all electrodes are statistically assessed using a permutation test that identifies clusters of electrodes with significant changes, while correcting for multiple comparisons.

[0057] The investigations for Working Memory (WM) include pencil and paper tests, which are administrated by a trained RC who is blinded to intervention allocation and not involved in data analysis. One of the tests is based on the Trail Making Test (TMT) and assesses changes from baseline. The TMT is one of the most commonly used pencil and paper neuropsychology practice instruments used. It consists of two parts: A and B. Part A involves the participant using a pencil to draw lines connecting numbered circles in sequence from 1 to 25; while part B involves the participant in connecting numbered and lettered circles in alternatingalphanumeric sequence. Both parts A and B, measure psychomotor speed, visual search and attention. The administration time: typically ranges from 5 to 10 min and the primary variables of interest are the total time to completion for both parts A and B, which can be calculated as a B-A difference or a B / A ratio. These parameters provide the index of the level of interference by addition of the flexibility component of part B.

[0058] Further tests of WM include Brooks spatial memory test. The Brooks spatial memory test requires a participant to visualize a 3x3 empty grid matrix in which one cell is designated as the starting square. The trained experimenter gives a series of verbal instructions including digits which participant has to maintain in their working memory and use to fill the empty grid. Following the instructions, participants recall the sequence by filling in the grid with the numbers. The administration time of this test range from 5 to 10 min. The primary variables of interest are percent of correct answers, and reaction time. The percent correct is calculated as the number of digits placed correctly divided by the total number of presented digits. Reaction time is computed as the average time that elapsed between the respond prompt and response. Change of these variables from a baseline are determine. Similarly, changes in the Benson Complex Figure test are also determined. The Benson complex figure test consists of 3 conditions: a copy phase, in which a figure is copied from an example, a recall phase in which the figure is drawn from memory after a 10-15 minute interval, and a recognition in which the target figure is recognized amongst tree distractor figures. The administration time of the Benson Complex Figure tests ranges from 15 to 30 min. The primary variables of interest are accuracy and placement, and proportion. All connections between elements are assessed (e.g., cleanliness, presence of extraneous lines, etc.) Recognition is either scored as correct (score 1) or incorrect (score 0).

[0059] The study also includes investigations of sleep quality. Participants wear an acti graph for 7 days during the assessment weeks (baseline, week 6, week 12, and week 18). Actigraphic monitoring employs an accelerometer (e.g.. ActiGraph GT9x), which is worn on the nondominant wrist of each study participant. Actigraphy has been demonstrated in prior studies to be well tolerated by older adults with cognitive impairment, and it is strongly correlated with polysomnography (PSG) and sleep logs. Prior to the participant wearing the wrist actigraphy, the PI and / or research team member sets the instruments to collect data, so participants begin logging data the day they receive the devices. Participants are instructed to wear the actigraphy accelerator for 7 consecutive days. On the eighth day following that specific assessment week, the -participants are asked to meet a research team member in person and instructed to bring the accelerator with them. During that visit the rest of the assessment are obtained. Follow-upreminders are made via phone (2 emails / text messages / calls per day) to the participant or caregiver.

[0060] A sleep regularity index (SRI) as the primary metric is calculated based on the actigraphy data. The SRI calculates the average percent probability that an individual is in the same sleep / wake state at any 2 time points 24 h apart. An index of 100 indicates someone who is asleep and awake at precisely the same times each day, while an index of 0 indicates a person who sleeps and wakes randomly. SRI has been used to identify ‘regular’ and ‘irregular’ sleepers and importantly, based on this metric, irregular sleepers show a delay in the timing of melatonin secretion, and lower peak light level exposures during the day, thus indicating circadian rhythm disruption. The range and quantiles for SRI are reviewed to ensure the cohort contains a good breadth sleep regularity. For context, one study defined ‘regular’ sleepers as having an index ranging 81 -87, while irregular ranged 35-64. Using the manufacturer software (ActiLife), sleep efficiency, total sleep time and sleep latency are calculated.

[0061] Returning to the types of stimulation used in the tests, for the auditory alpha (10 Hz) binaural beats frequency (BBF), two tones are played. One tone has a constant frequency of 240 Hz, while the other is at 230 Hz. Use of both channels (e.g., the left channel directed to the left ear and the right channel to the right ear) results in the subject hearing a simulated tone, and a perceived 10 Hz “difference” tone, which is the BBF. There are three components of the sound signal heard by subjects: ambient noise, and two pure sine wave tones. The ambient noise is selected by the subject from a list of music tones (no speech), with no consistent rhythmic component. Participants are at liberty to pick any of list of musical tones to play on a specific day (one tone per experimental day) and are instructed to listen to the full 30 min of their sound of choice on that day. Giving the participant the ability to choose from a list of sounds allows them to feel engaged in the process.

[0062] The audio content for this component is identical in each ear. The stereo signal of each sound file is constructed of two channels: left and right, each including the ambient sound and one of the tones. To ensure loudness comfort level, each audio fde fades in by volume over 30 sec to not startle the subjects, and similarly fades out over 30 sec at the end. With an additional 2 min of transition time and 30 total min of stimulation, each audio file is 33 min long. In addition, to ensure a comfortable listening (volume) level, participants have the ability to adjust the volume to a comfortable listening level. Changing the volume or loudness to the most comfortable level of the BBFs will not impact the pitch (frequency measured in Hz) of the BB. Volume or loudness is a description of amplitude (measured in decibels [dB]) of the waveformpresented (heard). When the volume is changed, amplitude changes, while frequency remains the same.

[0063] There are two possible versions of the pure tone audio files: 1) in which both channel tones are 240 Hz throughout (sham); and 2) in which the right channel is 240 Hz throughout while the left channel is 230 Hz (intervention). Combined with the six choices of ambient noise (as an example), there are twelve 33-min audio files. Subjects randomized to a group with sham audio stimulation receive the sound files with 240 Hz tones in both channels. Subjects randomized to an intervention audio stimulation receive one tone at 240 Hz and the other tone at 230 Hz in every audio file in opposite channels. The devices are given to participants during their baseline assessment. A list of folders containing the ambient sounds is uploaded on the device, which are based on their condition group. Files are pre-labeled based on condition day (i.e., day 1, day 2, day 3 etc.) and participants are instructed to click on the file by order of days.

[0064] In the study, 30 min of 40 Hz RL and 10 Hz alpha BBF impeded into 6 different sounds (as an example), are applied 6 times / week (Monday to Saturday), for 12 weeks (3 months). In the study red light (but can be other visible frequency) is presented visually via a device or apparatus. In one implementation, a light fixture containing arrays of red LEDs (peak wavelength = 630 nm) is employed. As noted below, other devices can be used to deliver the RL (“RL delivery device”). For implementations that use a light fixture, a position for the fixture is selected to be approximately 60 cm away from a location in which the patient is situated during the test. In the initial test, the rhythmic frequency of the light is set at 40 Hz and the stimulation signal is a square wave with a 50 % duty cycle (i.e., 12.5 ms light-on and 12.5 ms light-off) that delivers 60 lux at eye level. The use of red light w as chosen because red light at this light level does not affect the circadian system. If improvement in sleep is observed, it can be attributed to the RL or BBF. In the sham light condition, the duty cycle is delivered at a random interval (avoiding those resulting in 40 Hz second harmonics, such as 20, 30 and 50Hz) that does not peak at 40 Hz. Treatment-related characteristics such as treatment dose can be adjusted as it can potentially influence disease progression. Studies have suggested that longer treatment might be necessary to reduce beta-amyloid ( Aβ) in humans versus animal models.

[0065] While the treatments of providing 10 Hz and 40 Hz stimulation discussed above are particularly to subjects with mild cognitive impairment and / or Alzheimer’s disease, the treatment methods and system can also be usefully applied to treat a range of othercognitive / mental conditions, and neurodegenerative and / or mood disorders including, but not limited to, for example, pain. ADHD, anxiety. PTSD, and depression.System (Stimulus-Emitting Device(s)) Implementations

[0066] Apparatus and stimulus-emitting devices for delivering the 10 Hz and 40 Hz stimuli (e.g., BB and RL) can be implemented in numerous ways. In particular, one or more stimulusemitting devices can be used. The apparatus for delivery of BB and RL can be separate or can be integrated in a single device. For example, devices that deliver BB to a subject can include a headset (headphones), ear bulbs, other custom wearable devices such as those designed by AriBio Inc. of San Diego, California, and have audio output components (e.g., speakers, resonators). Examples of such devices are disclosed in Korean Pat. Reg. No. 10-2620620-0000 and Korean Pat. Reg. No. 10-2404071-0000, each of which is hereby expressly incorporated by reference. The RL delivery device can be implemented by a standalone apparatus such as the fixture with mounted LED array used in the study or can be a more ergonomic device that provides flickering light such as a virtual reality headset or other wearable, A virtual reality headset has the advantage that both BB and RL can be delivered via a single worn device, either simultaneously or sequentially. Controls mounted on the wearable device or as part of an external device in communication, such as wirelessly, with the wearable can allow for users to initiate the treatment, select from various operating modes, enter patient identification information, etc. For example, in the single worn device, there can be earcups or the like for delivering the BB and there can be a portion, such as a light visor or glasses for delivering the RL. Device 120 in Fig. IB generally illustrates a device that delivers BB (by earcups) and can deliver RL by means of LEDs that can be part of the device, such as incorporated in an eye shield that extends across the eyes or in a virtual headset or glasses type arrangement that once again covers the eyes.

[0067] It is to be understood that any structural and functional details disclosed herein are not to be interpreted as limiting the systems and methods, but rather are provided as a representative embodiment and / or arrangement for teaching one skilled in the art one or more ways to implement the methods.

[0068] The term “approximately” as used herein with respect to a nominal value means the nominal value plus a range encompassing plus or minus 5 percent from the value.

[0069] It is to be further understood that like numerals in the drawings represent like elements through the several figures, and that not all components and / or steps described and illustrated with reference to the figures are required for all embodiments or arrangements.

[0070] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. As used herein, the singular forms "a”, "an" and "the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms "comprises" and / or "comprising", when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0071] Terms of orientation are used herein merely for purposes of convention and referencing and are not to be construed as limiting. However, it is recognized these terms could be used with reference to a viewer. Accordingly, no limitations are implied or to be inferred.

[0072] Also, the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having,” "containing," "involving," and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0073] While the disclosure has been described with reference to exemplary embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the disclosed invention, hi addition, many modifications will be appreciated by those skilled in the art to adapt a particular instrument, situation or material to the teachings of the disclosure without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention includes all embodiments falling within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:

1. A method of treatment for improving cognitive or mental functions and neural activity in an individual comprising the step of: subjecting a body of the individual to a combination of 10 Hz stimulation and 40 Hz stimulation, wherein the 10 Hz simulation and 40 Hz stimulation induce respective alpha and gamma waves in the individual.

2. The method of claim 1, wherein the 10 Hz stimulation and 40 Hz stimulation are sequentially applied to the body.

3. The method of claim 2, wherein the 10 Hz stimulation is applied before the 40 Hz stimulation.

4. The method of claim 3, wherein the 40 Hz stimulation is applied within a predetermined time period after applying the 10 Hz stimulation.

5. The method of claim 4, wherein the predetermined time period comprises up to 6 hours.

6. The method of claim 4, wherein the predetermined time period comprises more than 6 hours.

7. The method of claim 1, wherein the 10 Hz stimulation and 40 Hz stimulation are concurrently applied to the body.

8. The method of claim 3, wherein the 10 Hz stimulation is applied prior to a sleep session and the 40 Hz stimulation is applied after waking up from the sleep session.

9. The method of claim 1, wherein the 10 Hz stimulation comprises sound and the 40 Hz stimulation comprises light.

10. The method of claim 9, wherein the light includes at least one of visible portion of the electromagnetic spectrum.1 1 . The method of claim 1 , wherein the 10 Hz stimulation comprises alpha binaural (BB) sounds and the 40 Hz stimulation comprises rhythmic light (RL) in a visible spectrum.

12. The method of claim 11, wherein the step of subjecting the individual to the alpha binaural sounds comprises the steps of: applying a first tone of a first frequency to a first ear of the individual; and applying a second tone of a second frequency that is 10 Hz apart from the first frequency to a second ear of the individual, wherein the first and second tones induce a difference tone of 10 Hz audible to the individual.

13. The method of claim 11 , wherein the rhythmic light flickers at 40 Hz.

14. The method of claim 1, wherein both the 10 Hz stimulation and the 40 Hz stimulation are delivered using binaural sound stimulation.

15. The method of claim 14, further comprising modulating the 40 Hz with a 10 Hz sine wave.

16. The method of claim 1, wherein both the 10 Hz stimulation and the 40 Hz stimulation are delivered using flickering RL in the 10 Hz and 40 Hz frequency ranges, respectively.

17. The method of claim 1. wherein both the 10 Hz stimulation and the 40 Hz stimulation comprise light stimulation.

18. The method of claim 17. w herein the 40 Hz rhythm comprises rhythmic light (RL) in a visible spectrum.

19. A method of treatment for improving cognitive or mental functions and neural activity in an individual comprising the steps of: inducing alpha waves of approximately 10 Hz in the individual by subjecting the individual to 10 Hz stimulation; andinducing gamma waves of approximately 40 Hz in the individual by subjecting the individual to random light flickering at a plurality of different light frequencies between 10 and 70 Hz.

20. The method of claim 19, wherein the different light frequencies comprise 20 Hz, 30 Hz and 50 Hz.

21. A method of augmenting a treatment for improving cognitive functions and neural activity in an individual with mild cognitive impairment and / or Alzheimer’s disease that includes application of 40 Hz stimulation to the individual, the method of augmenting comprising the step of: applying a 10 Hz stimulation to the individual prior to or concurrently with the application of the 40 Hz stimulation, wherein the 10 Hz simulation and 40 Hz stimulation induce respective alpha and gamma waves in the individual.

22. The method of claim 21, wherein the 10 Hz stimulation and 40 Hz stimulation are sequentially applied to the body.

23. The method of claim 21. wherein the 40 Hz stimulation is applied within a predetermined time period after applying the 10 Hz stimulation.24 The method of claim 23. wherein the predetermined time period comprises up to 6 hours.

25. The method of claim 23, wherein the predetermined time period comprises more than 6 hours.

26. The method of claim 21 , wherein the 10 Hz stimulation is applied prior to a sleep session and the 40 Hz stimulation is applied after waking up from the sleep session.

27. The method of claim 21, wherein the 10 Hz stimulation comprises sound and the 40 Hz stimulation comprises light.

28. The method of claim 21. wherein the 10 Hz stimulation comprises alpha binaural (BB) sounds and the 40 Hz stimulation comprises rhythmic light (RL) in a visible spectrum.

29. A system for improving cognitive or mental functions and neural activity in an individual comprising: one or more stimulus-emitting devices that are configured to apply to a body of the individual a combination of 10 Hz stimulation and 40 Hz stimulation, wherein the 10 Hz simulation and 40 Hz stimulation induce respective alpha and gamma waves in the individual.

30. The system of claim 29, wherein the one or more stimulus-emitting devices are configured to sequentially apply the 10 Hz stimulation and the 40 Hz stimulation.

31. The system of claim 29, wherein the one or more stimulus-emitting devices are configured to concurrently apply the 10 Hz stimulation and the 40 Hz stimulation.

32. The system of claim 29, wherein the one or more stimulus-emitting devices are configured to first apply the 10 Hz stimulation and then wait a predetermined time period before applying the 40 Hz stimulation.

33. The system of claim 29, wherein the one or more devices are configured to be worn over ears of the individual and include an array of LEDs for applying the 40 Hz stimulation.

34. The method of claim 1, wherein the method of treatment is applied to an individual with mild cognitive impairment and / or Alzheimer’s disease.

35. The method of claim 19, wherein the method of treatment is applied to an individual with mild cognitive impairment and / or Alzheimer’s disease.

36. The system of claim 29, wherein system is used by an individual with mild cognitive impairment and / or Alzheimer’s disease.

37. The method of claim 1, wherein the method of treatment is applied to an individual with at least one of ADHD, anxiety, PTSD, depression, and pain.

38. The method of claim 19, w'herein the method of treatment is applied to an individual with at least one of ADHD, anxiety, PTSD, depression, and pain.

39. The system of claim 29, wherein system is used by an individual with at least one of ADHD, anxiety, PTSD, depression, and pain.

40. The system of claim 33, wherein the one or more devices comprises a single wearable device that has a first part that is configured to be wom over ears of the individual for delivering the 10 Hz stimulation in the form of alpha binaural (BB) sounds and includes a second part that includes an array of LEDs for applying the 40 Hz stimulation in the form of rhythmic light (RL) in a visible spectrum.

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