Virtual reality health condition treatment system and method

Abstract

For example, systems and methods that can be used to display virtual reality scenarios and sensory stimulation protocols to patients suffering from various health conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority from European Patent Application No. 2230655, filed October 13, 2022, the contents of which are incorporated herein by reference in their entirety. [Technical Field]

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to treating physical conditions, and particularly, but not exclusively, to systems and methods using virtual reality in treating physical conditions. [Background technology]

[0003] Neurological disorders, accounting for 90 million deaths each year and 16% of all deaths worldwide, are the second leading cause of death and a leading cause of disability after heart disease. Neurological disorders include stroke, spinal cord injury, epilepsy, sleep disorders, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, primary progressive aphasia (PPA), frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, and posterior cortical atrophy. These disorders impair the patient's cognitive abilities and can further decline over time. As the population ages, the number of neurological disorders is expected to increase, placing a heavy burden on society and healthcare systems.

[0004] Dementia, affecting 46.8 million people worldwide, is one of the most devastating neurological disorders. The number of patients is expected to increase to 74.7 million by 2030 and to 131.5 million by 2050. More than 60% of dementia cases are due to Alzheimer's disease (AD). Among the neuropathophysiological features associated with AD, increased amyloid beta protein (Aβ), hyperphosphorylation of tau protein, microglial inflammatory activity, and dendritic degeneration can be observed. Furthermore, AD has been shown to disrupt neural oscillations, particularly theta-gamma coupling, and these impairments appear before any behavioral disturbances.

[0005] AD is a debilitating and life-threatening neurodegenerative disorder characterized by progressive cognitive decline manifested as memory loss, disorientation, and confusion, leading to a gradual but significant disability. Because existing treatments for Alzheimer's patients are expensive and offer limited clinical benefit, innovative solutions are urgently needed.

[0006] In recent years, the field of neuromodulation has seen rapid development, especially in applications for enhancing cognitive function and addressing cognitive decline. Among the various neuromodulation methods, such as transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), and sensory stimulation, the latter stands out for having a remarkable safety profile.

[0007] Sensory stimulation involves the in-depth delivery of sensory stimuli, such as visual, auditory, or vibratory inputs, at specific frequencies to affect firing patterns in sensory brain regions and downstream regions, such as the hippocampus, a memory center. Sensory stimulation differs from other forms of stimulation in that it does not deliver electrical current directly to the brain, unlike other invasive and non-invasive neuromodulation techniques, such as deep brain stimulation (DBS), TMS, and TES. Notably, DBS, TMS, and TES rely on electrical current to alter neural activity, sensory stimulation harnesses, and the output of specific stimulation frequencies to achieve similar results, providing safer alternatives for cognitive enhancement and treatment. Currently, there are no medically validated methods or hardware available to deliver sensory stimulation to treat or slow cognitive decline.

[0008] Several non-invasive brain stimulation (NIBS) techniques can modulate neural activity without skin insertion and have been shown to be promising alternatives to pharmacological treatments. Examples include electrical stimulation (e.g., transcranial direct current stimulation (tDCS) or transcranial alternating current stimulation (tACS)), magnetic stimulation (e.g., transcranial magnetic stimulation (TMS)), and multisensory stimulation (e.g., audiovisual stimulation (AVS)). Invasive techniques include deep brain stimulation (DBS) and optogenetics, which can trigger activity in specific brain regions, neural populations, and electroencephalograms (EEG) to modulate cognitive and motor functions.

[0009] tACS, tDCS, TMS, and AVS have all been shown to offer benefits for cognitive decline and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, PPA, frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, and posterior cortical atrophy. These techniques have also shown promise for accelerating recovery from brain injuries such as stroke. Second, noninvasive brain stimulation (NIBS) techniques allow for the identification of neural biomarkers for diagnostic assessment of a patient's cognitive and motor abilities.

[0010] The central nervous system (CNS) is regulated by chemical and electrical activity. Neurons, as part of the CNS, typically fire at frequencies ranging from approximately 1 Hz to approximately 120 Hz. Frequency bands, classified from lowest to highest, are termed delta, theta, alpha, beta, and gamma. They have been reported to be associated with and underlie specific cognitive and motor functions. For example, the gamma EEG frequency range is above 30 Hz. The gamma band has been shown to be associated with higher cognitive abilities, including decision-making, reasoning, and memory. Research has shown that Alzheimer's patients have abnormal gamma activity compared to healthy individuals of the same age category. NIBS, which aims to train gamma activity, is one approach to treating Alzheimer's disease and related conditions.

[0011] Several studies have shown that gamma entrainment using sensory stimulation (visual or auditory at 40 Hz) is effective in treating neuropathophysiological features of Alzheimer's disease in mouse models. In particular, it has been shown to improve cognitive function. Simultaneous delivery of visual and auditory gamma stimulation is more effective than delivery of a single stimulus using either modality alone. Recent findings have shown that this neurostimulation technique is safe, provides improvements in AD-related degenerative biomarkers, and also improves sleep quality. Furthermore, sensory stimulation (either visual or auditory, or both) has been shown to enhance human neural oscillations in the theta frequency band and potentially enhance memory performance, for example, in associative memory tasks. Furthermore, individuals at high risk for developing dementia (e.g., carriers of the APOE gene and those diagnosed with mild cognitive impairment (MCI)) may benefit from regular exposure to these types of sensory stimulation (preferably for one hour daily) to prevent or delay the onset of the disease.

[0012] Virtual reality (VR) involves a computer-generated simulation of three-dimensional images or environments that a person can interact with as if they were real or physical, using equipment such as a helmet with a screen inside. VR allows users to navigate and interact with the digital environment and perform specific tasks. Typical use cases for VR include gaming, communication, and education.

[0013] To the extent that stimulation approaches have traditionally been used to treat health conditions (e.g., neurological conditions), such implementations tend to be expensive and / or tend to demonstrate a lack of patient concentration. By way of example only, LEDs may be placed behind opaque lenses in eyeglass-like devices and flash at a controlled rate. In this case, the user closes their eyes during the flashing. For at least this reason, the experience is typically unengaging. Furthermore, control of LED flashing is typically accomplished in a rudimentary manner, such as by flashing the LED at a set rate selected by the user. Summary of the Invention [Problem to be solved by the invention]

[0014] In light of this, there is a need to address the above-mentioned impediments and deficiencies in conventional approaches to provide improved systems and methods for treating health conditions (eg, neurological conditions). [Means for solving the problem]

[0015] According to various aspects of the disclosure, a computer-implemented method is presented, comprising: providing, by a computing system, the stimulation protocol via a virtual reality headset; providing, by a computing system, a virtual reality scenario via a virtual reality headset; receiving, by a computing system, patient physiological data from one or more sensors; and adapting, by a computing system, either the stimulation protocol or the virtual reality scenario, or both, using the patient physiological data.

[0016] In some embodiments of the disclosed methods, the patient physiological data includes patient brain activity data.

[0017] In some embodiments of the disclosed methods, the provided stimulation protocol includes one or both of visual and auditory stimulation.

[0018] In some embodiments of the disclosed methods, the provided stimulation protocol includes one or more of 4 Hz stimulation, 40 Hz stimulation, combined 4 Hz / 40 Hz stimulation, beta range stimulation, or alpha range stimulation.

[0019] In some embodiments of the disclosed methods, the method further comprises: receiving, by a computing system, patient brain activity data from one or more sensors collected while the patient is performing a task that elicits an electroencephalographic state of interest; and identifying, by the computer system, patient-specific frequency values ​​from the received brain activity data that correspond to the electroencephalographic state of interest.

[0020] In some embodiments of the disclosed methods, the brainwave state of interest is beta, alpha, theta, or gamma.

[0021] In some embodiments of the disclosed methods, the method further comprises: detecting, by a computing system, abnormal neural activity from the received patient physiological data; and ceasing, by the computing system, either the provided stimulation protocol or the provided virtual reality scenario, or both.

[0022] In some embodiments of the disclosed methods, the provided virtual reality scenario comprises one or more of a cognitive task, a functional task, or a gamified task.

[0023] In some embodiments of the disclosed methods, the method further comprises: The method further includes determining, by the computing system, a score based on the patient's performance of the task.

[0024] In some embodiments of the disclosed methods, providing a stimulation protocol and providing a virtual reality scenario are performed as a therapy in combination with the administration of one or more pharmaceutical agents.

[0025] In some embodiments of the disclosed methods, the method further comprises: determining, by a computing system, whether the patient's attention is directed to the visual stimuli of the provided virtual reality scenario using an eye tracking system; Providing patient feedback regarding the attentiveness attribute via a virtual reality headset by a computing system.

[0026] In some embodiments of the disclosed methods, The stimulation protocol included visual stimulation; Providing a stimulation protocol includes: adjusting the provision of content displayed within the VR environment; Coordinating the provision of a frame within the VR environment, the frame being positioned around the displayed content; or adjusting the provision of at least one object in the VR environment; Contains one or more The adjustment is made at the frequency of interest.

[0027] In some embodiments of the disclosed methods, the method further comprises: providing remote access by a computing system; Remote access allows for access to patient progress reports and / or selection of patient treatment options.

[0028] According to various aspects disclosed herein, a system is provided, the system comprising: at least one processing unit; and a memory storing instructions that, when executed by at least one processor, cause the system to perform the computer-implemented method.

[0029] According to various aspects disclosed herein, a non-transitory computer-readable storage medium is presented that includes instructions that, when executed by at least one processing unit of a computing system, cause the computing system to perform the above-described computer-implemented method. [Brief explanation of the drawings]

[0030] [Figure 1] 1 illustrates an example of visual stimulus delivery according to various embodiments. [Figure 2] 1 illustrates an exemplary system implementation in accordance with various embodiments. [Figure 3] 1 illustrates an exemplary visual stimulus delivery approach in accordance with various embodiments. [Figure 4] 10 illustrates a further exemplary visual stimulus delivery approach according to various embodiments. [Figure 5] 10 illustrates a further exemplary visual stimulus delivery approach according to various embodiments. [Figure 6] 10 shows exemplary ratios for various groups of individuals versus age according to various embodiments. [Figure 7] 10 illustrates further exemplary ratios relative to age for various groups of individuals according to various embodiments. [Figure 8] 1 illustrates an exemplary architecture diagram in accordance with various embodiments. [Figure 9] 1A-1D illustrate exemplary schematic diagrams according to various embodiments. [Figure 10A] 1 shows an exemplary diagram of a VR headset in accordance with various embodiments. [Figure 10B] 1 shows a further exemplary diagram of a VR headset in accordance with various embodiments. [Figure 10C] 1 shows another exemplary diagram of a VR headset according to various embodiments. [Figure 10D] 1 shows a further exemplary diagram of a VR headset in accordance with various embodiments. [Figure 10E] 1 shows a further exemplary diagram of a VR headset in accordance with various embodiments. [Figure 10F] 1 shows yet another exemplary diagram of a VR headset in accordance with various embodiments. [Figure 10G] 1 shows a further exemplary diagram of a VR headset in accordance with various embodiments. [Figure 10H] 1 shows a further exemplary diagram of a VR headset in accordance with various embodiments. [Figure 11] 1 illustrates an exemplary computer in accordance with various embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0031] According to various embodiments, systems and methods may employ virtual reality (VR) environments in the treatment of health conditions. The treatment may include stimulating a patient's brain with sensory stimuli while the patient interacts with the VR environment. Additionally, in various embodiments, the systems and methods may monitor a patient's health, such as by measuring various physiological parameters of the patient. In this manner, the effects of sensory stimuli on the patient may be identified and such sensory stimuli may be adjusted appropriately. Measuring physiological parameters may enable the progression of a condition (e.g., disease) to be monitored.

[0032] Neurological conditions to which the functionality described herein may be applied include neurological disorders, chronic neurological diseases, and acute neurological disorders. By way of example only, neurological conditions to which the functionality described herein may be applied may include stroke, spinal cord injury, epilepsy, sleep disorders, Alzheimer's disease, Parkinson's disease, dementia (e.g., dementia with Lewy bodies), primary progressive aphasia (PPA), frontotemporal dementia, corticobasal syndrome, progressive supranuclear palsy, and posterior cortical atrophy.

[0033] For ease of description, functions are generally described throughout this specification in the context of neurological conditions, however, it should be understood that such functions may also be employed in the context of other health conditions.

[0034] A virtual reality headset may be used to provide a VR environment to the patient. Additionally, sensors and devices may be used to measure various physiological parameters of the patient. In various embodiments, measurements may be made in real time.

[0035] The systems and methods may employ a library of stimulation protocols. Additionally, the systems and methods may employ a library of virtual reality scenarios. In various embodiments, the virtual reality scenarios may be adaptive scenarios.

[0036] The systems and methods may select (e.g., in real time) one or more sensory stimulation protocols (e.g., a series of sensory stimulation protocols) from a library of stimulation protocols based on the patient's measured physiological parameters. Further, in various embodiments, the systems and methods may select (e.g., in real time) one or more virtual reality scenarios from a library of virtual reality scenarios based on the patient's measured physiological parameters. Further, in various embodiments, the selection of the described sensory stimulation protocols and / or the selection of the described virtual reality scenarios may include the use of one or more feedback loops. In this manner, the sensory stimulation protocols and / or the virtual reality scenarios may be adapted in response to the patient's responses determined by the measured physiological parameters.

[0037] A predetermined sensory stimulation protocol may be provided to the patient via the screen of a VR headset. Using a VR headset screen to provide the sensory stimulation protocol in this manner may offer advantages, including allowing the patient to select where in front of the patient's eyes the protocol's various sensory stimuli (e.g., rhythmic flashing of a VR object) are provided. Such variation in the placement of sensory stimuli during a session may provide numerous benefits to the patient. In contrast, with conventional approaches, visual stimuli are provided by LEDs surrounding the device's left and right eye lenses, and are therefore spatially fixed.

[0038] An additional benefit of using a VR headset screen to deliver a sensory stimulation protocol is that it allows for desired adjustment of the sensory stimulation (e.g., rhythmic sensory stimulation) directly on the screen. This can provide a more enjoyable and engaging immersive experience for patients. By way of example only, a gamified task can be provided to patients, in which the patient must fixate and track a flickering icon to score. Such a gamified task can not only increase patients' engagement with the sensory stimulation protocol (e.g., longer engagement times), but also improve the clinical benefits of the sensory stimulation protocol due to the correlation between attentional levels to sensory stimulation and neural entrainment. Furthermore, combining sensory stimulation with a VR environment can enhance the potential therapeutic effects of sensory stimulation. Indeed, because stimuli are better perceived when presented on the axis of the visual field rather than around it, delivering visual stimulation using a VR screen can more efficiently utilize the visual spectrum. This can result in benefits, including more effective neural entrainment (and therefore improved therapeutic outcomes). The level of entrainment may be interpreted, for example, as phase matching (e.g., significant phase matching) and / or an increase in the power of neural activity at the stimulation frequency. Therefore, entrainment serves as a measure of the efficacy of a sensory stimulation protocol, and entrainment level has been positively correlated with clinical outcomes. Furthermore, stimulation may be delivered during a cognitive task. By way of example only, the cognitive task may involve a face-name association task, in which a set of photographs of unfamiliar and / or familiar faces may be displayed in association with one or more specific names. In particular, the photographs may be presented at a frequency of interest (e.g., 40 Hz) in response to modulation (e.g., flicker). The patient may be asked to memorize these pairs. The patient may then be asked to recall them. Benefits, including improved clinical outcomes, may result from this approach.

[0039] According to various embodiments, the sensory stimuli provided to the patient may be rhythmic. Therefore, rather than being randomly provided, the sensory stimuli may be provided at a predetermined frequency. The frequency at which the sensory stimuli are provided may include, for example, gamma frequencies corresponding to a range of 30-100 Hz. Therefore, the screen of a VR headset typically needs to have a sufficiently high refresh rate. In particular, the screen typically needs to have a refresh rate that is an integer multiple of the frequency of the stimuli to be provided. For example, if the stimuli to be provided include 40 Hz visual stimuli, the minimum refresh rate for the VR headset screen may be 80 frames per second, according to the Nyquist rule. According to various embodiments, a VR headset screen refresh rate of 120 Hz or higher may be used. By way of example only, a VR headset screen refresh rate of 160 Hz, 200 Hz, or 240 Hz may reliably deliver 40 Hz visual stimuli.

[0040] Conventional displays, such as TV screens and monitors, typically have refresh rates that are too low to provide visual stimuli between 30 and 60 Hz, and particularly too low to provide visual stimuli around 40 Hz. Some conventional VR headsets may have displays with refresh rates ranging from 90 Hz to 120 Hz. However, such conventional VR headset displays typically exhibit inherent fluctuations in refresh rate. Thus, these conventional VR headset displays may prove inadequate for providing the sensory stimuli described herein. This discrepancy arises because conventional VR headsets are typically designed simply to immerse users in conventional VR scenarios (e.g., games or educational scenarios). Because refresh rate stability is a factor related to the accurate delivery of sensory stimuli, conventional VR headsets are typically suboptimal for delivering the visual stimuli described herein.

[0041] By way of example only, the measured physiological parameters may include electroencephalography (EEG), heart rate, pupillometry, eye movement, electrodermal conductance, body temperature, respiration rate, and heart rate variability (HRV). In various embodiments, the measured physiological parameters also include other physiological parameters that may be collected non-invasively using appropriate sensors to provide information (e.g., in real time) about the patient's physiological state.

[0042] When the patient's measured physiological parameters include brain activity, the employed sensors may include an EEG headset and EEG electrodes. Detecting brain activity using such an EEG headset and EEG electrodes may involve measuring electrical activity and then processing to identify which parts of the patient's brain are active (e.g., including consideration of where the sensors are placed relative to the patient's skin). In various embodiments, the patient's mental state may then be identified. Furthermore, in various embodiments, brain activity may be measured using functional near-infrared spectroscopy (fNIRS). Here, instead of directly monitoring electrical neural activity, cortical hemodynamic activity that occurs in response to neural activity may be estimated.

[0043] Measurement of brain activity, such as via EGG, may include measurement of EEG phase and / or amplitude. A sensory stimulation protocol may then be selected from a library of stimulation protocols to provide one or more sensory stimuli (e.g., visual stimuli) that coincide with the phases actually measured from the patient. In this manner, therapeutic effects may be optimized. Accordingly, functionality according to various embodiments may include selection of a stimulation protocol based on measured physiological parameters and adaptation of the stimulation protocol based on the measured physiological parameters. For example, an initial task may be administered to the patient to identify a patient-specific gamma frequency. As described in greater detail herein, the task may include providing visual grating stimuli. Stimuli may then be delivered at the identified patient-specific gamma frequency.

[0044] According to various embodiments, the VR headset may include an audio speaker (e.g., an integrated audio speaker). The audio speaker may be used to convey auditory sensory stimuli to the patient. The audio speaker may also be used to facilitate human-device interaction. In this regard, the audio speaker may be used to provide sounds (e.g., as commands and / or questions) embedded in the virtual reality scenario provided by the VR headset. In this manner, the systems and methods described herein may interact with the patient and encourage them to act in the provided virtual reality scenario.

[0045] According to various embodiments, the sensory stimuli provided to the patient may include visual or auditory stimuli, or both. Furthermore, the auditory and visual stimuli may be synchronized. For example, such presentation may maintain a phase lock between the visual and auditory stimuli over time. Such synchronization may be governed by identified phases of the patient's monitored electroencephalograms (e.g., theta and / or gamma electroencephalograms).

[0046] As described, the phase-locking feature may enable synchronization between auditory and visual stimuli. Furthermore, the phase-locking feature may be employed when providing sensory stimuli of different frequencies to a patient. By way of example only, a 4 Hz visual (or auditory) stimulus may be provided along with a 40 Hz visual (or auditory) stimulus. Continuing the example, the phase-locking feature may be used to synchronize the 4 Hz stimulus with the 40 Hz stimulus. As a further example of the phase-locking feature, the provided sensory stimuli may be phase-locked to the patient's measured brain waves (e.g., delivering a 40 Hz visual stimulus locked to a specific phase of theta waves detected in the auditory cortex). Furthermore, the provided sensory stimuli may be amplitude-synchronized with the patient's measured brain waves. Thus, synchronization may be achieved that may improve therapeutic outcomes (e.g., cognition) using a VR headset.

[0047] As described, sensory stimulation (e.g., visual stimulation) may be provided to the patient. Additionally, peripheral nerve stimulation and deep brain stimulation may also be provided to the patient. Peripheral nerve stimulation and deep brain stimulation may be provided using electrodes. For example, in the case of peripheral nerve stimulation, electrodes may be placed on the surface of the patient's skin. Here, nerves that may be stimulated include the vagus nerve in the neck, the median nerve in the forearm and wrist, and the radial nerve in the forearm and wrist. In some embodiments, the virtual reality headset system may include an electrical stimulator and electrodes that may be used to provide peripheral nerve or deep brain stimulation to the patient.

[0048] Providing deep brain stimulation to a patient, such as in conjunction with sensory stimulation to a patient, may prove advantageous in the treatment of various neurodegenerative disorders (e.g., Parkinson's disease, essential tremor, and Alzheimer's disease), and in the treatment of various psychiatric disorders (e.g., obsessive-compulsive disorder and major depression). Such combined invasive (deep brain stimulation) and non-invasive (sensory stimulation) neuromodulation modalities may be useful in the case of Parkinson's disease, where deep electrodes may be implanted in the subthalamic nucleus and other brain regions of the motor network.

[0049] Both peripheral nerve stimulation and deep brain stimulation involve electrical stimulation. The peripheral nerve stimulation and deep brain stimulation can be rhythmic, such as synchronized with the frequency of the sensory stimulation delivered by the VR headset. Alternatively, or in addition, the peripheral nerve stimulation and / or deep brain stimulation can be delivered in synchronization with a virtual reality scenario provided by the VR headset and delivered to assist the patient in performing tasks in the virtual reality environment.

[0050] The library (e.g., digital library or database) of stimulation protocols may include sensory stimulation protocols that provide sensory stimulation to a patient. The library of stimulation protocols may also include peripheral nerve stimulation protocols that provide peripheral nerve stimulation to a patient and deep brain stimulation protocols that provide deep brain stimulation to a patient. The sensory stimulation protocols may specify sensory stimulation including visual and auditory stimulation. The peripheral nerve stimulation protocols and deep brain stimulation protocols may specify electrical stimulation. The visual stimulation may be at a specific frequency (or multiple specific frequencies), such as between 1 Hz and 80 Hz, between 1 Hz and 100 Hz, or 4 Hz and / or 40 Hz. The auditory stimulation may be phase-locked to the visual stimulation. The electrical stimulation may include electrical stimulation for application to a peripheral nerve.

[0051] The library of stimulation protocols may include stimulation protocols that can be used to treat and / or prevent cognitive decline. For example, such a stimulation protocol may begin a session with visual (and / or auditory) stimulation at 4 Hz, 40 Hz, or both. The stimulation protocol may then adapt (e.g., in real time) the frequency (or frequencies) of these stimuli to be in phase with the patient's measured brainwave frequency (e.g., as measured via EEG). The adapted frequency may be similar to the starting frequency. For example, a 4 Hz starting frequency may be adapted to be between 3.8 and 4.2 Hz. As another example, a 40 Hz starting frequency may be adapted to be between 38 and 42 Hz.

[0052] Theta and gamma brain wave frequencies in healthy individuals are approximately 4-8 Hz and approximately 30-100 Hz, respectively. Alzheimer's patients may exhibit reduced EEG activity at or near 40 Hz. Furthermore, Alzheimer's patients may exhibit reduced EEG activity at or near 4 Hz. Furthermore, Alzheimer's patients may exhibit reduced EEG coupling between 4 Hz and 40 Hz. Some or all of these three aspects are suspected to be responsible (or partially responsible) for the memory performance exhibited by Alzheimer's patients. Therefore, stimulating at these frequencies may be advantageous. In this regard, as previously described, the library of stimulation protocols may include stimulation protocols that provide visual stimuli at both 4 Hz and 40 Hz. Furthermore, auditory stimuli may be synchronized (e.g., phase-locked) with these visual stimuli. For example, auditory stimuli may be applied together with visual stimuli from the beginning of the session.

[0053] A library (e.g., a digital library or database) of virtual reality scenarios may include virtual reality scenarios to present to a patient. By way of some examples only, the virtual reality scenarios may provide immersion with a 3D virtual visual universe, a sound environment (e.g., including music), and / or animated images. In various embodiments, it may be advantageous to have virtual reality scenarios from a library of virtual reality scenarios that include scenarios generated from places and spaces that the patient knows (or may know). Here, the familiarity of the resulting VR environment may improve patient outcomes.

[0054] By way of example only, a virtual reality scenario from the library of virtual reality scenarios may enable a patient to perform relaxation training, improve the patient's performance, and / or enable the patient to interact with the provided virtual reality universe. Such improvements in patient performance may include improvements in cognitive performance (e.g., related to memory, attention, and / or sleep) and functional performance (e.g., motor skills). For example, improvements in cognitive performance may be achieved by providing cognitive games to the patient via the VR scenario. Furthermore, a VR scenario from the library of VR scenarios may include a VR scenario that requires the patient to move in a way that improves the patient's motor skills. Such types of VR scenarios may be useful, for example, in the treatment of stroke and the treatment of Parkinson's disease.

[0055] A user interface may be provided. The user interface may allow for selection of a stimulation protocol. The user interface may also allow for selection of a VR scenario (or a series of VR scenarios), providing a personalized experience and potentially leading to increased engagement with the therapy. According to various embodiments, the selected stimulation protocol or the selected VR scenario may be changed during a session. For example, such changes may occur based on the patient's response to the stimulation (e.g., as measured by sensors in the VR headset). As another example, such changes may occur based on the patient's interaction with the provided VR environment. As a further example, such changes may occur based on a system algorithm (e.g., an algorithm for selecting an optimal stimulation protocol and / or VR scenario). Thus, in some examples, changes in the stimulation may include changes in shape, onset, frequency, intensity, illumination, color, sound, and volume. Next, in some examples, changes in the VR scenario may include changes in VR color, VR shape, VR brightness, and VR task.

[0056] In various embodiments, multiple layers may be used when providing the stimulation protocol and VR scenario to the patient via the VR headset. For example, a first layer may be used to provide the VR scenario and a second layer may be used to provide the stimulation protocol. Furthermore, in various embodiments, the stimulation protocol may be provided to the patient while the patient is performing a task in the VR environment. Furthermore, in other embodiments, the stimulation protocol may be provided to the patient while the patient is passively viewing the VR environment.

[0057] The system may also include one or more databases (or other storage locations) that hold patient-specific information. Such patient-specific information may indicate the stimulation protocols and VR scenarios provided to a given patient and their responses to those stimulation protocols and VR scenarios. The stored responses may include physiological activity measurements recorded by sensors, health scores, and brain activity records. The patient-specific data may also include a patient-specific ID and timestamp. The database may be accessible via the system's user interface and / or remotely by a medical team. Such access by the medical team may enable the team to personalize a treatment protocol, such as the nature of the initial stimulation protocol to be applied for a given patient's next session. The system may also include one or more software modules that transmit the patient-specific information to a remote server or database over a computer network (e.g., using encrypted transmission). In this manner, the medical team may be able to easily access the patient-specific information.

[0058] The system may include at least one server onto which a library of stimulation protocols and a library of VR scenarios are loaded. The at least one server may be connected to the control instrument via a wired or wireless communication link (e.g., an encrypted communication link). By way of example only, the communication link may employ WIFI, 4G, and / or 5G. Additionally, system updates (e.g., library updates) may also be provided.

[0059] The system may operate in a feedback-based manner, where, for example, physiological parameters may be monitored and recorded, and the stimulation protocol and / or VR scenario may be adapted accordingly (e.g., in real time). In other embodiments, the system may operate in a manner that does not use such feedback.

[0060] The functions described herein (e.g., relating to the selection and provision of stimulation protocols and VR scenarios, and relating to the analysis of physiological parameters received from sensors) may be performed via a computer program including program code instructions for performing such functions via a computer.

[0061] According to various embodiments, if an abnormal neural activity pattern (e.g., an epileptic pattern) is identified from the received physiological parameters measured by the sensors, the use of the stimulation protocol or VR scenario may be stopped. Various measured physiological parameters, including such abnormal neural activity patterns, may be taken into consideration. In this manner, action may be taken to prevent the onset of side effects (e.g., seizures) that may result from the use of the stimulation protocol or VR scenario.

[0062] In various embodiments, on the one hand, the stimulation protocol may be stopped immediately. On the other hand, the provision of the VR scenario may be stopped gracefully. In this manner, the VR scenario may be stopped without causing confusion to the patient. Such graceful stopping of the VR scenario may include the provision of an "emergency" scenario that provides VR images and / or sounds that serve to reduce the patient's confusion. Furthermore, in various embodiments, after stopping the stimulation protocol and / or VR scenario in response to the detection of an abnormal neural activity pattern, the system may select a new stimulation protocol and / or VR scenario.

[0063] Additionally, a stress alert function may be provided. As described herein, VR headsets may be used to treat neurological disorders in a non-invasive manner. Various patients (e.g., patients suffering from Alzheimer's disease) who use these VR headsets may primarily be elderly (e.g., over 65 years old). Currently, such elderly individuals may not be as comfortable using digital technology as younger generations. Furthermore, due to the immersive experience experienced when using a VR headset, it may be important to ensure that patients feel comfortable and safe while using the device and that they can stop the therapy whenever they wish. Furthermore, because VR headsets require covering a large portion of the patient's face, it may be difficult for caregivers and medical team members to assess whether the patient is comfortable.

[0064] Thus, the system may perform a test for the patient's stress state (e.g., a relapse test). In this manner, the system may send a warning signal to a caregiver or medical team member if a stress state is detected. The warning signal may indicate that the patient may be uncomfortable and that the caregiver or medical team member should take further action, such as removing the headset or asking the patient if they need assistance. By way of a few examples only, the warning signal may be provided to the caregiver or medical team member via a notification sent to their smartphone, in the form of a light located on the exterior of the VR headset (e.g., with a color change based on the patient's condition), and / or via a sound played through the VR headset's external speakers. In various embodiments, in addition to providing such a warning signal to the caregiver or medical team member, the patient may be contacted within the VR environment. By way of a few examples only, such contact may take the form of one or more of: a) displaying text and / or playing audio asking the patient if they are OK; b) text or audio reminding the patient that they may remove their VR headset if necessary; and c) providing breathing exercises (or other calming VR scenarios) to the patient. The system may consider one or more of heart rate data (e.g., average data and variability), pupillometry data, electrodermal response data, and EEG data to determine if the patient is experiencing a stress state.

[0065] Epileptic seizures are transient seizure symptoms caused by the synchronization of abnormal neuronal hyperactivity in the brain. "Epileptiform abnormalities" or "epileptic discharges" can be detected on an EEG. They appear as spikes, sharp waves, and spike-and-wave discharges. Seizures on EEG recordings can appear as bursts of abnormal discharges, called ictal epileptiform discharges. These discharges can increase in frequency and lead to rapid, sustained spike-and-wave discharges that progress to multiple spikes with buried waves at the peak of the seizure. Slow waves can then reappear and gradually decrease in frequency as the seizure subsides.

[0066] The detection of epileptic seizures may be performed by the system, for example, via its analysis and computation module. For example, the system may compare received EEG data to a system library containing representative wave patterns during epileptic seizures. As another example, the system may operate to detect changes in EGG waves (e.g., detect ictal epileptiform discharges, and thus frequency elevations). As a further example, the system may use a machine learning model trained on EEG data of patients experiencing epileptic seizures and on EEG data of patients not experiencing epileptic seizures. The EEG data of a patient experiencing an epileptic seizure may include an EGG pattern corresponding to an epileptic seizure onset.

[0067] According to various embodiments, the system may use the parameters received from the sensors to calculate diagnostic scores. These diagnostic scores may include cognitive function scores (e.g., sleep scores, memory scores, attention scores, and motor performance scores), disease risk scores, and brain health scores. The scores may be made available to a medical team, such as in the manners previously described.

[0068] The stimuli may be delivered and displayed on a screen of the headset. Referring to Figure 1, by way of example only, implementations may include: a) delivering visual stimuli via a passive approach, overlaying a stimulus layer (101) while the patient passively views the VR environment; b) delivering visual stimuli via an active approach, overlaying a stimulus layer (103) while the system performs a cognitive or motor task and the patient performs the task; c) delivering visual stimuli by adjusting the appearance of a displayed video or image (and / or the entire VR environment) (105); and d) delivering visual stimuli by adjusting the appearance of an object embedded in the VR environment (107).

[0069] Furthermore, with respect to visual stimuli, the visual stimuli may be generated by the system using sine waves and sine wave modulation (e.g., pure sine wave modulation) of brightness levels. By way of example only, the brightness level may be modulated from 0% brightness (e.g., completely black) to 100% brightness (e.g., completely white) with a 50% duty cycle. In some embodiments, colors other than white may be used. With this 50% duty cycle, for a 4 Hz stimulus, the brightness level may change from 0% to 100% in 125 ms and from 100% to 0% in 125 ms. Furthermore, with this 50% duty cycle, for a 40 Hz stimulus, the brightness level may change from 0% to 100% in 12.5 ms and from 100% to 0% in 12.5 ms. Furthermore, the visual stimuli may be generated by the system using square waves and isochronous modulation (i.e., on / off modulation) of brightness levels. By way of example only, a 50% duty cycle may be used. With this 50% duty cycle, for a 4 Hz stimulus, the brightness level may be 100% for the first 125 ms and 0% for the next 125 ms. Furthermore, with this 50% duty cycle, for a 40 Hz stimulus, the brightness level may be 100% for the first 12.5 ms and 0% for the next 12.5 ms.

[0070] When a combined 4 Hz and 40 Hz stimulus is used, the 40 Hz stimulus is embedded, by way of example only, in the 4 Hz frequency peak with a 0° phase offset (i.e., phase-locked). Furthermore, when an embedded stimulus pattern is employed, the embedding may include embedding waves of the same type (e.g., a sine wave embedded within a sine wave) or embedding waves of different types (e.g., an isochronous wave embedded within a sine wave). By way of example only, in the case of a combined 4 Hz and 40 Hz stimulus, a 40 Hz isochronous wave may be embedded within a 4 Hz sine wave. In some embodiments, implementing the wave embedding function may take into account the refresh rate of the VR headset.

[0071] Furthermore, with regard to using auditory stimuli to induce auditory entrainment, the auditory stimuli may be generated by the system using amplitude modulated (AM) tones. In particular, the use of such AM may involve modulating the carrier frequency according to the stimulus frequency. Using a carrier frequency between 250 Hz and 1000 Hz with a 100% modulation depth may be advantageous. Using these low carrier frequencies may produce significant auditory-evoked patient responses, and such low carrier frequencies may be well perceived by patients as they relate to speech perception. By way of example only, the volume may be set between 40 and 80 dB. In particular, a volume setting of 70 dB sound pressure level (SPL) may be optimal for sustainable auditory perception. For combined stimulus frequencies, the highest frequency may be embedded with a 0° phase offset relative to the peak of the lowest frequency. For example, for a combined stimulus frequency of 4 Hz and 40 Hz, the 40 Hz frequency may be embedded with a 0° phase offset relative to the peak of the 4 Hz frequency.

[0072] In addition to using AM modulation to create auditory entrainment, other approaches such as frequency modulation (FM) and isochrone modulation (IM) may be used. Such FM approaches may modulate a carrier frequency (e.g., a carrier frequency ranging from 250 Hz to 10 kHz). Such IM approaches may include on / off auditory tones provided at a system-selected frequency. In various embodiments, the system may adapt the carrier frequency and / or modulation depth. Furthermore, in various embodiments, auditory stimuli may be generated by the system via amplitude modulation of complex sound waves, thereby deviating from the use of pure tones as described above. These complex waveforms may include existing auditory elements, such as music, newly invented sounds, or both.

[0073] Multisensory audiovisual stimulation may be delivered by synchronizing visual and auditory stimuli. For example, a 4 Hz visual stimulus may be synchronized with a 40 Hz auditory stimulus. For example, a 0° phase offset between the visual and auditory stimuli may be used.

[0074] Regarding the frequency of the stimulation, the system may modulate the stimulation at a specific frequency, such as a frequency range of 1 Hz to 100 Hz. By way of example only, stimulation frequencies advantageous for Alzheimer's disease and mild cognitive impairment (MCI) may include a) 4 Hz only, b) 40 Hz only, and c) a combination of 4 Hz and 40 Hz. By way of further example only, stimulation frequencies advantageous for Parkinson's disease may include stimulation in the beta range, and stimulation frequencies advantageous for depression may include stimulation in the alpha range. Furthermore, patient-specific frequency values ​​around these frequencies may be used. For example, patient-specific frequency values ​​around 4 Hz may be calculated by the system from EEG recordings in the theta range (4 Hz ± 1 Hz). Similarly, patient-specific frequency values ​​around 40 Hz may be calculated by the system from EEG recordings in the gamma range (40 Hz ± 5 Hz). The system's adaptation of the stimulation frequency to what analysis of the EEG recordings indicates may be performed online or offline, and may be performed in conjunction with visual stimuli, auditory stimuli, and combinations of stimuli.

[0075] With regard to neural stimulation, in addition to audiovisual stimulation, electrodes for delivering neural stimulation may be present on or embedded in the VR headset. In this manner, the system may use the electrodes to deliver neural stimulation to specific neural targets (e.g., the brain, spinal cord, and peripheral nerves). The electrodes may be connected to a power source that can deliver specific patterns of pulses. In various embodiments, these stimulation patterns may be optimized according to data measured by sensors (e.g., measured electroencephalogram phase and / or amplitude data) to enhance therapeutic effects.

[0076] A session may begin with the selection of an initial sensory stimulation protocol and an initial virtual reality scenario (or series of virtual reality scenarios) to be displayed in the VR headset during the session. The selection may be made using, by way of example only, a control panel on the VR headset. The selection may be made by the patient (if the patient is sufficiently independent), by a caregiver, or by a medical team member. By way of example only, the initial sensory stimulation may include the delivery of 4 Hz visual stimuli, the delivery of 40 Hz visual stimuli, or the delivery of both 4 Hz and 40 Hz visual stimuli. The initial sensory stimulation protocol may include the delivery of both visual and auditory stimuli, where the auditory stimuli are phase-locked to the visual stimuli.

[0077] For example, a session may last from about 30 minutes to about 1 hour, unless stopped earlier upon detection of abnormal brainwave activity (e.g., as indicated by an epileptic EEG pattern) or at the request of the patient, caregiver, or medical team member. In various embodiments, a 1-hour session may be considered advantageous. Furthermore, in various embodiments, repeating such a session daily may be considered advantageous.

[0078] The initial sensory stimulation protocol and the initial VR scenario may be modified based on the system's analysis of the patient's measured physiological parameters. For example, the system may consider the brain wave phase and modify the frequency of the visual stimulation (and / or the frequency of the auditory stimulation) to achieve synchronization so that the stimulation is in phase with the patient's brain waves.

[0079] As previously described, the system may measure the phase of the brainwaves. Additionally, the system may measure the amplitude of the brainwaves. The system may then modify the amplitude of the stimuli based on the measured brainwave amplitude. For example, the intensity and / or color of a visual stimulus may be modified in response to the brainwave amplitude. In particular, the intensity may be increased or decreased, and the color may be changed to a predetermined color in the spectrum or a color blend. As merely some examples, when considering auditory stimuli, the intensity (i.e., volume) and / or frequency (i.e., pitch) of the auditory stimulus may be adjusted in response to the measured brainwave amplitude. In this manner, benefits may arise, including the generation of auditory stimuli that increase the brainwave amplitude.

[0080] Referring to FIG. 2 , the system may select a stimulation protocol from a library of stimulation protocols 201. Further, the system may select a VR scenario from a library of VR scenarios 203. The system may provide the selected stimulation protocol and the selected VR scenario using a VR headset 205, which may use a data link to the VR headset. The VR headset may include sensors that measure physiological response data (e.g., EEG data). Such data may be transmitted (e.g., in real time) through the data link to a physiological recording module 207 for recording. For example, the physiological recording module 207 may record raw data or perform preprocessing on the data before storing it.

[0081] The data may then be analyzed by the physiological response processing module 209. As previously described, the physiological response processing module 209 may send instructions to the library of stimulation protocols 201 to modify the stimulation protocols. As previously described, the physiological response processing module 209 may also send instructions to the library of VR scenarios 203 to modify the VR scenarios.

[0082] The library of stimulation protocols 201 may store instructions for providing visual stimulation protocols, auditory stimulation protocols, and combinations of auditory and visual stimulation protocols. The library of stimulation protocols 201 may also store instructions for providing peripheral nerve stimulation protocols and deep brain stimulation protocols. Thus, by way of example only, the library of stimulation protocols 201 may store instructions for providing vagus nerve stimulation, transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS). As previously indicated, stimulation may be provided as rhythmic stimulation.

[0083] In various embodiments, the various described stimulation modalities may be delivered, for example, daily (or on a different schedule) for a predetermined period of time, which may depend on factors such as whether the stimulation is active (provided during a given task) or passive (not provided during a given task) and the patient's underlying health condition.

[0084] The library of VR scenarios 203 may store meditation scenarios, relaxation scenarios, and breathing scenarios. The library of VR scenarios 203 may also store VR scenes, animated images, sounds, and music. Additionally, the library of VR scenarios 203 may store cognitive and motor tasks, as well as gaming scenarios. The cognitive and motor tasks may also require the patient's active participation during virtual reality immersion.

[0085] The VR headset 205 may include a screen to be placed in front of the patient's eyes and speakers to be placed near the patient's ears, so that the patient can experience a VR scenario selected by the system.

[0086] The system may include sensors for acquiring physiological data of the patient. The acquired physiological data may be stored by the physiological recording module 207. By way of example only, the physiological data acquired by the sensors may include EEG data, ECG (electrocardiogram) data, EOG (electro-oculogram) data, PPG (photoplethysmography) data, EMG (electromyogram) data, heart rate data, respiratory data, pupillometer data (including, for example, eye tracking data), electrodermal response data, accelerometer data, gyroscope data, and temperature data. Various sensors (e.g., sensors acquiring EEG data as described) may be included in the VR headset 205. Additionally, various sensors may be mounted on equipment such as belts, harnesses, and gloves. In this manner, sensors may be positioned at appropriate locations on the patient's body.

[0087] As previously described, the physiological response processing module 209 may perform operations including determining (e.g., in real time) the nature and changes in measured physiological parameters. The output of such analysis (e.g., physiological scores or exceedance of power thresholds) may be stored in memory located remotely from or within this module 209. In this manner, by way of example only, a) the evolution of parameters during a session may be ascertained, b) the evolution of parameters over time (e.g., changes in parameters between two sessions), and c) stimulation protocols and VR scenarios may be modified.

[0088] Additionally, the physiological response processing module 209 may calculate a health score (e.g., a global health score) based on either one physiological parameter or a combination of several physiological parameters. Additionally, the physiological response processing module 209 may calculate an entrainment score. In particular, the physiological response processing module 209 may consider the patient's measured EEG data collected during the session in relation to desired brainwave targets for the patient as specified by the stimuli provided to the patient. Additionally, the physiological response processing module 209 may evaluate and / or score tasks given to the patient in the virtual reality universe. Additionally, the physiological response processing module 209 may examine the patient's collected EEG data for abnormal neural activity patterns and terminate the session if such abnormal patterns are found, as previously described. In various embodiments, the operation of the physiological response processing module 209 may be implemented via a machine learning approach. Additionally, in various embodiments, the physiological response processing module 209 may quantify the patient's dominant brainwave frequency.

[0089] In various embodiments, the physiological response processing module 209 may include a machine learning model (MLM), such as an MLM using reinforcement learning (RL). The model may receive inputs including stimuli provided to the patient (e.g., 40 Hz sensory stimuli), EEG data received from the patient, and a desired entrainment state for the patient (e.g., gamma entrainment). The MLM may generate, as output, suggested stimulus changes to provide to the patient. If the suggested stimulus changes generated by the MLM are implemented, the patient achieves (comes close to) the desired entrainment state, and the MLM may receive a positive reward. Otherwise, the MLM receives no reward (or a negative reward). In this way, the MLM may learn to generate suggested stimulus changes more effectively over time.

[0090] The modules described with respect to Figure 2 may be implemented using software and / or hardware. Thus, the system of Figure 2 may include one or more executed software modules, one or more processing units (e.g., CPUs or GPUs), one or more amplifiers (e.g., EEG amplifiers), one or more communication devices (e.g., Bluetooth and / or WIFI devices), and one or more power sources.

[0091] The system may also include at least one display screen that communicates information about the session (e.g., in real time). By way of some examples only, the displayed information may include the progression of an entrainment score and / or the progression of a health score. As a further example, the display screen may also communicate (e.g., in real time) values ​​measured by sensors and the progress of the session (e.g., the patient's progress in completing a virtual reality scenario task, a description of the stimuli provided, and the time elapsed during the session). Thus, the displayed information may be available to the patient, a caregiver, a medical team member, etc. For example, the display screen may be integrated with the system of FIG. 2. As another example, the display screen may be remote from the system of FIG. 2, such as a computer, cell phone, or touch-sensitive tablet that communicates with the system of FIG. 2 (e.g., via a wireless link).

[0092] In various embodiments, one or more algorithms may be used to discard or correct sensor-measured physiological parameters that are identified as erroneous (e.g., outside of a range considered normal for the patient). In this manner, the system may prevent such physiological parameters from being further acted upon by the system (e.g., by the physiological response processing module 209).

[0093] The functionality described herein may yield numerous benefits. Thus, in some examples, such benefits may include: a) easy access and performance at home; b) easy remote monitoring of patient system use; c) easy neurological disorder diagnosis (e.g., time and cost savings); and d) easy delivery of non-invasive brain stimulation at home. As some further examples, additional benefits may include: a) increasing patient engagement with digital therapy by making it more engaging, fun, and enjoyable; b) improving and accelerating patients' path to neurological recovery (e.g., slowing neurological health decline); c) improving prevention, quality of care, medical interventions, and personalized medical guidance based on actual daily health measurements; and d) providing solutions for neurological disorders through targeted, individualized, and power precision medicine while facilitating access to brain health solutions. Furthermore, the functionality described herein may a) improve the quality of life of patients and caregivers without the need for advanced assistance; and b) saving medical teams time in monitoring neurological patients.

[0094] Stimulation delivery will now be described in greater detail. Both invasive and non-invasive neuromodulation techniques, when used for therapeutic purposes, may aim to modulate neural activity at frequencies associated with specific disease symptoms. For example, neuromodulation therapy involving deep brain stimulation at high frequencies (e.g., >120 Hz) may inhibit the excess beta power (e.g., 15-35 Hz) that may be found in motor brain regions of patients with Parkinson's disease. More generally, the frequency of stimulation to be delivered for treatment of a given neurological condition may be based on neural oscillations correlated with specific neurological conditions and symptoms.

[0095] The features described herein include approaches for transmitting audiovisual sensory stimuli with the goal of creating neural entrainment to specific frequencies. In one embodiment, the features described herein may serve to enhance neural synchronization (e.g., as evidenced by increased power) at frequencies associated with healthy cognitive abilities and thus impaired in patients suffering from cognitive impairment. Frequencies of interest in the features described herein may include frequencies in the theta and low gamma ranges (approximately 4-8 Hz and approximately 30-60 Hz, respectively) due to their role in higher cognitive functions (e.g., memory formation and sensory perception). Furthermore, in various embodiments, the system may support and transmit any frequency in the range of 0.1 Hz to 45 Hz. Furthermore, 1) exposure (e.g., prolonged exposure) of Alzheimer's patients to 40 Hz audiovisual stimuli can reduce brain atrophy, slow the progression of measured Alzheimer's disease, and maintain the ability to perform daily activities; and 2) audiovisual sensory stimulation (e.g., intense audiovisual sensory stimulation) at 4 Hz during cognitive tasks can improve associative memory performance. The features described herein include interventions that deliver audiovisual stimuli through a VR headset, including, by way of example only, stimuli at frequencies associated with cognitive function, such as within the theta range of 4-8 Hz and within the gamma range of 30-60 Hz.

[0096] According to various embodiments, two sensory stimulation protocols may be used: 1) an open-loop stimulation protocol using a non-patient-specific stimulation frequency; and 2) a closed-loop stimulation protocol using a patient-specific stimulation frequency.

[0097] As described, the open-loop stimulation protocol may use a non-patient-specific stimulation frequency. In other words, the open-loop stimulation protocol may use a fixed stimulation frequency. For example, sensory stimulation provided for the treatment of cognitive decline may occur at a predetermined frequency, such as 4 Hz, 40 Hz, or a complex pattern of 40 Hz embedded in a 4 Hz carrier wave. Here, the modulation rate of visual stimulation provided via a VR headset may occur at a predetermined frequency. Similarly, here, the modulation rate of auditory stimulation provided (e.g., via a phase-matching rate of volume control) may occur at such a predetermined frequency. Optionally, the visual and auditory stimulation may assume different stimulation frequencies (e.g., 4 Hz for the visual stimulation and 40 Hz for the auditory stimulation). In various embodiments, such two vibrations may be phase-matching.

[0098] As described, the closed-loop stimulation protocol can use a patient-specific stimulation frequency. In other words, the closed-loop stimulation protocol can involve personalized stimulation frequencies within a range of interest (e.g., theta and gamma). Thus, the closed-loop stimulation protocol can include finding patient-specific frequency values ​​associated with various cognitive processes.

[0099] To accomplish this, the system may use EEG sensors to record the patient's brain activity while the patient performs a task that elicits an electroencephalogram state of interest (e.g., a gamma state). The system may extract dominant frequencies from the EEG data (e.g., using the physiological response processing module 209). As just a few examples, extraction may be performed using power spectral density, Morlet wavelet, and / or Fourier transform approaches. In this manner, patient-specific frequency values ​​corresponding to the electroencephalogram state of interest may be identified. In various embodiments, in addition to identifying dominant frequencies, phase and amplitude may also be ascertained.

[0100] Stimulation may then be delivered to the patient using the identified patient-specific frequency values ​​that correspond to the electroencephalogram state of interest (e.g., gamma), thereby achieving neural entrainment in the electroencephalogram state of interest.

[0101] According to various embodiments, two approaches may be used to have a patient perform a task that elicits an EEG state of interest (e.g., theta or gamma state) while EEG sensors record the patient's brain activity as described. One such approach is endogenous EEG extraction through visual grid stimulation. A second such approach is low- and high-frequency sweeping.

[0102] For endogenous EEG extraction through visual grating stimulation, both moving and stationary grating stimuli may be repeatedly presented to elicit narrow-band gamma oscillations (e.g., 30-50 Hz) in the visual cortex. A task (e.g., a short task) that repeatedly presents visual grating stimuli may be presented to the patient (e.g., via a VR headset). The patient may perform the task, thereby enabling the extraction of endogenous EEG gamma frequencies. Regarding the above description, calculation of frequency values ​​may be performed via, as just a few examples, power spectral density and / or time-frequency analysis. As previously described, the identified frequency values ​​may be used to control the frequency at which visual and / or auditory stimuli are delivered. While the use of visual grating stimulation to identify patient-specific gamma frequencies has been described as an example, according to various embodiments, such an approach may be used to identify patient-specific frequencies for other EEG states.

[0103] For low-frequency and high-frequency sweeps, brain entrainment in the visual cortex caused by flicker can occur up to a stimulation frequency of approximately 90 Hz. Furthermore, the magnitude of flicker-induced entrainment can vary depending on the subject and the stimulation frequency. With this in mind, the latter low-frequency and high-frequency sweep approach uses a flicker-inducing task, in which the frequency of the flicker-inducing stimulus (e.g., provided via a VR headset) can be varied (e.g., gradually changed) while recording EEG. The range of frequencies tested can include, by way of example only, a) a low-frequency sweep around the theta frequency (e.g., from 3 Hz to 5 Hz, in 1 Hz increments) and b) a high-frequency sweep around the gamma frequency (e.g., from 35 Hz to 45 Hz, in 1 Hz increments). The sweep (e.g., theta sweep and / or gamma sweep) is typically repeated several times to obtain sufficient data to calculate appropriate parameters (e.g., power and / or phase alignment) across stimulation trials at a given frequency.

[0104] The frequency that leads to a higher level of entrainment in the theta and / or gamma sweep (e.g., as evidenced by power increase and / or phase matching) can be used as the frequency at which the visual and / or auditory stimuli are delivered (e.g., the rate at which the brightness of objects in the displayed VR environment flickers). For example, if subject A exhibits a higher power increase and phase matching at 42 Hz compared to stimulation at 10 other frequencies (e.g., 35 Hz to 45 Hz), then stimulation can be set to 42 Hz for that particular individual. While using low- and high-frequency sweeps to identify patient-specific theta and gamma frequencies is described as an example, such an approach can be used to identify patient-specific frequencies for other brainwave states, according to various embodiments.

[0105] Approaches for transmitting sensory stimuli via a VR headset will now be described in greater detail. Referring to FIG. 3, according to a first exemplary approach, visual stimuli may be transmitted via a frame 301 positioned around a video or image provided by a displayed VR environment. The frame may flicker at a frequency of interest. Next, referring to FIG. 4, according to a second exemplary approach, visual stimuli may be transmitted through the provided video or image 401 itself, which flickers at a frequency of interest. Further, referring to FIG. 5, according to a third exemplary approach, visual stimuli may be transmitted through one or more flickering components 501 in the displayed VR environment (e.g., objects therein). According to these approaches, the displayed VR environment may be an immersive 360° VR environment.

[0106] In a first exemplary approach, the patient's viewpoint may be placed in front of a large rectangular video or image screen provided by the VR environment. The size of the screen and the patient's distance from the screen may be comparable to when the patient watches a movie in a theater. A frame may surround all four sides of the screen. While the video plays or the image is displayed, the frame may flicker at a target stimulus frequency (e.g., alternating between different values ​​of brightness to create a desired visual flicker effect).

[0107] For the second exemplary approach, the patient's viewpoint may be positioned in front of a large rectangular video or image screen provided by the VR environment, similar to the first approach. However, unlike the first approach, there is no frame surrounding the video or image. Instead, while the video is playing or the image is displayed, the video or image itself (and / or the entire VR environment) may flicker at a target frequency to convey the stimulus. By way of example only, the video or image may rapidly alternate between different brightness values ​​to create a desired visual flicker effect. In various embodiments, the flickering of the video or image may take the form of a flickering landscape in the VR environment.

[0108] For a third exemplary approach, the patient's viewpoint may be placed within a VR environment. The VR environment may, by way of example only, provide a calming, safe digital space for the patient to receive stimuli. One or more components (e.g., objects) within the VR environment (e.g., objects within the patient's field of view) may flicker at a target frequency. In this manner, a desired visual stimulus may be conveyed to the patient.

[0109] The content displayed to the user through the VR headset can be, by way of example only, videos, images, or a 360° VR environment. Furthermore, the displayed content can be passive or active content. Such passive content can include content that does not require the patient to engage with it other than perhaps gazing at what is displayed. Such active content can include content that the patient engages with. For example, such content can include cognitive, functional, and / or gamified tasks. For example, such tasks can be aimed at assessing or improving the patient's cognitive or functional abilities.

[0110] As just a few examples, the content, whether passive or active, may take the form of 1) natural or digital representations of landscapes (e.g., forests, beaches, or open spaces), 2) everyday living locations (e.g., homes, backyards, streets, or urban areas), 3) animated environments, and / or 4) personal patient memories (e.g., family photos or family memories). For personal patient memories, the patient may upload the corresponding content to the system, for example, using a mobile phone. The system may then apply VR synthesis techniques to the uploaded content and embed it for viewing in a VR environment.

[0111] For auditory stimuli, according to the three exemplary approaches described, providing the auditory stimuli can include providing a sound source within the VR environment (e.g., located at one or more locations within the VR environment). In this manner, the patient can hear the auditory stimuli through a VR headset. As previously described, the provided auditory stimuli can be modulated at a target stimulus frequency. In various embodiments, both visual and auditory stimuli can be provided at a target frequency and synchronized.

[0112] On the other hand, for sensory stimulation to be successful in producing neural entrainment, the rate at which the stimuli (e.g., visual and / or auditory stimuli) are presented (e.g., flicker rate) should typically be stable, while the patient's attention should typically be focused on the stimuli. According to various embodiments, the system can act to enhance such a patient's focus.

[0113] To improve the patient's focus on the provided visual stimuli, the system may act to determine whether the patient is paying attention to the visual stimuli. According to various embodiments, an eye-tracking system may be used. The eye-tracking system may be integrated into a VR headset. The eye-tracking system may assess the patient's level of visual attention to the visual stimuli (e.g., the flickering of a particular object in the VR environment). Furthermore, feedback regarding the level of visual attention may be provided to the patient.

[0114] The eye-tracking system may allow for the determination of the coordinates (e.g., exact gaze coordinates) of the patient's gaze. In this way, the system may know whether the patient is looking at a portion of the VR environment that displays a visual stimulus (e.g., a flicker). In various embodiments, the eye-tracking system may also determine whether the patient's eyes are open, which is an important factor in ensuring that the visual stimulus is perceived by the patient to an extent that sufficient neural entrainment can occur.

[0115] For example, if the eye tracking system determines that a patient's eyes are closed, it may display a message on the VR headset screen and / or play an audio message asking the patient to open their eyes. As another example, if the eye tracking system determines that 1) the patient's eyes are open, but 2) the eye gaze is directed toward coordinates that do not correspond to the location where a visual stimulus is being delivered (e.g., delivered for a particular period of time), an action may be taken. The action may include providing the patient with a visual (e.g., text) or audio feedback message within the VR environment. The feedback message may direct the patient's attention to the visual stimulus. For example, the feedback message may characterize the visual stimulus as "a portion of the VR environment that flickers" or by using similar language. As another example, the action may include a change in the VR environment and / or a change in the visual stimulus (e.g., a change in the VR object adjusting its brightness). As an example, suppose the VR environment includes a white triangular object that flickers (e.g., flickers at 40 Hz). Continuing with this example, if the patient is not directing their visual attention to this triangle, a glowing feature (or other feature) may be drawn around the triangle to direct the patient's attention to the triangle. In various embodiments, continuous attention feedback (e.g., a cursor displayed on top of or to one side of the VR environment) may be provided to the patient.

[0116] Changes in alpha (e.g., 8-12 Hz) synchronization (e.g., observed as power changes) are thought to affect or reflect the application of visual attention to different aspects of visual stimuli. In particular, the relationship between alpha power and visual attention is clearly inverse. More specifically, when a person's attention is actively focused on a visual task, alpha power tends to decrease in the occipital and parietal cortices, the former areas responsible for processing visual information, and the latter areas responsible for spatial processing and attentional orientation.

[0117] Thus, according to various embodiments, when an eye tracking system is utilized to determine whether a patient's eye gaze is directed toward a visual stimulus, additional operations may be performed. According to these additional operations, the system may analyze EEG data received from an EEG sensor that receives signals from the occipital and / or parietal regions of the patient's brain. In this manner, the system may assess the patient's level of attention to the visual stimulus toward which the patient's eye gaze is directed.

[0118] For example, if an eye tracking system determines that a patient's eye gaze is directed toward a given visual stimulus, it can record occipital and / or parietal nerve activity during the sensory stimulation. The identified alpha fluctuations (e.g., fluctuations in alpha power) can then be used as a proxy for visual attention. For example, using a) a power threshold for alpha activity recorded during the stimulation period and / or b) a change in alpha power compared to one or more periods immediately prior to the onset of the stimulation, the system can assess whether the level of attention to the visual stimulus is satisfactory. If the system determines that the level of attention is not satisfactory, it can take action. For example, within a VR environment, the patient can be provided with a visual or text message directing the patient to pay more attention to the visual stimulus.

[0119] It has been found that there is a correlation between pupil dilation and cognitive processes such as auditory memory load and auditory processing demands in improving a patient's attention to presented auditory stimuli. Thus, according to various embodiments, a system may use a pupillometry approach to measure pupil dilation during presentation of auditory stimuli to assess a patient's attention to the auditory stimuli. For example, an eye-tracking system may be used to measure such pupil dilation.

[0120] The system may use the identified pupil dilation measurement information to provide a measure of treatment efficacy. For example, the system may measure the patient's baseline pupil diameter when the patient is not concentrating on an auditory stimulus (or not concentrating on an auditory task). The system may then interpret a recurrence of this baseline pupil diameter (or a similar pupil diameter) as indicating that the patient is not concentrating on a subsequent auditory stimulus (or auditory task). The system may interpret this state of not concentrating as a decrease in task engagement, which in turn indicates a decrease in predicted neural entrainment and, therefore, a decrease in clinical benefit.

[0121] Furthermore, the system may provide feedback to the patient within the VR environment based on this lack of focus. For example, the feedback may encourage the patient to focus on the stimuli, such as by adding an item to the stimulation protocol (e.g., a break from the stimulation environment and performing a breathing task). As another example, the feedback may alter the VR environment in which auditory stimuli are being delivered. In particular, this alteration may serve to increase the patient's enjoyment and motivation, thus increasing attention to the task at hand. By way of example only, the patient may be provided with an icon within the VR environment prompting the patient to pay more attention to the auditory stimuli in order to earn a higher score on a gamified stimulation task. Generally, the described approach of assessing attention to auditory stimuli using pupillometry is used in sensory stimulation protocols in which only auditory stimuli are delivered. This is because brightness fluctuations corresponding to the provided visual stimuli (e.g., modulated flashes of light) may affect the impact pupil diameter and thus adversely affect the auditory-evoked pupil response approach.

[0122] As previously described, according to various embodiments, different health-related scores are collected, and the scores are primarily measured digitally and non-invasively. By way of example only, such scores may include physiological measurements (e.g., heart rate and body temperature), arousal measurements (e.g., saccade velocity, pupil dilation, and eye blink velocity measurements), motor function, and cognitive scores (e.g., measuring performance through cognitive tasks performed through a VR headset). Such motor function measurements may involve, for example, a smartwatch containing an accelerometer and gyroscope. Data collection from the accelerometer and gyroscope may, for example, be synchronized with a motor task displayed on a VR headset to record the tremor level of a patient with essential tremor during specific movements.

[0123] The functionality described herein is comprehensive and encompasses not only treating neurological disorders but also tracking disease progression and assessing treatment efficacy. These three aspects may be operationally related. For example, a cognitive task may be provided to a cognitively impaired patient along with the delivery of 40 Hz audiovisual stimuli. Such actions may serve to 1) treat the patient's neurological disorder, 2) collect cognitive scores on that same task over time to track disease progression, and 3) assess treatment efficacy (e.g., with respect to sharing corresponding scores with medical team members).

[0124] By way of example only, health scores that may be collected by the functionality described herein include behavioral scores, neurological scores, and scores related to tracking motor function.

[0125] As for behavioral scores, by way of example only, such scores may be obtained from the following tasks: a) free recall task, b) cued recall task, c) working memory task, d) spatial memory task, e) episodic memory task, f) associative memory task, g) semantic memory task, h) procedural memory task, i) source memory task, j) implicit memory task, k) prospective memory task, and l) pattern recognition task. Here, associative memory decline may be a significant indicator of cognitive decline in Alzheimer's disease patients. Typically, an associative memory task, involving pairing visual and auditory stimuli during encoding and subsequent recall testing, produces an associative memory score (e.g., percent correct). This score may be monitored longitudinally, thereby serving as a proxy for tracking disease progression. Performance trajectories on associative memory tasks may serve as a measure of associative memory decline. When combined with other assessment scores and clinical information, this may provide a comprehensive overview of a patient's evolving disease status. According to various embodiments, functional abilities other than memory may be scored with or without providing stimuli during the scoring process.

[0126] For neural scores, different neural oscillations (e.g., brain activity collected at specific frequencies via EEG sensors) may be correlated (and in some cases coincidentally associated) with different aspects of memory formation and retrieval. Examples include: a) oscillations in theta, alpha, and gamma bands, as well as coupling between theta and gamma oscillations, during wakefulness; and b) slow oscillations, alpha oscillations, and ripple waves during sleep.

[0127] Therefore, the functions described herein can include longitudinal recording of neural activity during different memory tasks to monitor disease progression. Typically, such functions are used in a patient-specific manner, since subject-to-subject variations in neural activity levels are observed. For example, the technique of extracting intrinsic electroencephalograms through visual grid stimulation described above can be used to extract gamma frequencies from patients.

[0128] Gamma oscillations may be linked to a wide range of sensory and higher cognitive functions, such as attention, perception, and memory formation. Two deficiencies, particularly those associated with Alzheimer's disease, are reduced gamma oscillation power and cognitive impairment. This observation is replicated using grating stimulation, where reduced intrinsic EEG gamma power can be observed in cognitively impaired patients (e.g., patients with mild cognitive impairment and / or Alzheimer's disease) compared to age-matched controls. According to various embodiments, the level of intrinsic EEG gamma produced by visual grating stimulation can be assessed longitudinally to track the progression of a patient's cognitive impairment. Techniques employed to calculate the power of intrinsic EEG gamma oscillations may include, by way of example only, power spectral density, Morlet wavelet analysis, and Fourier transform. Furthermore, neural scores can be devised at different frequencies (e.g., theta-gamma and cross-frequency coupling between theta and gamma) based on various neural signal processing methods (e.g., amplitude, power, and phase analysis). As previously mentioned, in various embodiments, scores related to motor function may be ascertained, where different oscillations may be advantageous, for example, in the case of Parkinson's disease, it may be advantageous to track the evolution of beta and gamma oscillations during periods of rest and motor tasks.

[0129] According to various embodiments, a theta-gamma scoring system may be employed. Theta-gamma cross-frequency coupling has been shown to be impaired in cognitively impaired patients with dementia or mild cognitive impairment (MCI) compared to healthy individuals of the same age group. The strength of this coupling has also been shown to correlate with cognitive performance (e.g., working memory). In particular, increases in theta or decreases in gamma, individually, are associated with cognitive decline.

[0130] According to the functionality described herein, the theta-gamma ratio can be used as 1) an early marker of disease, 2) a risk marker, and / or 3) a marker of disease progression. Alone or in conjunction with other biomarkers (e.g., heart rate, pupillometry, and / or proteins such as amyloid-beta), the theta-gamma ratio can generate health and disease progression scores indicative of treatment efficacy. As one example, the theta-gamma ratio can be calculated by quantifying the relative power at frequency peaks in both the theta and gamma ranges during a resting EEG session. As another example, the theta-gamma ratio can be calculated based on cross-frequency phase-amplitude coupling (PAC) and phase synchronization (e.g., including power, intensity, and / or onset measurements).

[0131] By way of example only, a baseline ratio score may be established by measuring and quantifying the ratio for a cohort of healthy individuals aged 50 to 85 years, divided into five-year age groups. A linear assessment of the ratio's evolution may correspond to the normal evolution of the ratio in healthy individuals without markers of Alzheimer's disease or MCI. The patient's ratio may then be compared to this linear evolution. A difference may then be extracted from the comparison to quantify the level of disease progression. While the ratio naturally increases with normal aging, this increase is amplified in Alzheimer's disease and MCI patients. This amplification or difference may be quantified to determine the theta-gamma score. Referring to FIG. 6, the relationship between ratio and age is shown for Alzheimer's disease patients 601, MCI patients 603, and healthy individuals 605.

[0132] According to a first use case, the ratio may be used as a risk factor measure for asymptomatic progression of MCI or Alzheimer's disease, either independently or in combination with prodromal disease biomarkers (e.g., cerebrospinal fluid (CSF), genetic profiles (such as APOE4), and other blood biomarkers such as proteins. According to a second use case, the ratio may be used as a biomarker, e.g., along with other biomarkers, as part of a clinical diagnosis. Then, according to a third use case, the ratio may be used as a biomarker of disease progression in conjunction with a treatment protocol, such as sensory stimulation delivered via a VR headset as described herein.

[0133] The evolution of the theta-gamma score can be determined via a number of approaches. According to a first exemplary approach, the patient's ratio can be compared to a reference value. According to a second exemplary approach, the patient's ratio can be compared to both a) the patient's own ratio over time and b) the theoretical evolution of the ratio over time determined by a predictive algorithm for individuals consistent with the patient's condition (e.g., Alzheimer's disease or MCI). Consequently, two parameters can serve as 1) the evolution relative to an untreated individual and 2) the evolution relative to the user's own ratio. This metric, referred to as deviation from the curve, can correspond to the treatment effect. Referring to FIG. 7, the relationship between ratio and age is shown for an untreated Alzheimer's patient 701, an untreated MCI patient 703, a healthy individual 705, and a treated Alzheimer's patient 707. Such a treatment can be sensory stimulation provided via the VR headset described herein.

[0134] As reflected in Figure 7, sensory stimulation provided via the VR headset can have a beneficial effect on the ratio. For example, in Figure 7, compare line 701 for Alzheimer's disease patients not receiving sensory stimulation treatment with line 707 for Alzheimer's disease patients receiving sensory stimulation treatment. As shown, at least for patients about 70 years of age or older, line 707 for Alzheimer's disease patients receiving sensory stimulation treatment is closer to line 705 for healthy individuals than line 701 for patients not receiving sensory stimulation treatment.

[0135] The delivery of sensory stimuli (e.g., visual and auditory stimuli) can affect endogenous brain waves through long-term potentiation neuroplasticity. For example, the delivery of stimuli in the theta and gamma ranges (e.g., a combination of 4Hz and 40Hz) can have an effect on the evolution of the ratio compared to patients who do not receive treatment. Therefore, this ratio evolution can be used to provide patients, medical teams, etc. with a progress score that directly reflects the impact of the delivered sensory stimuli on the patient's electrical brain activity.

[0136] According to various embodiments, the system software may perform various monitoring operations. These monitoring operations include, by way of example only, monitoring device availability (e.g., to ensure stability and reliability of treatment) and monitoring hardware / firmware performance. Based on this monitoring, the system software operations may be optimized and updated. In this manner, benefits may arise, including improved treatment efficacy.

[0137] The systems described herein can be used by patients suffering from neurodegenerative disorders at home without medical supervision. The system software can include instructions and tutorials to guide patients on how to use the system (e.g., a VR headset) and how to behave while stimuli are being delivered. Additionally, the system software can assess whether the patient is following the provided instructions.

[0138] As just a few examples, these usage instructions may a) require the patient to sit in a quiet place while using the system, b) require the patient to use any prescribed corrective lenses (e.g., glasses) while using the system, and c) require the patient to perform various maintenance actions between sessions, such as charging the system's VR headset.

[0139] By executing these usage instructions, the system may improve the functionality of the system's software and may also enhance the user's interaction with the system. Execution of the usage instructions by the system may use, by way of example only, sensors integrated with the VR headset (e.g., a patient-facing camera) and analysis of various software, hardware, and firmware logs (e.g., to monitor battery levels during certain sections). Furthermore, execution of the usage instructions by the system may be performed in compliance with applicable privacy regulations.

[0140] According to various embodiments, the system can be used as a combination of therapeutic elements. Because the etiology of Alzheimer's disease is multifactorial, using multiple therapeutic interventions that address several molecular targets of Alzheimer's disease-related pathology can be a useful approach to altering disease progression. It has been shown that the clinical efficacy of combination therapy can be higher than that of monotherapy.

[0141] Typically, combination therapy involves the use of multiple drugs. However, by incorporating the systems described herein, different types of combination therapy can emerge: Combination therapy, utilizing one or more pharmaceutical agents on the one hand and a digital therapeutic in the form of the system described herein on the other, has the potential to enhance the benefits of pharmaceutical agents throughout the entire process, from development through commercial use and post-marketing surveillance.

[0142] The synergistic effects of the sensory stimulation and pharmacological interventions described herein not only enhance patient outcomes by targeting multiple targets, but also have the potential to a) monitor disease progression (e.g., using neural and cognitive biomarkers), b) increase engagement through the VR environments described herein, and c) collect real-world data to assess drug safety and enable decentralized clinical trials. The descriptions of combination therapies, including those described above, have generally focused on the treatment of Alzheimer's disease. However, such combination therapies may also be used to treat other conditions.

[0143] The deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain are hallmarks of Alzheimer's disease. In addition to this molecular pathology, disruption of the amplitude or synchronization of gamma-band oscillations further contributes to cognitive decline in Alzheimer's disease.

[0144] Previous approaches to treating Alzheimer's disease have typically focused on reducing Aβ plaque accumulation. However, the sensory stimulation approach described herein offers an alternative approach, resulting in effects on both neuroimmune mechanisms and gamma wave activity. Neuroimmune responses have been measured in humans as modulation of cytokines and immune factors in the CSF of prodromal AD patients. Neuronal entrainment and, subsequently, increased gamma wave activity can be observed in humans in at least the visual cortex, prefrontal cortex, and deeper structures such as the hippocampus. By eliciting a neuroimmune response and generating neural entrainment, the sensory stimulation described herein offers a multifaceted approach that may slow neurodegeneration measured in humans, for example, by reducing hippocampal atrophy, reducing ventricular enlargement, enhancing default mode network connectivity, improving sleep quality, and maintaining daytime activity as assessed by the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale.

[0145] Thus, integrating the sensory stimuli described herein with pharmacological interventions provides a comprehensive approach that targets multiple aspects of the multiple molecular pathologies involved in Alzheimer's disease, ultimately enhancing patient outcomes. This holistic strategy may therefore be advantageous in combating the devastating effects of Alzheimer's disease. Furthermore, the sensory stimuli described herein, when applied alone, may prove beneficial for conditions including, but not limited to, Alzheimer's disease.

[0146] The systems described herein (including sensors such as EEG and ECG), in conjunction with the cognitive tasks described above in VR, can identify new neurocognitive biomarkers for early diagnosis of neurological disorders and enable ongoing disease monitoring. Such information can be used, by way of example only, to a) more effectively assess or predict drug response and b) adjust medication dosage and treatment schedules to maximize treatment benefit, minimize side effects, and enable optimal patient stratification. Regarding engagement, patients with cognitive disorders have been found to typically prefer VR environments over non-VR environments, as measured by at least improvements in mood and apathy in cohorts participating in immersive cognitive training and tasks. Thus, the systems described herein can promote active patient engagement through immersive VR experiences, cognitive tasks, treatment guidance, and access to autobiographical memories through reminiscence, by way of example only. The interactivity of the system can encourage patients to actively participate in their treatment, thereby promoting compliance with sensory (e.g., audiovisual) stimuli and any medications provided to patients as part of a combination therapy approach. Furthermore, the system can be used at home without requiring supervision by a medical professional, and patients using the system may experience a sense of control over their health improvement.

[0147] Additionally, various capabilities of the system, including but not limited to sensors (e.g., EEG and ECG sensors), may enable the system to collect real-world evidence. The collected real-world evidence may be used in many ways, for example, to facilitate the defense of safety claims related to drug profiles. Furthermore, the remote monitoring capabilities of the system may provide advantages, including but not limited to, providing pharmaceutical companies with the opportunity to decentralize clinical trials. Such decentralization is consistent with recent developments such as, for example, Medicare's decision to cover drugs based on real-world efficacy data.

[0148] According to various embodiments, the VR headset can include indicator lights that can enhance the patient experience through interaction and providing useful information. Additionally, in various embodiments, the VR headset can be connected to a charger or directly to an AC power source for charging.

[0149] The user interface of the VR headset is represented, at least in part, through the indicator lights, which may be located, by way of example only, on the top side of the VR headset. The indicator lights may serve as visual cues to communicate various device statuses and interactions with the VR headset, thereby enhancing a patient's engagement with the VR headset.

[0150] The indicator light may be constructed, by way of example only, from red, green, and blue (RGB) light-emitting diodes (LEDs). The LEDs may be coordinated to create the illusion of a continuous, uniform band of light. This design choice may provide the advantage that the indicator light is not only functional but also aesthetically pleasing.

[0151] To facilitate user interaction, the indicator lights may be synchronized with, by way of example only, either proximity sensors or touch sensors discretely located on the upper region of the headset. The proximity sensors serve to detect the patient's presence, thereby enabling automatic device activation. When the VR headset is activated, the indicator lights may also be illuminated, thereby signaling the device's operating status to the patient.

[0152] In various embodiments, the indicator light may remain discretely hidden within the housing of the VR headset when in an inactive state, thus maintaining the sleek and unobtrusive appearance of the VR headset. Then, when the VR headset is activated, the indicator light may emit a discernible and informative light through the housing. The indicator light may be used to communicate various device states to the user. Some exemplary device states include the following states: Device Operation: When the VR headset is turned on, according to various embodiments, the indicator light may change to a bright white hue and then gradually increase in brightness, creating an elegant, smooth, linear fade effect.

[0153] Pairing Mode: For embodiments that support pairing, when the VR headset is ready to be paired with another device, by way of example only, the indicator light may change to a subdued blue hue and exhibit a gradual fading brightness, which may provide benefits including further enhancing the patient's understanding of the status of the VR headset.

[0154] Medical Alerts (e.g., Seizure Detection): In various embodiments, upon detection of a critical condition, such as a patient experiencing a seizure, the indicator light may shift to a conspicuous red color and begin a pulsing pattern. In this manner, the indicator light may immediately attract attention (e.g., to a medical team member or caregiver) and communicate the urgency of the situation.

[0155] Low Battery: To alert the patient to a low battery condition, according to various embodiments, the indicator light may change to a vivid orange hue and employ a dynamic linear fade effect to draw attention to the need for charging.

[0156] Further Device Status: Depending on the particular use case and requirements, the indicator light can be configured to convey the status of other devices and any interactions deemed necessary.

[0157] If the VR headset incorporates an auto-off feature, according to various embodiments, the indicator light may return to a subdued white hue and then gradually decrease in brightness from a noticeable linear effect to a smaller line, while ultimately fading completely. Further in this regard, in various embodiments, the VR headset may include an auto-off circuit that activates when the headset is removed and placed on a surface. This circuit may automatically power off the VR headset if it remains unused for an extended period of time (e.g., three minutes).

[0158] Thus, an indicator light system in a VR headset may provide benefits including enhancing patient interaction and understanding of the device's status, contributing to providing a more immersive and user-friendly VR experience.

[0159] An architectural diagram of an example use of the described system according to various embodiments is shown in Figure 8. According to the example of Figure 8, the system may include a wearable device 801 (such as the VR headset described above), a computing unit 803, a network unit 805, a first data repository 807, a second data repository 809, a classification / autonomous decision-making system 811, a request gateway 813, a patient database system 815, a mobile backend 817, and a tailored stimulus designer 819.

[0160] The computing unit 803 may include an encryption engine, a de-identification engine, a signal amplifier, and an analog-to-digital converter. In various embodiments, the computing unit 803 may also include a pre-processing module. The computing unit 803 may also include a memory unit, one or more processing units, a random access memory (RAM), a read-only memory (ROM), and a power source. The encryption engine may encrypt various data handled by the system, including patient-specific data. The de-identification engine may anonymize various data handled by the system, including patient-specific data. The signal amplifier may amplify various signals described herein, such as EEG signals. The analog-to-digital converter may digitize various signals described herein, such as EEG signals. The memory unit, processing unit, RAM, and ROM may be as described below. The network unit 805 may support various communication capabilities described herein, such as remote access by medical team members. The network portion 805 may include Internet of Things (IoT) capabilities, thereby enabling the system to act as an internet-connected data collector and / or be accessed via the internet, where such IoT may be implemented in a secure manner.

[0161] The classification / autonomous decision-making system 811 may perform various operations, including analyzing physiological data (e.g., EEG data) and selecting a stimulation protocol and / or VR scenario, as described herein. The adjusted stimulation designer 819 may perform various operations, including interfacing with the wearable device 801, as described herein, to implement the stimulation protocol and / or VR scenario selected by the classification / autonomous decision-making system 811. In various embodiments, communication between the classification / autonomous decision-making system 811 and the adjusted stimulation designer 819 may include instant notification and / or time synchronization, thereby supporting functionality including real-time control of the stimulation and VR environment.

[0162] The mobile backend 817 may include patient electronic reporting capabilities, account management capabilities, treatment selection capabilities, and analytics capabilities. In various embodiments, the mobile backend 817 may also include signal processing capabilities. The mobile backend 817 may provide functionality including enabling medical team members to access patient progress reports, manage patient accounts, make treatment selections, and access generated analytics data (e.g., health and disease progress scores as described herein). The patient database system 815 may store various patient data (e.g., patient progress reports and health scores) as described herein. The first data repository 807 and the second data repository 809 may store various data collected and generated by the system, such as collected sensor data (e.g., EEG data) and data corresponding to the selection and / or generation of stimulation protocols and / or VR scenarios. The request gateway 813 may perform various intermediary operations, including access control, between the patient database system 815 and other system elements (e.g., the classification / autonomous decision-making system 811).

[0163] 9 is a schematic diagram illustrating various capabilities of the system described herein. As shown in FIG. 9, the capabilities may include a sensory stimulus delivery capability 901, a physiological response measurement capability 903, a stimulus adjustment capability 905, a digital brain clinic capability 907, and a risk state identification capability 909.

[0164] The sensory stimulation delivery capabilities 901 may include passive stimulation, in which no task is provided to the patient, and active stimulation, in which a task is given to the patient as described herein. Both passive and active stimulation may include partial adjustment of the VR environment (e.g., one or more VR objects flicker at a target frequency) or complete adjustment of the VR environment (e.g., the entire VR environment flickers at a target frequency). The physiological response measurement capabilities 903 may include measurement of neural response, cardiac response, eye response, muscle response, and skin response. The stimulation adjustment capabilities 905 may include stimulation parameter adjustment to optimize neural entrainment and improve health scores. Such stimulation parameters may include waveform, onset, frequency, and intensity (e.g., illuminance, color, and volume).

[0165] The digital brain clinic capability 907 may enable the system to interface with devices such as personal computers, tablets, and smartphones. In particular, the digital brain clinic capability 907 may provide access / sharing of patient data, disease progression tracking, and disease treatment management by medical team members and caregivers. In various embodiments, the digital brain clinic capability 907 may provide secure local storage of patient data on devices such as those described. The risk state characterization capability 909 may include measuring the patient's physiological response (e.g., neural response) and then executing an epileptiform activity recognition algorithm. Based on the execution of the epileptiform activity recognition algorithm, epileptiform activity may be identified or not identified. If epileptiform activity is identified, action may be taken, such as discontinuing stimulation (or adjusting stimulation frequency) (911) and sending an alert to caregivers and medical team members (913). The risk state identification capability 909 may also implement the stress state alert function previously described.

[0166] Further, with reference to FIG. 9 and the description herein thus far, further operations may include identifying optimal stimulation parameters (915) and determining visual attention levels (917). Further, with reference to FIG. 9 and the description herein thus far, operations may also include monitoring device usability (919), conducting cognitive and physiological measurements (921), and calculating cognitive and physiological scores (923). Further, with reference to FIG. 9 and the description herein thus far, operations may also include monitoring hardware / firmware performance (e.g., to ensure stability and reliability of therapy) (925) and optimizing / updating the system's software (e.g., to ensure stability and reliability of therapy) (927). Further, with reference to FIG. 9 , in various embodiments, other than sensory stimulation, further synchronized neural stimulation techniques may be provided to the patient (929). These further techniques may include tACS, tDCS, and TMS.

[0167] Further, referring to FIG. 9, the system's functionality may include an open-loop stimulation protocol function (928), a closed-loop stimulation protocol function (931), a data storage strategy function (933), an improved concentration strategy function (935), a risk mitigation strategy function (937), and a product optimization feedback function (939).

[0168] 10A-10H show various views of an exemplary use of a VR headset in accordance with various embodiments. In particular, FIG. 10A shows a left side view 1001 of the VR headset, FIG. 10B shows a right side view 1003 of the VR headset, FIG. 10C shows a top view 1005 of the VR headset, FIG. 10D shows a bottom view 1007 of the VR headset, and FIG. 10E shows a rear view 1009 of the VR headset. Furthermore, FIG. 10F shows an outer perspective view 1011 of the VR headset, FIG. 10G shows an inner perspective view 1013 of the VR headset, and FIG. 10H shows a rear view 1014 of the VR headset. These figures also show various VR headset elements, including a headband 1017, headband adjustments 1019, indicator lights 1021, a screen 1023, and sensors (e.g., EEG sensors) 1025.

[0169] Hardware and Software According to various embodiments, the various functions described herein may be performed by and / or with the aid of one or more computers. Such computers may be and / or incorporate, as just a few examples, personal computers, servers, smartphones, systems-on-chips, and / or microcontrollers. Such computers may, in various embodiments, run Linux, MacOS, Windows, or other operating systems.

[0170] Such a computer may be and / or incorporate one or more processing units operatively connected to one or more memory or storage units, where the memory or storage units contain data, algorithms, and / or program code, and the processing unit or units may execute and / or manipulate the program code, data, and / or algorithms. Figure 11 illustrates an exemplary computer that may be employed in various embodiments of the present invention. The exemplary computer 1101 includes a system bus 1103 operatively connecting two processing units 1105, 1107, a random access memory (RAM) 1109, a read-only memory (ROM) 1111, input / output (I / O) interfaces 1113, 1115, a storage interface 1117, and a display interface 1119. The storage interface 1117 is in turn connected to a mass storage device 1121. Each I / O interface 1113, 1115 may be, by way of example only, Universal Serial Bus (USB), Thunderbolt, Ethernet, Bluetooth, Long Term Evolution (LTE), 5G, IEEE 488, and / or other interfaces. Mass storage device 1121 may be, by way of possible examples only, a flash drive, a hard drive, an optical drive, or a memory chip. Each processing unit 1105, 1107 may be a well-known processing unit, such as an ARM-based or x86-based processing unit, by way of example only. Computer 1101, in various embodiments, may include or be connected to a touchscreen, a mouse, and / or a keyboard. Additionally, computer 1101 may include or be attached to a card reader, DVD drive, floppy disk drive, hard drive, memory card, ROM, etc., whereby media containing program code (e.g., for performing various operations and / or the operations described herein) may be inserted for loading the code into the computer.

[0171] According to various embodiments of the present invention, a computer may execute one or more software modules designed to perform one or more of the above operations. Such modules may be programmed using, for example, Python, Java, JavaScript, Swift, C, C++, C#, and / or other languages. Corresponding program code may be stored on a medium such as, for example, a DVD, CD-ROM, memory card, and / or floppy disk. While an arbitrary division of operations among particular software modules has been shown, this is for illustrative purposes only, and other divisions of operations may be employed. Thus, any operation shown to be performed by one software module may instead be performed by multiple software modules. Similarly, any operation shown to be performed by multiple modules may instead be performed by a single module. Operations shown to be performed by a particular computer may instead be performed by multiple computers. Furthermore, various embodiments may employ peer-to-peer and / or grid computing technologies. Furthermore, various embodiments may employ remote communication between software modules. Such remote communications may include, for example, JavaScript Object Notation-Remote Procedure Call (JSON-RPC), Simple Object Access Protocol (SOAP), Java Messaging Service (JMS), Remote Method Invocation (RMI), Remote Procedure Call (RPC), sockets, and / or pipes.

[0172] Furthermore, in various embodiments, the functionality described herein may be implemented using application-specific circuitry, such as via one or more integrated circuits, application-specific integrated circuits (ASICs), or field-programmable gate arrays (FPGAs). In various embodiments, a hardware description language (HDL) may be employed to illustrate the functionality described herein. Such an HDL may be Verilog or Very High Speed ​​Integrated Circuit Hardware Description Language (VHDL), as just a few examples. More generally, various embodiments may be implemented using hardwired circuitry, with or without software instructions. Thus, the functionality described herein is not limited to any specific combination of hardware circuitry and software, nor to any particular source of instructions executed by a data processing system. [Explanation of symbols]

[0173] Library of 201 stimulation protocols Library of 203 VR scenarios 205 VR headset 207 Physiological Recording Module 209 Physiological Response Processing Module

Claims

1. 1. A computer-implemented method comprising: providing, by a computing system, the stimulation protocol via a virtual reality headset; providing, by the computing system, a virtual reality scenario via the virtual reality headset; receiving, by the computing system, patient physiological data from one or more sensors; adapting, by the computing system, one or both of the stimulation protocol or the virtual reality scenario using the patient physiological data; A method comprising:

2. The computer-implemented method of claim 1 , wherein the patient physiological data includes patient brain activity data.

3. 10. The computer-based method of claim 1, wherein the provided stimulus protocol includes one or both of visual and auditory stimuli.

4. 10. The computer-based method of claim 1, wherein the provided stimulation protocol includes one or more of 4 Hz stimulation, 40 Hz stimulation, combined 4 Hz / 40 Hz stimulation, beta range stimulation, or alpha range stimulation.

5. receiving, by the computing system, patient brain activity data from one or more sensors collected while the patient is performing a task that elicits an electroencephalographic state of interest; identifying, by said computer system, from said received brain activity data, patient-specific frequency values ​​corresponding to said electroencephalographic state of interest; The computer-implemented method of claim 1 further comprising:

6. 6. The computer-implemented method of claim 5, wherein the electroencephalogram state of interest is beta, alpha, theta, or gamma.

7. detecting, by said computing system, abnormal neural activity from said received patient physiological data; stopping, by the computing system, one or both of the provided stimulus protocol or the provided virtual reality scenario. The computer-implemented method of claim 1 further comprising:

8. The computer-implemented method of claim 1 , wherein the provided virtual reality scenario comprises one or more of a cognitive task, a functional task, or a gamified task.

9. determining, by the computing system, a score based on the patient's performance of the task; The computer-implemented method of claim 8 further comprising:

10. 10. The computer-implemented method of claim 1, wherein the steps of providing the stimulation protocol and providing the virtual reality scenario are performed as a therapy in combination with the administration of one or more pharmaceutical agents.

11. determining, by the computing system, whether the patient's attention is directed to the visual stimuli of the provided virtual reality scenario using an eye tracking system; providing, by the computing system via the virtual reality headset, patient feedback regarding the attentiveness determination; The computer-implemented method of claim 1 further comprising:

12. the stimulation protocol includes a visual stimulus; providing the stimulation protocol includes: adjusting the presentation of the displayed content within the VR environment; Coordinating the provision of a frame within the VR environment, the frame being positioned around the displayed content; or adjusting the presentation of at least one object within the VR environment. including one or more 10. The computer-implemented method of claim 1, wherein the adjustment is made at a target frequency.

13. providing remote access by said computing system; Further including, 10. The computer-implemented method of claim 1, wherein the remote access allows for one or both of access to patient progress reports and selection of patient treatment options.

14. In the system, At least one processing unit; a memory storing instructions that, when executed by said at least one processing unit, cause said system to perform the computer-implemented method of claim 1; A system including:

15. In a non-transitory computer-readable storage medium, instructions that, when executed by at least one processing unit of a computing system, cause the computing system to perform the computer-implemented method of claim 1; a non-transitory computer-readable storage medium comprising:

Images