Method and Apparatus for a Wearable Device for Closed-Loop Transcranial Photobiomodulation Stimulation with Cognitive Testing

Abstract

Devices and methods for stimulation and modulation of brain activity using transcranial photobiomodulation (PBM) or electroencephalogram or heart rate variability (HRV) biofeedback, and devices and methods for analyzing and monitoring evoked electroencephalogram (EEG) electrical activity before and / or after neurocognitive testing using event-related potentials (ERP) and evoked and stimulated EEG oscillations (ERO) measurements in a human user. Electroencephalography (EEG) and photobiomodulation (PBM) devices in the form of wearable devices with headphones for stimulating the brain with PBM or using biofeedback training with simultaneous EEG monitoring, as well as a description of a method for testing a person's cognitive and physiological state during cognitive testing using the provided devices, are described. PBM light is pulsed to stimulate an increase in target brain activity by providing additional energy to mitochondria and activating other photosensitive brain processes. PBM stimulation is combined with an EEG sensor to detect EEG responses during cognitive testing using event-related potentials (ERP) and evoked and stimulated EEG oscillations (ERO) for the assessment of the user's cognitive state and treatment of functional outcomes.

Description

[Technical field]

[0001] Previous related applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 313,625, filed February 23, 2022.

[0002] The present invention relates to devices and methods for stimulating, monitoring, and analyzing electrical activity generated by a person's brain. Specifically, the present invention provides electroencephalography (EEG) and photobiomodulation (PBM) devices for monitoring and stimulating electrical activity generated by a person's brain during cognitive testing. Methods for stimulating a person's cognitive and physiological states using the provided PBM devices or biofeedback methods, as well as methods for assessing electrocortical responses using EEG and event-related potential (ERP) responses and EEG oscillations (ERO) evoked during executive function testing, are also described. The present invention provides continuous or pulsed PBM light to stimulate increased brain activity, provide additional energy to mitochondria, and enhance cognitive function assessed with EEG sensors and cognitive testing. [Background technology]

[0003] Transcranial neurostimulation is the deliberate modulation of central nervous system activity. Traditionally, this has been done by transcranial electrical or magnetic stimulation, including but not limited to, via transcranial alternating current stimulation (tES), transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), or pulsed electromagnetic field stimulation (pEMF). Another method of transcranial neurostimulation is photobiomodulation (PBM), which uses non-ionizing light energy to generate photochemical changes within cortical cellular structures, typically mitochondria. This technique has primarily been used to reduce pain and inflammation and speed the healing process of damaged tissues.

[0004] Photobiomodulation has been shown to photostimulate brain cytochrome c oxidase activity and activate other light-sensitive chemical processes in the brain. Current data showed that photons in the 600 nm to 1,100 nm wavelength range are absorbed by cytochrome c oxidase and increase the activity of the mitochondrial respiratory chain, resulting in increased adenosine triphosphate (ATP) production. Transcranial PBM in the near-infrared range also alters nitric oxide (NO) levels, while near-infrared PBM modulates reactive oxygen species (ROS) and reactive nitrogen species, resulting in increased energy processes in mitochondria. Modulation of the expression of numerous genes in both mitochondria and brain cells occurs (Hamblin, 2016).

[0005] Transcranial photobiomodulation (tPBM) has been shown in numerous clinical studies as a safe, side-effect-free, non-invasive neuromodulation method for symptom relief in various neurological and psychiatric conditions. Several studies have reported cognitive enhancement resulting from tPBM, for example, Saltmarche et al. (2017) reported significant improvement in cognition in mild to moderate dementia cases. De la Torre et al. (2020) reviewed the effects of reduced energy supply in the aging brain and provided a rationale for tPBM therapy for mild cognitive impairment (MCI), as well as several neurological conditions including Parkinson's disease, depression, traumatic brain injury, and stroke. The review describes studies showing that tPBM enhances neuronal metabolism, resulting in anti-inflammation, anti-apoptosis, antioxidant response, neurogenesis, and synaptogenesis. The applications and usefulness of tPBM are not limited to only neurological and psychiatric conditions. Blanco et al. (2017) applied laser stimulation to the prefrontal cortex and found that prefrontal rule-based learning was substantially improved after transcranial infrared laser stimulation in healthy participants. El Khoury et al. (2019) investigated whether tPBM could modulate brain activity in young adults using fMRI (functional magnetic resonance imaging). fMRI findings showed that tPBM influenced brain activity, but only if the cortical area was functionally active during the performance of the task. Vargas et al. (2017) described beneficial neurocognitive effects of tPBM in older adults during the performance of attention (psychomotor vigilance task) and memory (delayed match-to-sample task) tests, recording EEG and fMRI effects. EEG and fMRI results showed that tPBM increased resting-state EEG alpha, beta, and gamma band power and enhanced more pronounced prefrontal BOLD-fMRI responses. Wang et al. (2019) demonstrated the effects of tPBM on EEG activity by using tPBM to modulate EEG measurements and recording the EEG before, during, and after application of continuous wave tPBM to the right frontal region of human subjects.Results showed that tPBM increased EEG power of alpha (8-13 Hz) and beta (13-30 Hz) rhythms across several scalp topographies. Berman & Nichols (2019) review the utility of transcranial PBM in combination with EEG biofeedback in the treatment of neurodegenerative disorders such as Alzheimer's and dementia.

[0006] U.S. Patent No. 10,987,521 by Chicchi describes a system and method for treating brain disorders using PBM therapy, alleging that treatments in Parkinson's disease, Alzheimer's disease, concussion, depression, stroke, and other brain diseases or brain injuries have shown dramatic improvements under such treatment protocols. U.S. Patent Application Publication No. 2009 / 0254154 and U.S. Patent Application Publication No. 2010 / 0204762 by De Taboada disclose devices and methods for indicating the location of treatment sites for phototherapy on the brain. In some embodiments, the device is a headpiece wearable by the patient. There are further patents describing portable wearable tPBM devices, many of which have been filed by Lim, including both transcranial and intranasal PBM devices (Australian Patent Application Publication No. 2015388475, WO 2019 / 053625). The described system also uses EEG as a technique to measure the brain's electrical activity in the delta, theta, alpha, beta, and gamma EEG bands, among other methods. U.S. Patent Application Publication No. 2019 / 0335551 by Williams et al. describes a PBM system for many users that includes capabilities such as multiple physiological monitoring biosensors (EEG, EMG, ECG, etc.).

[0007] Most directly relevant are a series of patents by Huang (US 2021 / 0001147, US 2021 / 0016103, US 10,821,298, US 2021 / 0023391) disclosing methods and apparatus for brain function enhancement that describe a system for transcranial optical biostimulation of a subject's brain. The patents present drawings from a pilot study in which EEG band changes using spectral analysis are presented during tPBM along with fMRI changes induced by tPBM. Additionally, the patents describe improvements in reaction time and accuracy in neurocognitive tests such as psychomotor vigilance and delayed match-to-sample tests. These patents describe cognitive enhancement following tPBM in older adults with results showing that tPBM increased EEG alpha, beta, and gamma, and that tPBM induced fMRI responses.

[0008] However, the prior art has no evidence of transcranial photobiomodulation utilized with event-related potentials (ERPs) recorded in cognitive testing, including any studies in which the effects of transcranial photobiomodulation are investigated in either clinical conditions or any patent disclosures. This represents a significant limitation of the prior art, as ERP techniques are one of the most informative methods of exploring and monitoring stages of information processing in the brain. Measurements such as the amplitude and latency of selected ERP waves recorded in specific topographies allow the analysis of high-level processing stages, including sensory and perceptual-related processes, as well as attention, cortical inhibition, memory updating, error monitoring, and other cognitive activities also referred to under the definition of executive function (Luck, 2014). ERPs not only provide a method of investigation of cognitive processes in typical individuals, but also provide a sensitive tool for assessing differences in patients with neurological and psychiatric disorders. Despite significant advances in functional brain imaging such as fMRI, ERP-based metrics still represent an important tool in neurology and psychiatry, as some neuropsychiatric disorders correlate with known changes in ERP patterns that can serve as valid biological neural markers for functional diagnosis or for a better understanding of cognitive dysfunction in psychiatric and neurological disorders.

[0009] Patents have been filed describing portable wearable devices with EEG and event-related potential (ERP) capabilities, including some with disclosed methods of ERP analysis and several cognitive tests with described ERP recordings. Among them is a wearable system that can analyze and evaluate a person's brain health by integrating the use of EEG and ERP metrics during cognitive testing. Such systems can provide early detection of neurological and psychiatric disorders such as mild cognitive impairment (MCI), dementia including Alzheimer's disease, and other dementia-type disorders, as well as brain injury conditions such as mild traumatic brain injury (mTBI). Some of these patents, for example, U.S. Pat. No. 9,675.292 and European Patent No. 2260760 by Fadem, describe ERP systems suitable for clinical use that include an integrated headset for performing evoked response (ERP) tests. Another patent, namely WO 2020 / 223397 by McLoughlin, describes a mental fitness assessment system in healthy individuals, claiming that EEG and ERP measurements are indicative of a person's emotional or cognitive state and allow assessment of a person's mental fitness state based on electrocortical metrics.

[0010] During the normal process of aging, humans may experience some degree of age-related cognitive decline (ARCD), resulting in increased difficulty in demanding situations and a decreased ability to focus attention under time pressure conditions. ARCD patients experience cognitive decline and reduced performance efficiency in tasks that require attention, short-term and long-term memory, fast motor reactions, rapid decision-making, and processing and understanding of situational demands. Testing with ERP and EEG oscillations (ERO) is known to be one of the best techniques for assessing the state of cognitive decline in both elderly and younger users with a predisposition to cognitive decline, or after a disease or disorder known to be associated with cognitive decline, such as concussion, TBI, or infection resulting in "brain fog" after the disease.

[0011] Other useful EEG measurements in cognitive testing are based on wavelet-based time-frequency analysis of EEG oscillations (EROs) in response to stimuli in cognitive testing. Further information on EEG time-frequency wavelet-based analysis, as well as EEG evoked and induced gamma oscillations (EROs), can be found in the publication by Tallon-Baudry & Bertrand (1999), which describes evoked and induced EEG gamma oscillations (30-100 Hz, the most usable gamma range is in the range of 35-45 Hz). This review focuses on the literature on gamma oscillatory activity in humans, describing different types of gamma responses and how to analyze them. The evidence presented by the researchers suggests that one particular type of gamma activity, specifically induced gamma oscillations, can be observed during the construction of object representations. This paper describes evoked and induced gamma EEG oscillations and their role.

[0012] Neural gamma band oscillations, together with other EEG band oscillations, can be recorded in different scalp topographies (as well as in cortical and subcortical regions) and can be evoked or induced by different stimuli or tasks, such as ERP design tests. Event-related oscillatory activity (ERO) in various frequency bands (e.g., delta, theta, alpha, etc.) reflects different aspects and stages of information processing. Alpha oscillatory responses increase in simple working memory tasks and decrease in demanding memory tasks. Beta oscillatory responses are important in attention-related tasks and in some emotion tests, such as the recognition of human facial expressions. Event-related theta oscillatory responses are thought to be related to memory processes.

[0013] Wavelet analysis is useful for single-trial analysis of EEG oscillations in rare responses, such as the immediate response-locked ERP that occurs after a committed error in a speeded cognitive task that requires a motor response. Clemans et al. (2012) reported that when response-locked ERPs were used as a measure of error processing, the error-related negativity (ERN) and error-related positivity (Pe) occurring after a committed error in a speeded reaction time test could be recorded in the form of low-frequency (4-8 Hz) EEG oscillations in midline frontal and fronto-central EEG sites. Error processing using time-frequency analysis in the form of wavelet transform is described as an alternative method to separate theta waveforms in the time-frequency domain and obtain single time-frequency correlations of ERN and Pe for each error trial. These results of the present study indicate that the proposed alternative single-trial time-frequency error analysis method is suitable for detecting error-related processes in both healthy subjects and patients with psychiatric disorders.

[0014] Davoudi et al. (2021) describe frequency-amplitude coupling as a new approach for decoding attention-related processes in cognitive tasks. The method is described in the patent as reflecting information processing in the brain and referring to inter-frequency coupling. Some EEG frequencies exhibit phase-amplitude coupling processes, for example, theta-gamma phase-amplitude coupling is commonly assumed to play an important role in perception, memory, and attention (Canolty et al., 2006; Koster et al., 2014).

[0015] The overview of the state of the art and current limitations related to the present invention indicates the technical needs that must be addressed. Transcranial photobiomodulation (tPBM) has been gaining attention in both scientific literature and patents, judging by the growing number of research papers that fully explain the neurobiological mechanisms of the effects of light in the 600-1100 nm range on the brain, as well as the growing number of patents disclosing it. The effects of tPBM are very detailed and scientifically justified, and are widely accepted. This positions tPBM as one of the most common and viable neuromodulation techniques without side effects. Patents have been filed that describe the effects of tPBM on brain activity, including several patents that include EEG recordings and functional magnetic resonance imaging (fMRI) results of tPBM in healthy subjects and various neurological and psychiatric patients, with more widely accepted target diseases including dementia, mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, stroke, and traumatic brain injury (TBI). In addition, several patents disclose applications and methods for cognitive enhancement. Although only a few, some patents combine tPBM with neurofeedback, while some patents cover the effects of tPBM on changes in EEG activity, especially alpha, beta, and gamma activity, along with improved cognitive function and performance in cognitive tests (i.e., reaction time and accuracy).Some of the above devices (tPBM and EEG) are wearable, but only a few can be operated with a smartphone / tablet.

[0016] There are numerous patents describing apparatus and methods for wearable EEG systems for various indications and multiple embodiments, including those disclosing the application of various event-related potential (ERP) tests. Some of them have detailed descriptions of stimulus-locked ERPs and response-locked error-related negativity (ERN) and error-related positivity (Pe) potentials. There are patents describing the application of time-frequency analysis of EEG responses using wavelet transforms and justifying the usefulness of the methods for single-trial analysis of EEG responses.

[0017] The literature contains many publications on gamma oscillations in tasks similar or identical to ERP paradigms, including descriptions of evoked and induced gamma, and phase-amplitude coupling of theta and gamma, and other EEG rhythms, as useful measures of cognitive function (Lisman & Jensen, 2013; Koster et al., 2014). Elicited and induced gamma oscillations, theta oscillations, and their coupling are areas not covered by patents or publications on any form of photobiomodulation or biofeedback. Some patents cite the use of other biometrics along with EEG, such as heart rate (HR), heart rate variability (HRV), and other vital signals, as possible embodiments. There is a large body of patent and published scientific literature focusing on HRV biofeedback and EEG biofeedback, as well as the utility of biofeedback training for various clinical and sexual performance improvement applications (Lehrer & Gevirtz, 2014; Sherlin et al., 2011).

[0018] A review of the state of the art shows that current tPBM systems and methods do not disclose the effects of transcranial photobiomodulation on cognitive test performance through EEG recordings for ERP testing and induced and stimulated EEG oscillations in cognitive testing. The availability of such systems is needed to enhance brain stimulation methods and utility by providing the availability to monitor improvements in behavior, EEG, ERP and heart rate variability (HRV) measurements assessed with cognitive testing.

[0019] Thus, there remains a need for new and improved methods and systems for brain function improvement to overcome the limitations mentioned above. There is a need for a wearable transcranial photobiomodulation-based physiological and neurological stimulation device that has the capability to provide one or more continuous wave or pulsed light sources, such as lasers and LEDs, to stimulate specific regions of the brain and to enable the utilization of physiological measurements using EEG and HRV for evaluation of the effects of tPBM protocols or to input modifications of tPBM protocols. Furthermore, there is a need in the art for a device that can be used for EEG training using either EEG or heart rate variability (HRV) biofeedback in addition to tPBM, and has the capability to test EEG or HRV biofeedback training results using ERPs and evoked EEG oscillations during cognitive testing.

[0020] What is needed in the art are wearable tPBM systems and methods for conducting a battery of cognitive tests, such as the Flanker test, auditory and visual oddball tests, and other executive function tests that provide information about processing, such as focused and sustained attention, cortical inhibition, error monitoring and correction function, or the combination of tPBM with biofeedback training that reflect changes induced by tPBM.

[0021] More specifically, what is needed is a tPBM system and method that allows for the presentation of stimuli in a visual modality delivered via a controller connected to a wearable device and a smartphone or tablet, or in an auditory modality delivered via headphones, to be synchronized with EEG signals recorded using an EEG sensor mounted on the wearable device, allowing for precise timing of stimulus events and EEG recording during each presented stimulus. What is needed in the art is the ability to record behavioral responses as well as EEG metrics in the above cognitive tests performed during or after a tPBM session, or after a tPBM session combined with biofeedback.

[0022] What is further needed in the art is an improved methodology for detection of EEG responses to stimuli during cognitive testing, including the ability to recognize and identify EEG oscillations with averaging methods as well as the ability to analyze EEG signals in single trial mode using EEG oscillations occurring in the theta and gamma bands in response to stimuli and processed using wavelet transform based time-frequency analysis methods.

[0023] Additionally, what is needed in the art are practical and effective devices and methods for applying tPBM to a user's brain and recording event-related potentials, evoked and induced EEG oscillations, changes in heart rate variability, and behavioral responses during cognitive testing to assess reaction time of a motor response in the form of pressing a button on a controller, and to evaluate the accuracy of the response assessed using metrics such as the number of percentages of total errors, number of incorrect responses including missed responses, errors of omission, or incorrect button presses, or commission errors where a button is pressed when no response is required.

[0024] What is further needed in the art are devices and methods for applying tPBM to a user's brain to improve the results of EEG biofeedback (neurofeedback) or heart rate variability (HRV) biofeedback, with the ability to evaluate the results of tPBM on the effectiveness of neurofeedback or HRV biofeedback training using functional measures of ERP and EEG oscillation (ERO) changes in cognitive tests.

[0025] The present invention uses continuous wave stimulation along with pulsed PBM light at a targeted frequency known to provide additional energy to mitochondria at the target location.

[0026] The present invention also combines PBM stimulation with electroencephalography (EEG) and heart rate variability sensors, as well as experimental systems for conducting cognitive tests aimed at assessing attention, working memory, cortical inhibition, performance monitoring and other executive functions using EEG oscillation (ERO) and ERP measurements. This allows for novel joint application of tPBM-based neurostimulation protocols to assess human performance in cognitive tests using correlates of executive functions and one's mental focus state. Summary of the Invention

[0027] The present invention provides a wearable head-mounted device with headphones and adjacent cognitive test controller unit incorporating embedded tPBM and EEG and other biometric sensors. Data collected from the sensors provides data patterns that are analyzed during cognitive tests administered before, during, or after individual tPBM sessions or following a course of tPBM therapy, EEG biofeedback, or heart rate variability (HRV) biofeedback. Biometric data includes, but is not limited to, EEG (electroencephalography), heart rate, pulse rate, heart rate variability (HRV), and other physiological measurements. The present invention utilizes physiological signals such as EEG recorded at Fz, Cz, and Pz, and photoplethysmogram (PPG) or pulse oximetry recorded from the ear for biometrics. Analysis of EEG and physiological biometric data and presentation of stimuli during cognitive testing are processed using a smartphone or tablet, and / or a remotely located computer. [Brief description of the drawings]

[0028] The present invention will be better understood from the following detailed description of several embodiments, taken in conjunction with the accompanying drawings, in which: [Figure 1]FIG. 1 shows one embodiment of a wearable device with headphones for photobiomodulation stimulation using biosensors and a biodata processing and monitoring unit, and a cognitive stimulation controller with buttons for recording motor responses. [Diagram 2] Figure 2 shows the arrow flanker test paradigm with examples of stimuli in the cognitive test. [Diagram 3] FIG. 3 shows the waveforms of the error-related negativity (ERN) and error-related positivity (Pe) locked to the error response. [Figure 4] FIG. 4 shows single-trial ERN and Pe measures processed using a time-frequency wavelet-based transform. [Diagram 5] FIG. 5 shows frontal event-related potentials (ERPs) in response to target and non-target stimuli in the visual perception test. [Figure 6] Figure 6 shows evoked and induced EEG gamma oscillations in the 35-35 Hz range in response to target and non-target stimuli in a visual perception test processed using a time-frequency wavelet transform. [Figure 7] 7 shows theta and gamma frequency oscillations and their frequency coupling during cognitive testing. A more detailed understanding of the disclosed apparatus and method will be obtained from the following description of the embodiments, taken in conjunction with the figures, drawings and claims of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] Each of the example embodiments of the present invention is provided by way of a detailed description of the present invention and should not be considered as limiting the present invention. Those skilled in the art will appreciate that modifications may be made to the present invention within the scope or spirit of the apparatus, systems, and methods of the present invention.

[0030] Additionally, in the present invention, the terms "person", "user", "wearer", "patient", "human being", "individual", "subject" and the like are used interchangeably to refer to a person using the present invention. "Treatment" or "stimulation" or "therapy" or "training" or "session" or "assessment" or "test" as used herein covers the treatment of a person to obtain a benefit or intended result in a person / user / wearer / patient / human being / individual, aimed at analyzing cognitive function or preventing cognitive decline, or providing short-term or long-term cognitive improvement resulting from said treatment.

[0031] In one aspect, the present invention provides an EEG and PPG sensor in a head-mounted device 1 with headphones 2 and 3 as shown in FIG. 1. In the embodiment shown in FIG. 1, the headphones of the present invention combine EEG sensors 5, 6 and 7 for EEG (electroencephalography) and event-related potentials (ERP) and EEG oscillations (ERO) measurements with a phoplethysmography (PPG) sensor 9 for heart rate variability (HRV) measurements in a wearable head-mounted device with headphones. In one embodiment, the PPG sensor 9 is integrated inside an over-ear headphone design that reduces ambient noise allowing for improved accuracy. The present invention provides a wearable head-mounted headphone set 1 with embedded biometric sensors that collect physiological signals from the user. The device includes Bluetooth (wireless) audio and data transmission 17 that can be used to connect the device 1 to a smartphone / mobile device 15 with a graphic touch screen display 16, said smartphone / mobile device 15 having a wireless wi-fi connection to a remotely located computer 18. The device 1 may also include a rechargeable battery, a speaker, a microphone, and has wires 13 connecting the headphones to the cognitive test controller 10.

[0032] Electrodes are used to collect EEG signals. Figure 1 shows electrodes placed at Fz 5, Cz 6, and Pz 7 locations according to the international 10-20 system, including reference and ground electrodes at A1 or A2 or M1 and M2 locations. Photobiomodulation LEDs, such as one of those four shown in Figure 1, are embedded in the head-mounted device 1.

[0033] Photoplethysmography methods are used to collect additional biometrics to measure heart rate (HR), HRV, and pulse volume. Photoplethysmography (PPG) is an optical measurement of the absorption of specific wavelengths of light by the body. A PPG sensor, including an LED and a light sensor, is placed inside one of the earpieces and positioned against the outer ear. Pulse PPG uses a reflectance method for measurements. By placing the pulse sensor 9 inside the earpiece 3 over the ear, signal noise from ambient light is reduced. The PPG data is converted into biosignals such as, but not limited to, heart rate, heart rate variability, and pulse rate.

[0034] The invention may be better understood with reference to the following examples, in which the results of tPBM stimulation are assessed using cognitive tests involving behavioral responses such as reaction time and accuracy, event-related potentials (ERPs), EEG oscillations, and event-related EEG oscillations (EROs), where the cognitive tests may be completed by a person before, during, or after transcranial photobiomodulation (tPBM).

[0035] In one example of a cognitive testing protocol, the present invention can stimulate the brain using tPBM to perform cognitive testing with reaction time and accuracy, as well as ERP and EEG oscillatory recordings at sites Fz, Cz, and Pz, which are considered the most common topographical sites for ERP analysis. Other locations and / or alternative locations can also be selected. This protocol can be performed with tPBM stimulation before, during, or after the administration of a forced-choice neurocognitive test, such as the Eriksen Flanker Test (Eriksen & Eriksen, 1976). This modification of the Flanker Test uses behavioral motor responses, such as button presses, to assess reaction time and accuracy, as well as EEG-based assessment of stimulus-locked and response-locked event-related potentials (ERPs) and EEG oscillations (EROs).

[0036] The Flanker test (Eriksen & Eriksen, 1974) using EEG recordings is a task aimed at assessing attention using ERP techniques. The Flanker test is one of the focused attention tasks that can be used to assess executive functions, including cognitive processes such as selective attention, response inhibition, performance monitoring, and working memory. In the Flanker task, the user usually determines which of multiple stimuli presented in the center of a string of letters is the target to respond to, while ignoring the stimuli presented to the left and right of the central stimulus, the so-called flankers. In the most common modification, the Flanker task requires spatial selective attention and executive control. In this task, irrelevant flankers must be inhibited in order to respond to the relevant target stimulus located in the center. Incongruent trials with mismatch flankers different from the central target stimulus result in slower reaction times and an increased number of commission errors. In order to effectively resolve the interference of the flanker stimuli during the performance of the Flanker task and to effectively resolve the conflict between competing distracting stimuli and the response, it is necessary to exercise attention.

[0037] This test is particularly interesting because it allows for the analysis of error processing, monitoring and correction processes that are thought to be controlled by frontal and central cortical regions (Falkenstein et al., 2000; Nieuwenhuis et al., 2001). These regions can be stimulated by transcranial photobiomodulation in the present invention. In the Flanker test, when a commission error occurs, the response-locked ERPs of interest are the error-related negativity (ERN) and the error-related positivity (Pe). The ERN is a negative-going ERP wave that begins to peak approximately 50 ms after the error. In one embodiment, the ERN is measured during a response inhibition paradigm, such as the Flanker task. In this paradigm, the user sees a target arrow stimulus within a set of other arrow stimuli on either side of a target arrow that indicates the correct direction to press either the left or right button. In some trials of the test, the flanker is the same as the target (congruent trials), while in other cases, the flanker is different from the central target arrow (incongruent trials).

[0038] The arrow version of the Eriksen Flanker task is widely used to elicit the ERN. In some variations, signs such as "<" and ">" are used to indicate the direction of the response. An example of the arrow flanker test is shown in Figure 2. In each trial, participants view five arrows presented for 150 ms or 200 ms. Participants are asked to respond as quickly and accurately as possible to indicate the correct direction of the central arrow and press the left or right button on the controller. Participants have approximately 800 ms to 1000 ms from the onset of the stimulus to respond. Half of the trials are congruent (< < < < < < or >> > > >), responding to the left and responding to the right, respectively, while the other half are incongruent (e.g., >> < > > or < < > < <). Users take short rests throughout the task. The long version of the task allows 360 or up to 720 trials, while the shorter version allows fewer errors, although the shorter version also allows for more trials.

[0039] In yet another embodiment, a modified version of the Flanker test is used that includes a No-Go component in the task. The Flanker with Go / NoGo task modification combines the Flanker task with the Go / NoGo response paradigm (Ruchsow et al., 2005). In this version, the visual stimuli include four arrows and one non-arrow symbol, such as "=", presented centrally for, for example, 150 ms or 200 ms. The intertrial interval is 1000 ms. If the central target arrow is either "<" (Go press left button) or ">" (Go press right button), a left or right hand response is required. In addition, there are trials that include incongruent NoGo stimuli (< < = < < or > > = > >). These NoGo trials (central "=") require refraining from responding and result in more commission errors. In this modified version of the Flanker protocol, the number of Go-congruent, Go-incongruent, and NoGo-incongruent trials can be adjusted.

[0040] Response-locked ERN and Pe potentials are triggered by committed error responses and reflect processes related to error detection, error monitoring, and error recognition. These error-specific components are the error-related negativity (ERN, more rarely called Ne) and the error-related positivity (Pe). The ERN is a response-locked negative ERP deflection that appears between 0 and 150 ms after the onset of an incorrect behavioral response (commission error). The ERN is followed by a positive wave called the Pe potential (range 100 ms to 200 ms). The waveforms of the ERN and Pe stimulus-locked ERP components are shown in Figure 3. The Pe is thought to be related to the conscious recognition of an error or the attribution of motivational importance to a committed error. It is suggested that the ERN indicates an early automatic response to error detection, whereas the Pe reflects the conscious understanding of the error. The ERN / Pe wave is associated with self-monitoring, self-correction, and delayed post-error responses and is interpreted as a biomarker of error processing and committed error recognition ( Falkenstein et al., 2000 ; Nieuwenhui et al., 2001 ).

[0041] Behavioral response measures in the Flanker test may include mean reaction time and response accuracy (percentage correct). For each test session, the number and percentage of commission and omission errors are calculated. Stimulus-locked ERPs in the Flanker test, including those with NoGo trials in the present embodiment, are the posterior (parietal, Pz) N200 ERP and P300 (P3b) in only correct responses to congruent and incongruent stimuli. In a modified version of the Flanker test with Go-NoGo trials, additional measures of interest include difference waves NoGo-N2 and NoGo-P3 at the Fz site. Both NoGo-N2 and NoGo-P3 are calculated as the difference between NoGo-N2 and NoGo-P3 and Go-N2 and GoP3 at frontal sites (e.g., Fz) within windows typical of the N200 (180ms-320ms) and P300 (300ms-500ms) ERPs. These measures are considered EEG biomarkers of cortical inhibition processes. These are also registered in flankers without NoGo trials.

[0042] Longer versions of the task can have 360 ​​or 720 trials, and shorter versions of the task are also acceptable, but produce fewer errors. In an embodiment of the Flanker test where a shorter version is used and the number of error trials is small, in yet another embodiment, the method of analysis of the error-related EEG response uses a single-trial time-frequency analysis based on the wavelet transform. Single-trial analysis of EEG activity is important to detect and analyze the error-related negativity (ERN) in response to commission errors. In this embodiment, it is proposed that a method of ERN and Pe analysis using the wavelet transform is used. The single-trial EEG data from errors in the Flanker task in this embodiment can be processed using a continuous wavelet transform. The coefficients from the transform corresponding to the theta range are averaged to isolate the theta waveform in the time-frequency domain. Time-frequency ERN and measurements called Pe are obtained from these waveforms for midline frontal and central EEG sites (Fz and Cz) for each error trial. Comparisons of amplitudes and latencies for the time-frequency ERN and Pe in flanker tests administered before, during, or after a tPBM session, or during the course of tPBM, are performed to assess the impact of stimulation on the user's error monitoring and correction functions. This single-trial time-frequency error analysis method is suitable for examining error processing when users commit only a few errors (Clemans et al., 2012). An illustration of the wavelet-based time-frequency analysis of the single-trial ERN and Pe is shown in Figure 4.

[0043] In yet another embodiment of the device and method, a visual or auditory oddball test can be used to evaluate the cognitive state of the user before, during, or after transcranial photobiomodulation or after a course of tPBM treatment. In the example of the visual oddball test, an ERP test paradigm is used for cognitive process and attention measurement. The visual oddball paradigm is often used to elicit the P3 (P300) cognitive ERP component (Polich & Herbst, 2007, Herrmann & Knight, 2001). In the traditional visual two-stimulus oddball test, a target stimulus is presented infrequently among frequent standard stimuli. In the three-stimulus oddball test version, a rare target stimulus is presented together with frequent standard stimuli and infrequently occurring distractor stimuli (which can be the same rare stimulus or some novel distractors). The user must respond to the target stimulus that is in focus and ignore the other stimuli. Target and novel stimuli evoke large positive P3 (or P300) potentials, specifically accompanied by a frontal P3a component at Fz and a parietal P3b component at Pz electrodes, with peak latencies within 300–400 ms after the stimulus. Parietal P3 (P3b) amplitudes are interpreted as updating the mental representation of the stimulus. In the three-stimulus version of the visual oddball test, novel distractor stimuli elicit a frontal P3a ERP that is interpreted as a marker of attentional orienting. Figure 5 shows the P3a component elicited at the frontal Fz site in response to target and non-target stimuli. Thus, in the three-stimulus modified version of the visual oddball test with novel distractors, the P300 (P3) potential is further divided into P3a and P3b subcomponents (Polich, 2007). The P3a elicited by infrequent, uncued, novel stimuli is localized to the frontal cortex (e.g., Fz) or central cortex (Cz) and has a relatively short latency compared to the P3b component elicited in response to attended, infrequent stimuli and localized to parietal regions (e.g., Pz).

[0044] The P3a component reflects processes related to the selection of stimuli related to attentional orientation. The amplitude of P3a reflects processes indicative of focal attention. P3b reflects processes related to the allocation of attentional resources during the performance of a cognitive task and is related to the updating of working memory. P3b amplitude reflects attentional resources allocated to processing stimuli, whereas P3b latency reflects the speed of stimulus classification. Target detection in the visual oddball paradigm described above is also associated with a delayed response in parietal regions (e.g., Pz), starting at 200 ms and lasting up to 500 ms, including a negative N2 (N200) and a positive P3b component. Both P3a and P3b are analyzed to calculate the peak amplitude and latency of the peaks in a preselected window, although in some cases the average or area of ​​the components (magnitudes are calculated) are used instead of the maximum peak, and in more rare cases the peak-to-peak amplitude of N2 vs. P3b is used.

[0045] In the simplest modification, two visual stimuli, e.g., the letters "O" and "X", are designed as standard and target stimuli, respectively. The user is instructed to press "X" for the target stimulus and to make no response for the standard stimulus. Furthermore, the user's reaction time and correct target detection are recorded. Two types of errors are expected: commission errors "false alarms" (i.e., a key pressed when the standard stimulus was presented, reflecting impulsivity) and omission errors (forgot to press a key when the target stimulus appeared, reflecting inattention).

[0046] In yet another example of an embodiment, a three-stimulus visual oddball test with novel distractors can be used. This ERP test uses the letters "X", "O" and novel distractors ("v", "^", ">" and "<" symbols) as stimuli. One of the stimuli ("O") is presented in 80% of trials (frequent standard), a novel stimulus (e.g., ">") is presented in 10% of trials (2.5% for each of the symbols) (rare distractors), while a third stimulus ("X") is presented in the remaining 10% of trials and represents a target. The user is instructed to press a button when the target letter appears on the screen. Event-related potentials (ERPs) locked to the stimulus event (triggered by the target) reflect the activation of neural structures in primary sensory cortex and association cortical areas related to higher cognitive processes. ERP analysis provides temporal information about processes such as attention. Early ERP components such as P100, N100, and P200 are typically associated with early attentional selection mechanisms, whereas later components (N200, P300 / P3b) are more often associated with stimulus organization and interpretation.

[0047] A negative ERP (N200) located over centro-parietal regions occurs within a window of 180 and 320 ms post-stimulus. This component is thought to be related to signaling for categorization, perceptual closure, and attentional focus, and the formation of perceptual representations. The visual N200 is larger when the stimuli contain perceptual features or attributes that define the target to which attention should be directed in the test. In a three-stimulus oddball task, the P3a is interpreted as an orienting response to a novel distractor, whereas the P3b is considered as an index of sustained attention to the target.

[0048] In another embodiment of the device and method, the systems analysis of the EEG response uses time-frequency wavelet-based analysis of the EEG in a single trial, more specifically, EEG evoked and induced gamma (35-45 Hz or 30-80 Hz) oscillations and EEG frequency (e.g., theta 4-8 Hz and gamma 35-45 Hz) phase-amplitude coupling methods. Cognitive testing can be completed by the human before, during, or after transcranial photobiomodulation (tPBM).

[0049] In another embodiment of the cognitive test in the present invention, a wavelet-based time-frequency analysis of event-related EEG gamma oscillations is used. During the processing of the collected EEG data, oscillatory responses in the gamma band centered at 35-45 Hz or in the broader gamma range (e.g., 30-80 Hz) are separated into two main groups: evoked and induced responses. These two gamma responses are differentiated based on their temporal location and whether they are time-locked to the stimulus. Event-related oscillations are divided into "evoked" and "induced" components depending on their relationship to the event, i.e., the stimulus. Early, or so-called "evoked" gamma responses occur in the range of 40-180 ms after the stimulus. These evoked responses are believed to result from early information processing related to sensory processes and early stages of stimulus perception (Basar, 2013). They are tightly time-locked to a specific stimulus. On the other hand, induced gamma oscillatory responses that occur later appear better within a post-stimulus window ranging from 250-500 ms. Figure 6 shows evoked and induced gamma oscillations in waveforms in the 35-45 Hz range in response to target and non-target stimuli during cognitive testing. Stimulated gamma oscillation responses are observed in tasks that require higher-order processes of short-term memory (Herrmann et al., 2014). Event-related gamma oscillations are associated with indications of perceptual and cognitive processes and are thought to represent the integration of attentional resources and cognitive processes.

[0050] Previous studies have revealed that evoked and induced responses reflect different neural processes and mechanisms (Basar, 2013; Herrmann & Demiralp, 2005; Tallon-Baudry & Bertrand, 1999). In the art, it has been reported that induced gamma oscillation power increases at approximately 40 Hz during short-term memory tasks and is associated with the maintenance of object representations in short-term memory (Tallon-Baudry & Bertrand, 1999). In the present invention, single-trial evoked and induced gamma oscillation power is applied using EEG recordings during cognitive tests such as flanker tests and visual or auditory oddball tests to evaluate and assess the sensory and cognitive processes of the device user before, during, or after a transcranial photobiomodulation session or after a course of tPBM or biofeedback treatment.

[0051] In yet another embodiment of the invention, the method of cognitive testing examines attentional processes operating in early pre-attentional sensory processes, such as early orientation in sustained attention, by time-frequency measurements of EEG oscillations in several EEG bands during task execution. Of particular interest in this regard are theta (4-8 Hz) and gamma oscillations centered at 40 Hz. Figure 7 shows the phase-amplitude coupling of theta and gamma oscillations between evoked and induced oscillations in response to stimuli in cognitive testing. Previous studies suggest that theta oscillations indicate neural processes involved in working memory, attention, and the integration of sensory stimuli following long-term memory processes (Davoudi et al., 2021; Lisman and Jensen, 2013).

[0052] It is known to those skilled in the art that EEG oscillations exhibit phase-amplitude coupling in certain physiological states or during the performance of certain tasks, and studies on neural oscillations suggest that interactions between brain regions are processed by cross-frequency coupling between low-frequency band phase and high-frequency band amplitude. In particular, cross-frequency coupling between theta (4-8 Hz) phase and gamma (range mainly centered around 40 Hz, e.g., 35-45 Hz) amplitude may play an important functional role in cognitive activities such as attention and working memory (Canolty et al., 2006). Specifically, it is known that EEG responses to visual stimuli are characterized by easily observed changes in theta and gamma oscillations. The cross-frequency coupling method in the present method measures the association between theta oscillation phase and gamma power. Larger theta-gamma coupling values ​​translate into larger gamma amplitudes during theta phase (Lisman & Jensen, 2013). Theta-gamma coupling has been shown to be a functional role of importance for processes related to short-term and long-term memory. Research suggests that phase-amplitude coupling between theta phase and gamma amplitude represents a cognitive control mechanism (Koster et al., 2014). In the present embodiment, event-related evoked and induced theta and gamma EEG oscillations are analyzed for the calculation of theta and gamma activity phase-amplitude coupling for the evaluation of the user's cognitive processes in response to the effects produced by transcranial photobiomodulation or biofeedback.

[0053] Cognitive tests in various embodiments of the present invention may include memory tests, physical response tests, speech processing tests, visual processing tests, emotional response tests, attention tests, executive function tests, learning tests, reaction time tests, peripheral vision tests, intelligence tests, and language tests. During cognitive tests, one or more of ERP, ERO, EEG, and HRV data may be evaluated.

[0054] In one embodiment, the invention utilizes a cognitive assessment, where the assessment subject performs a cognitive assessment trial, then receives tPBM stimulation, followed by an additional cognitive assessment trial. Sensors of the invention are used to collect biometric signals from the subject during the cognitive assessment and tPBM stimulation, including (but not limited to) EEG, heart rate, pulse rate, heart rate variability (HRV), and other physiological measurements.

[0055] In one variation, the phases of pre-tPBM trial, tPBM stimulation, and post-tPBM trial may be performed one after the other, while in yet another variation, the subject may be provided with rest during one or more of these phases. In another variation, the subject may be provided with tPBM stimulation during some or all of the cognitive assessment trials.

[0056] In one embodiment, differences in ERP components including, but not limited to, P300, P3a, P3b, N200, ERN, Pe, reaction time, reaction time after error, No-Go N2, No-Go P3, before and after tPBM stimulation may be assessed. Further comparative measures based on pre-tPMB trials, active tPMB trials, and post-tPBM trials may include difference waves, timing, amplitude, and other measures.

[0057] In yet another embodiment, cognitive assessment trials may be analyzed for evoked and induced gamma oscillation power, timing, amplitude, and cross-frequency coupling between theta (4-8 Hz) phase and gamma (35-45 Hz), as well as other EEG measures. Here, comparative measures may be calculated to assess differences in timing, amplitude, and frequency between pre-tPMB trials, active tPMB trials, and post-tPBM trials. In the present invention, application of single-trial evoked and induced gamma oscillation power during cognitive tests, such as flanker tests or visual or auditory oddball tests with EEG recordings, is used to evaluate and assess the sensory and cognitive processes of the device user before, during, or after a transcranial photobiomodulation session, or after a course of tPBM or biofeedback therapy.

[0058] In one embodiment of the present invention, the cognitive assessment trial involves the user performing a memory-based test, where the user is presented with images, sounds, letters, and / or numbers to memorize for a set period of time. After another period during which the user may be distracted by performing another task, the user is asked to identify the memorized items. In this embodiment, performance measures may be compared between pre-tPMB trials, active tPMB trials, and post-tPBM trials. This embodiment may be combined with analysis of EEG oscillations.

[0059] In the present invention, measurements from cognitive testing using tPBM may be utilized to assess cognitive function and / or diagnose cognitive conditions, such as, but not limited to, mild cognitive impairment (MCI), dementia, Alzheimer's, autism spectrum disorder (ASD), obsessive-compulsive disorder (OCD), anxiety, ADD and ADHD, where the measurements may be compared to statistical norms, compared to calibrated algorithms, or used in artificial intelligence networks.

[0060] In another embodiment, closed-loop adaptation of tPBM stimulation and cognitive assessment is performed over the course of one or more treatment sessions and one or more assessment trials to optimize results, where the user's response to tPBM stimulation is measured and adapted throughout the cognitive assessment trials, where tPBM adaptations include, but are not limited to, frequency, timing, duration, duty cycle, location, and dosage, where adaptations are selected by the system to optimize the subject's cognitive performance and measurements.

[0061] Alternative embodiments include, but are in no way limited to, incorporating the neurofeedback and neurostimulation modalities of the present invention into other suitable wearable devices other than headphones. Those skilled in the art will appreciate that such alternative embodiments are possible so long as they allow stimulation and measurement of the appropriate regions of the wearer's brain. Those skilled in the art will also appreciate that application of other known PBM, EEG and HRV biofeedback and ERP and EEG-oscilloscope (ERO) testing protocols are possible within the scope of the present invention. The examples provided herein are exemplary in nature and are not intended to limit the scope of the present disclosure.

[0062] The above-described embodiments should be considered as examples of the present invention, rather than limiting the scope of the present invention. In addition to the above-described embodiments of the present invention, review of the detailed description and the accompanying drawings will show that there are other embodiments of the present invention. Thus, many combinations, permutations, variations, and modifications of the above-described embodiments of the present invention that are not expressly described herein will nevertheless fall within the scope of the present invention.

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Claims

1. A wearable device for stimulating and monitoring the brain, comprising: at least one transcranial PBM stimulator; at least one EEG sensor; the device is configured to provide stimulation from the transcranial PBM stimulator to a brain of a human being to alter electrical activity of the brain of the human being; the device is further configured to monitor the electrical activity using the EEG sensor; A wearable device, wherein the device is further configured such that changes in electrical activity detected using the EEG sensor can be evaluated using cognitive tests.

2. 10. The wearable device of claim 1, wherein the device is further configured to receive results of a cognitive test and, based on the results, provide further stimulation from the transcranial PBM stimulator to the brain of the human to influence subsequent cognitive test results.

3. 3. The wearable device of claim 2, further comprising at least one additional sensory stimulation device for providing visual or auditory stimulation, the device being further configured to provide further stimulation to the brain of the human from the additional sensory stimulation device based on the results and EEG sensor data.

4. 4. The wearable device of claim 3, wherein the cognitive test can be selected from the group consisting of a memory test, a physical response test, a speech processing test, a visual processing test, an emotional response test, an attention test, an executive function test, a learning test, and a language test, and during the cognitive test, one or more of ERP, ERO, EEG, and HRV data are assessed.

5. 5. The wearable device of claim 4, wherein the further stimulation from the transcranial PBM stimulator and the additional sensory stimulator is adjusted to affect one or more of ERP, ERO, EEG, and HRV.

6. 3. The wearable device of claim 2, further comprising at least one additional biometric sensor configured to provide recording of biometric data of the wearable device for monitoring responses during the PBM stimulation and cognitive testing.

7. 7. The wearable device of claim 6, wherein the at least one additional biometric sensor is a heart rate sensor using a photoplethysmogram (PPG) or a pulse oximeter sensor or an ECG sensor or a GSR sensor.

8. 3. The wearable device of claim 2, wherein the at least one transcranial PBM stimulator can be a near-infrared laser or an LED emitting light at a wavelength between 600 and 1150 nm.

9. 3. The wearable device of claim 2, comprising at least two transcranial PBM stimulators that can be pulsed at different frequencies.

10. 3. The wearable device of claim 2, wherein the at least one EEG sensor is configured to acquire data regarding the brain's electrical activity during a cognitive test simultaneously with the at least one transcranial PBM stimulator providing pulsed near-infrared light to the brain.

11. 7. The wearable device of claim 6, wherein the at least one EEG sensor and the at least one additional biometric sensor are configured to acquire biometric data during a cognitive test simultaneously with the at least one transcranial PBM stimulator providing pulsed near-infrared light to the brain.

12. The wearable device of claim 2 , wherein the wearable device is in the form of a head-mounted interface.

13. The wearable device of claim 12 , wherein the wearable device is in the form of a set of head-mounted headphones.

14. 10. The wearable device of claim 1, wherein the device is further configured to provide further stimulation to the human's brain over time based on cognitive test results and evaluate resulting changes in cognitive test results.

15. 15. The wearable device of claim 1, wherein the device is further configured to provide stimulation from the transcranial PBM stimulator to the brain of the human and evaluate results of cognitive tests to assess or diagnose cognitive function or status.

16. 1. A method for optimizing a biometric parameter of a human, comprising: at least one transcranial PBM stimulator; at least one EEG sensor; providing the human with a wearable brain stimulation and monitoring device comprising: the device is configured to provide stimulation from the transcranial PBM stimulator to a brain of a human being to alter electrical activity of the brain of the human being; the device is further configured to monitor the electrical activity using the EEG sensor; the device is further configured such that changes in electrical activity detected using the EEG sensor can be evaluated using a cognitive test; the device is further configured to receive results of a cognitive test and, based on the results, provide further stimulation from the transcranial PBM stimulator to the brain of the human to influence a subsequent cognitive test result; administering a cognitive test to the human; measuring one or more of EEG, ERP, ERO, and HRV data of the human during a cognitive test; providing transcranial PBM stimulation to the human before, during, or after the cognitive test; performing transcranial tPBM to optimize EEG or ERP data of the human based on results of the cognitive test; A method comprising:

17. 17. The method of claim 16, wherein measuring the ERP of the human comprises assessing one or more of P300, P3a, P3b, N200, ERN, Pe, reaction time, reaction time after an error, No-Go N2, and No-Go P3.

18. 17. The method of claim 16, wherein measuring the EEG data of the human comprises assessing EEG oscillations in one or more EEG bands, including theta and gamma bands.

19. 17. The method of claim 16, further comprising measuring at least one additional biometric parameter before, during, and after PBM stimulation and providing biofeedback to the wearer.

20. 17. The method of claim 16, further comprising providing audio or visual stimuli to the human in addition to PBM stimuli to further optimize feedback of the human's biometric parameters.

21. 17. The method of claim 16, wherein the at least one other biometric sensor can be a heart rate sensor using a photoplethysmogram (PPG) or a pulse oximeter sensor or an ECG sensor or a GSR sensor.

22. 17. The method of claim 16, wherein the at least one PBM stimulator can be a near-infrared laser or an LED that emits light at wavelengths between 600 and 1150 nm and can be pulsed at different frequencies.

23. 17. The method of claim 16, wherein the at least one EEG sensor can acquire data regarding the brain's electrical activity during cognitive testing simultaneously with the at least one PBM stimulator providing pulsed near-infrared light to the brain.

24. 17. The method of claim 16, wherein the at least one EEG sensor and the at least one additional biometric sensor provide biometric data that can be used to assess results of the cognitive test contemporaneously with operation of the PBM stimulator.

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