HK1241675A1 - Neurocerebral assessment using stimulated eeg response - Google Patents

Abstract

The present disclosure provides methods, systems and devices for assessing brain neural activity and/or characteristics by providing at least two TMS stimulation pulses, obtaining an EEG indicative of brain activity responses associated with the at least two TMS stimulation pulses and compare the brain activity responses to evaluate neural characteristic of the brain.

Description

Neurobrain assessment using stimulated EEG response

Technical Field

The present disclosure relates generally to the field of neurobrain and neurological function assessment.

Background

It has proven essential in many fields to obtain insight about brain activity and function, such as assessment of cognitive abilities, detection/diagnosis of neuro-related conditions, behavioral studies and others.

Current methods of obtaining these insights include brain imaging, mental state testing, physical and neurological examinations, blood tests, and the like. Some of these methods typically require the subject to be actively involved in performing mental actions and/or to be able to detect only severe and late conditions in the brain, and in many current methods, accuracy/precision is not always sufficient.

Accordingly, there is a need in the art for methods, devices and systems for assessing brain activity and function that are capable of accurately detecting early conditions without requiring active participation of the subject in various mental tasks.

Summary of The Invention

The following embodiments and aspects are described and illustrated in conjunction with systems, tools, and methods, which are meant to be exemplary and illustrative, not limiting in scope. In various embodiments, one or more of the above-described problems have been reduced or eliminated, while other embodiments are directed to other advantages or improvements.

According to some embodiments, provided herein are devices, systems, and methods for assessing a neurocerebral state and/or condition of a subject. According to some embodiments, the assessment is achieved by stimulating the brain and analyzing the brain's response to the stimulation. According to some embodiments, the stimulation comprises inducing a magnetic field/flux on at least some regions of the brain. According to some embodiments, the brain response measurements are obtained using at least one electrode configured to measure activity of at least one region of the brain. According to some embodiments, measuring brain activity comprises detecting electrical and/or electromagnetic activity of a neural network within the brain. According to some embodiments, the measurement of brain activity may include the use of electroencephalography ("EEG").

According to some embodiments, the stimulation is designed to induce a responsive activity in the brain. According to some embodiments, response activity is analyzed to assess neurological/neuro-brain characteristics, function, behavior, and/or various conditions.

According to some embodiments, stimulating the brain may include a plurality of stimuli. According to some embodiments, the plurality of stimuli may be temporally spaced apart therebetween and/or sequentially. According to some embodiments, the plurality of stimuli is a stimulation pulse train. According to some embodiments, analyzing may include analyzing at least some brain responses resulting from at least some of the stimuli of the stimulation pulse train. According to some embodiments, assessing the neurobrain state and/or condition of the subject is achieved by comparing the at least some brain responses to a set of expected/predetermined brain responses of a normal brain and/or one or more brains with a neuro/neuro-brain condition.

Advantageously, such assessment does not require active mental participation by the subject, for example in solving a mental puzzle or undertaking various cognitive tasks. Advantageously, such assessment is objective and accurate, and may not be susceptible to variations and inconsistencies associated with current methods of assessing brain activity and function.

According to some embodiments, the assessment may indicate various mental, neurological/neurobrain conditions in its early stages. Advantageously, such indication/detection at an early stage may provide an opportunity to provide effective treatment of the detected condition.

According to some embodiments, the stimulation and/or measurement is non-invasive. Advantageously, non-invasiveness may facilitate safety, convenience, and even reduce the cost of evaluating and/or detecting various conditions.

According to some embodiments, there is provided a method for assessing brain activity of a subject, the method comprising providing at least three electrical stimulation pulses at a predetermined intensity to a brain region of the subject, detecting at least three respective electroencephalogram (EEG) signals, obtaining each signal in response to each of the at least three TMS pulses, making a comparison between at least two EEG signals obtained in response to at least two TMS pulses, and assessing brain activity of the subject based at least on the comparison.

According to some embodiments, the electrical stimulation pulses comprise magnetically induced electrical stimulation pulses.

According to some embodiments, the magnetically induced electrical stimulation pulses comprise Transcranial Magnetic Stimulation (TMS) pulses.

According to some embodiments, the electrical stimulation pulse is an electrically induced electrical stimulation pulse.

According to some embodiments, the brain activity comprises one or more cranial nerve characteristics.

According to some embodiments, the one or more cranial nerve properties include excitability, plasticity, or both.

According to some embodiments, the predetermined intensity is based on a motion threshold intensity associated with the subject.

According to some embodiments, the method further comprises establishing a motor threshold intensity associated with the subject, comprising providing a plurality of TMS pulses of varying intensity to a motor-related region of the brain, monitoring a motor response of the subject, and detecting the intensity above which the motor response is observed.

According to some embodiments, the predetermined intensity is greater than 80% of the exercise threshold intensity.

According to some embodiments, the predetermined intensity is less than 120% of the exercise threshold intensity.

According to some embodiments, the method further comprises providing a first TMS pulse to a first region of the brain of the subject, detecting a first EEG signal obtained in response to the first TMS pulse, providing a second TMS pulse to the first region of the brain of the subject, detecting a second EEG signal obtained in response to the first TMS pulse, providing a third TMS pulse to the first region of the brain of the subject, detecting a third EEG signal obtained in response to the first TMS pulse, comparing between at least two of the first EEG signal, second EEG signal and third EEG signal, and assessing brain activity of the subject based at least on the comparison.

According to some embodiments, the method further comprises providing at least three TMS pulses to a second region of the brain of the subject, detecting at least three EEG signals, obtaining each signal in response to each of the at least three TMS pulses, comparing between at least two EEG signals obtained in response to at least two TMS pulses, and evaluating brain activity of the subject based on the comparison between the at least two EEG signals and based on EEG signals obtained in response to a TMS pulse provided to the first region and EEG signals obtained in response to a TMS pulse provided to the second region.

According to some embodiments, the first region and the second region comprise a right hemisphere and a left hemisphere, respectively.

According to some embodiments, the comparing comprises comparing amplitudes of the characterized EEG differential time markers or initial EEG responses to TMS, slopes (rise times) of the characterized EEG differential time markers or initial EEG responses to TMS, areas under the curve (AUC) of the TMS responses, or either the entire AUC or the single priority target characterizing EEG differential markers, and/or any combination thereof.

According to some embodiments, there is provided a system for assessing brain activity of a subject, the system comprising: an electrical stimulation apparatus configured to provide electrical stimulation pulses to a region of the brain of a subject; an electroencephalogram (EEG) device configured to monitor neural activity in a brain of a subject and provide an EEG signal indicative thereof, and a processing circuit configured to make a comparison between at least two EEG signals obtained in response to at least two electrical stimulation pulses, and to assess the brain activity of the subject based at least on the comparison.

According to some embodiments, the electrical stimulation device comprises a Transcranial Magnetic Stimulation (TMS) device, and the electrical stimulation pulses comprise TMS pulses.

According to some embodiments, the brain activity comprises one or more cranial nerve characteristics.

According to some embodiments, the one or more cranial nerve properties include excitability, plasticity, or both.

According to some embodiments, the TMS device is configured to provide at least one TMS stimulation pulse comprising a plurality of TMS stimulation pulses, wherein the plurality of TMS stimulation pulses are separated in time.

According to some embodiments, the processing circuitry is configured to compare between at least two EEG signals obtained in response to at least two TMS pulses of a TMS stimulation pulse train, and to assess brain activity of the subject based at least on the comparison.

According to some embodiments, the TMS device is further configured to: at least one TMS stimulation session is provided that includes a plurality of TMS stimulation bursts, wherein the TMS stimulation bursts are separated in time by inter-burst intervals.

According to some embodiments, the processing circuitry is configured to obtain EEG signals indicative of brain activity responses associated with at least some of the TMS stimulation bursts, and to generate a representative EEG burst activity response comprising representative EEG pulse activity responses.

According to some embodiments, the inter-burst interval has a duration of at least 20 seconds.

According to some embodiments, the representative EEG burst comprises an average of EEG signals indicative of brain activity responses associated with at least some TMS stimulation bursts.

According to some embodiments, the processing circuitry is further configured to make a comparison between the at least two representative EEG impulse activity responses and to assess brain activity of the subject based at least on the comparison.

According to some embodiments, the processing circuitry is configured to perform the comparison based on at least the amplitude of the characterized EEG different time markers or initial EEG response to the TMS, the slope (rise time) of the characterized EEG different time markers or initial EEG response to the TMS, the area under the curve (AUC) of each TMS response (charge transfer), or the entire AUC or a single priority target characterizing the EEG different markers, or any combination thereof.

Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more technical advantages may be readily apparent to one skilled in the art from the figures, descriptions, and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some, or none of the enumerated advantages.

In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following detailed description.

Drawings

Exemplary embodiments are described below with reference to the accompanying drawings. In the drawings, identical structures, elements or parts that appear in more than one figure are generally labeled with the same reference numeral in all the figures in which they appear. Alternatively, elements or portions that appear in more than one figure may be labeled with different numbers in different figures in which they appear. The dimensions of the components and features shown in the figures are generally chosen for convenience and clarity of presentation and are not necessarily shown to scale. The figures are listed below.

Figure 1 schematically illustrates a neurobrain assessment setup according to some embodiments;

fig. 2 schematically illustrates a stimulation pulse train according to some embodiments;

fig. 3 schematically illustrates a stimulation session according to some embodiments;

figure 4 schematically illustrates an EEG response to a stimulation pulse train in a healthy brain, according to some embodiments;

fig. 5 schematically illustrates a stimulation intensity operating range according to some embodiments;

fig. 6 schematically illustrates a method for establishing a motion threshold, in accordance with some embodiments;

figure 7 schematically illustrates a method for providing a stimulated EEG response pulse train, according to some embodiments; and

fig. 8 schematically illustrates a method for providing a stimulated EEG response session, according to some embodiments.

Detailed Description

In the following description, various aspects of the present disclosure will be described. For purposes of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the various aspects of the disclosure. It will be apparent, however, to one skilled in the art that the present disclosure may be practiced without specific details presented herein. In addition, well-known features may be omitted or simplified in order not to obscure the present disclosure.

The brain is central to the nervous system in most invertebrates and all vertebrates, and is the most complex organ within the vertebrate body, including billions of neurons, each of which is connected by synapses to thousands of other neurons to perform mental tasks critical to the function and health of the animal. In humans, the cognitive abilities of our brain play an important role in defining a person's role, contribution and well-being within society as well as in individuals. The nervous system of the brain is called the neurocerebral system.

Unfortunately, our brain is susceptible to a variety of conditions that may impair its ability to perform mental tasks. Some of these conditions include neurodegenerative disorders that may affect the structure or function/characteristics of neurons of the brain, and may even include neuronal death. Several disorders belonging to the category of neurodegenerative disorders include parkinson's disease, ALS, alzheimer's disease, huntington's disease and others. Other conditions that may affect the brain may include chronic pain, ADD/ADHD, other types of dementia besides alzheimer's disease and some other types that affect our ability to perform routine tasks in daily life, and some may even impose intolerable/intolerable obstacles.

Although it may affect the severity of conditions of the brain, the detection/diagnosis of these conditions often occurs after the conditions have reached an advanced stage and have begun to significantly affect the function of the human. Unfortunately, the effectiveness of the potential treatment is compromised due to the delayed/advanced phase of the condition.

According to some embodiments, systems, devices and methods for assessing neurobrain function and/or characteristics are provided. According to some embodiments, the assessment may be performed by inducing stimulation of the brain and measuring the activity of the brain (or neural networks therein) in response to the stimulation. According to some embodiments, the assessment may be performed by inducing multiple stimuli to the brain and measuring the activity of the brain (or neural structures therein) in response to the stimuli.

According to some embodiments, the reactive activity of the brain may be indicative of some feature of neural structures and/or neural network functions within the brain, and these features may facilitate the assessment of neurobrain function and/or features, thereby facilitating the detection/diagnosis of various conditions affecting the brain.

According to some embodiments, such assessment may be indicative of a brain/neurological condition even before the subject and/or its observer perceives a significant behavioral/functional effect. Advantageously, the ability to detect a condition even before a significant effect can facilitate early detection of the condition and potentially aid in the effectiveness of the treatment.

According to some embodiments, the devices, systems and/or methods may be used to assess the progression and/or status of a diagnosed subject. According to some embodiments, the devices, systems and/or methods may be used to measure the stage/severity of a disorder or condition. According to some embodiments, devices, systems, and/or methods may be used to detect and/or assess neural network abnormalities.

According to some embodiments, such an assessment may provide an accurate indication of a particular condition, thereby mitigating the risk of misdiagnosis and undesirable complications associated therewith.

According to some embodiments, the stimulation is electrical stimulation. According to some embodiments, the stimulation is electrically induced electrical stimulation. According to some embodiments, the stimulation is magnetic induction electrical stimulation. According to some embodiments, the stimulation is transcranial magnetic stimulation.

According to some embodiments, the stimulation comprises inducing a magnetic flux/field to the brain or a part thereof. According to some embodiments, the magnetic stimulation may comprise Transcranial Magnetic Stimulation (TMS). According to some embodiments, the stimulation may comprise a plurality of TMS magnetic pulses at a determined intensity. According to some embodiments, TMS strength may refer to the flux of an induced magnetic field. According to some embodiments, TMS intensity may be measured/presented in tesla units. According to some embodiments, TMS strength may be measured/presented as a percentage of a reference value.

According to some embodiments, measuring the response activity may be facilitated by measuring electrical/electromagnetic activity of neural structures in the brain. According to some embodiments, measuring reactive activity may be facilitated by utilizing at least one electrode configured to measure changes in electrical/electromagnetic fields indicative of activity of a particular neural network in the brain. According to some embodiments, measuring the reaction activity may be facilitated by utilizing an EEG device/system.

Reference is now made to fig. 1, which schematically illustrates a setup 100 for stimulation responsive neurological function assessment of a subject 152 by a caregiver 150, according to some embodiments. As shown, caregiver 150 positions a stimulation device, such as, but not limited to, TMS inducer 102, at a location on/near the head of subject 152. TMS inducer 102 is supplied with control signals and power from a controller, such as TMS-controller 112. The TMS-controller 112 may be configured to enable controllable stimulation by the TMS unit 112. According to some embodiments, the controllable stimulation may include control of intensity, duration, frequency, flux, and/or other stimulation related parameters and stimulation patterns.

At least some brain activity sensors, such as EEG electrodes 104, are placed on the head of the subject 152 and are configured to measure neural activity of the brain of the subject 152 in a region defined by them. According to some embodiments, the EEG electrodes 104 are communicatively linked with an analyzer/controller (e.g., EEG analyzer 114) configured to obtain EEG signals from the EEG electrodes 104.

According to some embodiments, EEG analyzer 114 or other processing circuitry (e.g., a remote server, cloud computing service, local computer, etc.) is configured to analyze the obtained EEG signals and detect reaction activity associated with inducing electrical stimulation, such as TMS stimulation induced by TMS inducer 102. According to some embodiments, the EEG analyzer 114 is configured to detect neurological characteristics of the brain of the subject 152 (or its neural structures) by measuring the intensity of the reactive activity and comparing the intensity to model/reference activities that are assumed to be expected for various conditions and/or lack thereof. According to some embodiments, the EEG analyzer 114 is configured to detect neural network activity characteristics of the brain of the subject 152 (or its neural structure) by measuring the intensity of the reactive activity and comparing ratios between various pairs thereof, and comparing the intensity to model/reference activities assumed to be expected for various conditions and/or lack thereof.

According to some embodiments, the EEG analyzer 114 is configured to analyze EEG signals in dependence on their amplitude, slope, frequency, delay, area under the curve, etc. According to some embodiments, the EEG analyzer 114 is configured to perform frequency analysis of the EEG signal. According to some embodiments, the EEG analyzer 114 is configured to perform noise reduction filtering on the EEG signal. According to some embodiments, the EEG analyzer 114 is configured to perform noise cancellation filtering on the EEG signal. According to some embodiments, the EEG analyzer 114 is configured to perform temporal analysis of the EEG signal.

According to some embodiments, a neuronal stimulator (e.g., TMS unit 102) is configured to induce a plurality of stimulation pulses. According to some embodiments, the plurality of stimulation pulses are substantially equal in intensity. According to some embodiments, the plurality of stimulation pulses are substantially equal in duration. According to some embodiments, the plurality of stimulation pulses are substantially similar in slope. According to some embodiments, the plurality of stimuli differ in intensity, duration, and/or slope.

Reference is now made to fig. 2, which schematically illustrates a stimulation pulse train 200, according to some embodiments. Stimulation pulse train 200 may include a plurality of stimulation events, such as stimulation pulse 220, configured to evoke stimulation evoked by a stimulator device (e.g., TMS) at a determined time and intensity. According to some embodiments, the stimulation pulse train 200 may further comprise an EEG monitor 230 for measuring the response activity to the stimulation pulses 220. According to some embodiments, the EEG monitor 230 may be continuous throughout the period of the stimulation pulse train 200. According to some embodiments, the EEG monitor 230 may be intermittent.

According to some embodiments, stimulation pulses 220 include a first stimulation pulse 222a, followed by a first pulse delay interval 232a, a second stimulation pulse 222b, followed by a second pulse delay interval 232b, a third stimulation pulse 222c, followed by a third pulse delay interval 232c, a fourth stimulation pulse 222d, followed by a fourth pulse delay interval 232d, a fifth stimulation pulse 222e, followed by a fifth pulse delay interval 232 e.

According to some embodiments, the pulse delay intervals 232a, 232b, 232c, 232d, 232e are configured to enable differentiation between EEG recording/monitoring of the reaction activity associated with each of the stimulation pulses 222a, 222b, 222c, 222d, 222 e.

According to some embodiments, the stimulation pulses 222a, 222b, 222c, 222d, 222e may be substantially equal in intensity. According to some embodiments, the stimulation pulses 222a, 222b, 222c, 222d, 222e may vary in intensity.

According to some embodiments, the stimulation pulses 222a, 222b, 222c, 222d, 222e may be substantially equal in duration. According to some embodiments, the stimulation pulses 222a, 222b, 222c, 222d, 222e may vary in duration.

According to some embodiments, the pulse delay intervals 232a, 232b, 232c, 232d, 232e may be substantially equal in duration. According to some embodiments, the pulse delay intervals 232a, 232b, 232c, 232d, 232e may vary in duration.

According to some embodiments, the duration of the pulse is in the range of 0.5ms to 2 ms. According to some embodiments, the duration of the pulse is in the range of 1ms to 1.5 ms. According to some embodiments, the duration of the pulse is approximately 1 ms.

According to some embodiments, the delay interval is in the range of 100ms to 2 s. According to some embodiments, the delay interval is in the range of 250ms to 1 s. According to some embodiments, the delay interval is approximately 500 ms. According to some embodiments, the frequency of the pulses within the pulse train is in the range of 0.1Hz to 10 Hz. According to some embodiments, the frequency of the pulses within the pulse train is in the range of 1Hz to 5 Hz. According to some embodiments, the pulse frequency is about 2 Hz.

According to some embodiments, the response activity of the neural network in the brain is expected to vary between successive stimulation pulses. This may be due to the neural structural features of plasticity and excitability. As a result, the response activity associated with the second stimulation pulse may be significantly higher than the response activity associated with the first stimulation pulse. In addition, in the latter stimulation pulses, a gradual decrease of the response activity can be expected.

The amount/rate of increased and/or decreased activity may be indicative of characteristics of the neuronal network (neural structure), such as plasticity and firing and inhibition. Thus, irregularities in these characteristics can be detected and correlated to various conditions that may cause changes in these characteristics.

According to some embodiments, the stimulation pulse train may comprise 1 or more stimulation pulses. According to some embodiments, the stimulation pulse train may comprise 2 or more stimulation pulses. According to some embodiments, the stimulation pulse train may include 3 or more stimulation pulses. According to some embodiments, the stimulation pulse train may include 4 or more stimulation pulses. According to some embodiments, the stimulation pulse train may comprise 5 or more stimulation pulses. According to some embodiments, the stimulation pulse train may comprise 2 to 10 stimulation pulses. According to some embodiments, the stimulation pulse train may include 10 or more stimulation pulses.

According to some embodiments, multiple stimulation bursts may be induced to produce a stimulation session. According to some embodiments, the bursts are substantially similar between them. According to some embodiments, the pulse trains are separated in time by a relaxation interval/period therebetween (inter-pulse train interval). According to some embodiments, the inter-burst intervals (relaxation intervals/periods) are configured to eliminate reaction effects ("memory") between different bursts. According to some embodiments, the reactive activity associated with at least some of the bursts contributes to noise reduction and/or eliminates inconsistent/pending measurements.

As used herein, the term "inter-burst interval" may be interchangeable with the term "relaxation cycle" and may refer to a time period between bursts configured to facilitate separation and/or mitigation of effects between different stimulation bursts.

Reference is now made to fig. 3, which schematically illustrates a stimulation session 300, in accordance with some embodiments. The stimulation session may include a plurality of stimulation bursts 326. According to some embodiments, the stimulation bursts may be spaced apart in time, e.g., a first stimulation burst 328a followed by a first waiting period 332a, a second stimulation burst 328b followed by a second waiting period 332b, a third stimulation burst 328c followed by a third waiting period 332c, followed by a fourth stimulation burst 328 d.

According to some embodiments, each of the wait periods 332a, 332b, and 332c is configured to mitigate/eliminate a substantial portion or any effect that may occur between the reactive activities associated with the stimulation bursts (inter-burst intervals) 382a, 382b, 382c, and 382 d.

According to some embodiments, the term inter-burst interval may be interchanged with the terms "waiting period", "relaxation period" or "buffering period".

According to some embodiments, the reaction activity associated with each burst may be expected to be similar due to the inter-burst interval period. Thus, any outstanding reaction activity associated with a certain burst that does not match or is similar to reaction activities associated with other bursts may be considered false or may be ignored and not considered.

According to some embodiments, the reaction activity associated with at least some of the bursts is compared to noise reduction, averaging, statistical analysis, or the like.

According to some embodiments, inter-burst intervals 332a, 332b, and 332c may have substantially similar durations. According to some embodiments, wait periods 332a, 332b, and 332c may have different durations.

According to some embodiments, the inter-burst interval period may be at least 20 seconds. According to some embodiments, the inter-burst interval period may be at least 30 seconds. According to some embodiments, the inter-burst interval period may be at least 40 seconds. According to some embodiments, the inter-burst interval period may be at least 50 seconds. According to some embodiments, the inter-burst interval period may be at least 60 seconds. According to some embodiments, the inter-burst interval period may be in a range from 10 seconds to 20 minutes. According to some embodiments, the inter-burst interval period may be in a range from 20 seconds to 10 minutes. According to some embodiments, the inter-burst interval may be in the range from 30 seconds to 50 minutes.

According to some embodiments, a stimulation session may include 2 or more analog pulse trains. According to some embodiments, a stimulation session may include 3 or more stimulation bursts. According to some embodiments, a stimulation session may include 5 to 10 stimulation bursts. According to some embodiments, a stimulation session may include 10 or more stimulation bursts.

According to some embodiments, the stimulation pulse train may be substantially as shown in fig. 2.

According to some embodiments, some parameters, characteristics, and/or features that may be considered for evaluating neural network characteristics may include one or more of the following: amplitude, slope, frequency, delay, area under the curve and the ratio between them. According to some embodiments, these parameters may be responsive to or associated with the stimulation pulses.

Reference is now made to fig. 4, which schematically illustrates EEG response activity to stimulation bursts in a normal brain, according to some embodiments. As shown, the stimulation pulse train includes four stimulation pulses, the EEG recording of which is shown in a first pulse recording 406a, a second pulse recording 406b, a third pulse recording 406c and a fourth pulse recording 406 d. After each pulse recording, there is a response recording, namely a first response recording 408a, a second response recording 408b, a third response recording 408c, and a fourth response recording 408 d. As shown, the second and third response records 408b, 408c are larger than the first response record 408a, which may be due to excitatory or plastic properties of the relevant neural network, while the fourth response record 408d is substantially reduced in response compared to the remaining records, which may be due to adaptive properties of the relevant neural network.

According to some embodiments, a response that is different from a normal response or normal response range may be indicative of various abnormal neural network characteristics.

According to some embodiments, the intensity of the pulse is determined as a percentage of the reference value. According to some embodiments, the reference value is determined as a percentage from a motion threshold determined by the individual.

According to some embodiments, the motor threshold is a stimulation intensity at which a motor response may be triggered and/or detected as a result thereof.

According to some embodiments, the motor threshold is established by gradually increasing the stimulation intensity until a motor response is detected. According to some embodiments, the motion threshold may vary from person to person. According to some embodiments, the local electrical stimulation is induced in the brain using a TMS stimulator, and the motor threshold may be in the range of 1.5 to 2.5 tesla. According to some embodiments, the motion threshold may be in the range of 1.7 to 2.3 tesla. According to some embodiments, the motion threshold may be in the range of 1.8 to 2.2 tesla. According to some embodiments, the motion threshold may be in the range of 1.9 to 2.1 tesla. According to some embodiments, the motion threshold may be in a range of 48% to 52% of the maximum TMS device strength. According to some embodiments, the motion threshold may be about 50% of the maximum TMS device strength.

Once a motion threshold is established for a person, an "operating range" can be evaluated/calculated, which is a range of intensity values where reactive activity can be observed and where the activity corresponds to the intensity of the stimulus. According to some embodiments, the term "operating range" may be interchanged with the terms "relevant range" or "active range".

According to some embodiments, the "operating range" is in the range of 60% to 140% of the motion threshold. According to some embodiments, the "operating range" is in the range of 80% to 120% of the motion threshold. According to some embodiments, the "operating range" is in the range of 50% to 150% of the motion threshold.

According to some embodiments, the intensity of the stimulation pulse may be a value within an "operating range". According to some embodiments, the intensity of the stimulation pulse may be referred to as an "operating point".

Reference is now made to fig. 5, which schematically illustrates a stimulation intensity operating range, in accordance with some embodiments. As shown, the EEG response to low stimulus intensity is relatively constant until the stimulus intensity exceeds a certain value (lower threshold), and then the EEG response reacts/increases as the stimulus intensity increases until the stimulus intensity reaches another value (upper threshold) where the EEG response no longer responds to the increase in stimulus intensity.

According to some embodiments, the operating range is a range of intensity values between a lower threshold and an upper threshold.

Reference is now made to fig. 6, which schematically illustrates a method 600 for establishing a motion threshold, in accordance with some embodiments. According to some embodiments, the TMS device/unit is positioned (step 606) at a determined location on/near the subject's head, then magnetic stimulation pulses are induced (step 608), and then the mechanical response is monitored (step 610) for detecting the triggered motor movements. According to some embodiments, if motion movement is detected and a motion threshold is established (step 612), the motion threshold is provided (step 616), otherwise the pulse intensity is changed (step 614), and iterative steps induce magnetic stimulation pulses (step 608).

According to some embodiments, the changing of the pulse intensity (step 614) includes increasing the pulse intensity.

Reference is now made to fig. 7, which schematically illustrates a method 700 for providing a stimulated EEG response session, in accordance with some embodiments. According to some embodiments, an EEG cap is placed on the head of a subject (step 704), then a TMP device is positioned on/near the head of the subject (step 706), then a motion threshold ("MT") is established (step 708), then a magnetic stimulation pulse with an intensity of X% of the established MT is evoked (step 710). According to some embodiments, X% is a predetermined percentage of MT. The EEG response activity is then monitored (step 712) according to the operating range/value based on the motion threshold, and then optionally steps 710 and 712 are repeated, e.g. 20% up to 150%, when the stimulation amplitude rises to a certain level by a predetermined percentage (step 714), with a "pulse waiting" delay between iterations (step 716), and the response activity is analyzed (step 722).

Reference is now made to fig. 8, which schematically illustrates a method 800 for providing a stimulated EEG response session, in accordance with some embodiments. According to some embodiments, an EEG cap is placed on the head of a subject (step 804), then a TMP device is positioned on/near the head of the subject (step 806), then a motion threshold is established (step 808), then magnetic stimulation pulses are induced according to an operating range/value based on the motion threshold (step 810), then EEG response activity is monitored (step 812), then steps 810 and 812A are optionally repeated (step 814), with a "pulse waiting" delay between iterations (step 816), then optionally steps 810 to 814 are repeated B times (step 818), with a "pulse train waiting" (relaxation) delay between iterations (step 820), and response activity is analyzed (step 822).

According to some embodiments, a stimulation threshold is established. According to some embodiments, the stimulation threshold is a TMS stimulation intensity value above which reactive neural activity may be observed/detected.

According to some embodiments, the TMS stimulation intensity is "supra-threshold", selected to have a higher intensity than the stimulation threshold.

According to some embodiments, the TMS stimulation intensity is "subthreshold", selected to have an intensity lower than the stimulation threshold.

According to some embodiments, the analysis is performed after the stimulation session. According to some embodiments, the analysis is performed during a stimulation session.

According to some embodiments, a and B are predetermined numbers/values.

As used herein, the terms "neuron," "neural structure," "neural network" may be interchangeable.

As used herein, the term "TMS" may refer to transcranial magnetic stimulation, which is a non-invasive method for stimulating brain regions. In TMS, a magnetic field generator such as a coil or electromagnet is placed near/on the head of the subject receiving the stimulation, an electrical current is conducted through the coil, and a magnetic flux gradient is induced due to the change in the electrical current through the coil. According to some embodiments, the coil (or electromagnetic coil) is connected to a pulse generator or controller or stimulator configured to deliver current to the coil.

As used herein, the term "EEG" may refer to an electroencephalogram, which is generally a non-invasive method for recording electrical activity of the brain along the scalp. EEG measures voltage fluctuations caused by ionic currents within neurons/neural structures of the brain. According to some embodiments, EEG may refer to the recording of spontaneous and/or stimulated electrical activity of the brain over a period of time.

As used herein, the term "plasticity" may refer to neural plasticity or brain plasticity, which may include synaptic and/or non-synaptic plasticity, and may refer to changes in neural pathways and synapses and/or structures due to changes in behavior, environment, neural processes, thinking, mood, injury, and stimulation, among others.

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

While various exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain modifications, additions and sub-combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced are interpreted to include all such modifications, additions and sub-combinations as are within their true spirit and scope.

Claims (26)

1. A method for assessing brain activity of a subject, the method comprising:

providing at least three electrical stimulation pulses at a predetermined intensity to a region of the brain of the subject;

detecting at least three respective electroencephalogram (EEG) signals, each signal obtained in response to each of the at least three TMS pulses;

comparing between at least two EEG signals obtained in response to the at least two TMS pulses; and

assessing brain activity of the subject based at least on the comparison.

2. The method of claim 1, wherein the electrical stimulation pulses comprise magnetically induced electrical stimulation pulses.

3. The method of claim 2, wherein the magnetically induced electrical stimulation pulses comprise Transcranial Magnetic Stimulation (TMS) pulses.

4. The method of claim 1, wherein the electrical stimulation pulse comprises an electrically induced electrical stimulation pulse.

5. The method of claim 3, wherein the brain activity comprises one or more cranial nerve characteristics.

6. The method of claim 5, wherein the one or more cranial nerve properties comprise excitability, plasticity, or both.

7. The method of claim 3, wherein the predetermined intensity is based on a motion threshold intensity associated with the subject.

8. The method of claim 7, further comprising establishing a motion threshold intensity associated with the subject, comprising:

providing a plurality of TMS pulses to motor-related regions of the brain at different intensities;

monitoring the subject for a motor response; and

the intensity above which the motor response is observed is measured.

9. The method of claim 7, wherein the predetermined intensity is greater than 80% of the motion threshold intensity.

10. The method of claim 7, wherein the predetermined intensity is less than 120% of the motion threshold intensity.

11. The method of claim 3, further comprising:

providing a first TMS pulse to a first region of the subject's brain;

detecting a first EEG signal obtained in response to the first TMS pulse;

providing a second TMS pulse to a first region of the subject's brain;

detecting a second EEG signal obtained in response to the first TMS pulse;

providing a third TMS pulse to a first region of the subject's brain;

detecting a third EEG signal obtained in response to the first TMS pulse;

comparing at least two of the first, second and third EEG signals; and

assessing brain activity of the subject based at least on the comparison.

12. The method of claim 3, further comprising:

providing at least three TMS pulses to a second region of the subject's brain;

detecting at least three EEG signals, each signal obtained in response to each of the at least three TMS pulses;

comparing between at least two EEG signals obtained in response to the at least two TMS pulses; and

brain activity of the subject is assessed based on a comparison between at least two EEG signals and an EEG signal obtained in response to a TMS pulse being provided to a first region and an EEG signal obtained in response to a TMS pulse being provided to a second region.

13. The method of claim 12, wherein the first and second regions comprise the right and left hemispheres of the brain, respectively.

14. The method of claim 3, wherein the comparison comprises a comparison between:

the amplitude of the initial EEG response to TMS or different time markers of the characterized EEG,

slope (rise time) of characterized EEG different time-stamps or initial EEG response to TMS

The area under the curve (AUC) of the TMS response, either the entire AUC or a single priority target characterizes different markers of the EEG,

or any combination thereof.

15. A system for assessing brain activity of a subject, the system comprising:

an electrical stimulation device configured to provide electrical stimulation pulses to a region of the brain of a subject;

an electroencephalogram (EEG) device configured to monitor neural activity in the brain of the subject and provide EEG signals indicative of neural activity in the brain of the subject; and

processing circuitry configured to make a comparison between at least two EEG signals obtained in response to at least two electrical stimulation pulses and to assess brain activity of the subject based at least on the comparison.

16. The system of claim 15, wherein the electrical stimulation device comprises a Transcranial Magnetic Stimulation (TMS) device and the electrical stimulation pulses comprise TMS pulses.

17. The system of claim 16, wherein the brain activity comprises one or more cranial nerve characteristics.

18. The system of claim 17, wherein the one or more cranial nerve characteristics comprise excitability, plasticity, or both.

19. The system of claim 16, wherein the TMS device is configured to:

providing at least one TMS stimulation pulse comprising a plurality of TMS stimulation pulses,

wherein the plurality of TMS stimulation pulses are separated in time.

20. The system of claim 19, wherein the processing circuitry is configured to compare between at least two EEG signals obtained in response to at least two TMS pulses of the TMS stimulation pulse train, and to assess brain activity of the subject based at least on the comparison.

21. The system of claim 19, wherein the TMS device is further configured to:

providing at least one TMS stimulation session comprising a plurality of TMS stimulation bursts,

wherein the TMS stimulation bursts are separated in time by inter-burst intervals.

22. The system of claim 21, wherein the processing circuitry is configured to obtain EEG signals indicative of brain activity responses associated with at least some of the TMS stimulation bursts, and to generate a representative EEG burst activity response comprising a representative EEG pulse activity response.

23. The system of claim 21, wherein the inter-burst intervals have a duration of at least 20 seconds.

24. The system of claim 21, wherein a representative EEG burst comprises an average of EEG signals indicative of brain activity responses associated with at least some of the TMS stimulation bursts.

25. The system according to claim 21, wherein said processing circuitry is further configured to make a comparison between at least two representative EEG pulse activity responses and to assess brain activity of said subject based at least on said comparison.

26. The system of claim 16, wherein the processing circuitry is configured to perform the comparison based on at least:

the amplitude of the initial EEG response to TMS or different time markers of the characterized EEG,

slope (rise time) of characterized EEG different time-stamps or initial EEG response to TMS

The area under the curve (AUC) of each TMS response (charge transfer), the entire AUC or a single priority target characterizes EEG different markers, or any combination thereof.