Training for stress disorders

Abstract

1. A method for training a subject diagnosed with a trauma-induced stress disorder, comprising: selecting a challenge believed to induce symptoms of the stress disorder in the subject; exposing the subject to the challenge; recording with at least one electrode electrical signals produced by the subject's brain in conjunction with the exposure; processing the recorded electrical signals to estimate activity levels in at least one specific brain region; providing at least one indicator of the estimated activity levels to the subject; and repeating the recording, processing, and providing.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 777,187, filed December 9, 2018, which is incorporated by reference in its entirety. [Background technology]

[0002] The present invention in some embodiments relates to training for stress disorders, and more particularly, but not exclusively, to training for post-traumatic stress disorder. Summary of the Invention

[0003] Some examples of some embodiments of the present invention are listed below. It should be noted that elements of any example can be used in combination with elements of other examples.

[0004] Example 1. A method for training a subject diagnosed with a stress disorder, comprising: Subjects diagnosed with a stress disorder were exposed to a trauma-related challenge, During said exposure, providing feedback to said subject regarding the activity level of one or more brain regions and / or neural circuits. The method includes:

[0005] Example 2. The method of Example 1, wherein said exposure to said trauma-related challenge affects activity of said one or more brain regions and / or neural circuits.

[0006] Example 3. Recording electrical signals from the subject during or after the exposure; The method of Example 1, comprising generating an electrical fingerprint (EFP) related to a current activity level of the one or more brain regions and / or neural circuits based at least in part on the recorded electrical signals, and wherein the delivering is delivery of feedback responsive to the current activity level of the one or more brain regions and / or neural circuits.

[0007] Example 4. The method of Example 3, wherein delivering said feedback comprises modifying said trauma-related challenge depending on a current activity level.

[0008] Example 5. The method of example 3 or 4, wherein said electrical signals are EEG and / or EMG electrical signals.

[0009] Example 6. The method of any one of the above examples, wherein said trauma-related challenge comprises a challenge selected to activate the amygdala and / or amygdala-related neural circuitry.

[0010] Example 7. The method of any one of the above examples, wherein the trauma-related challenge comprises a challenge tailored to the subject's particular trauma and / or particular stress disorder.

[0011] Example 8. The method of any one of the above examples, wherein said stress disorder comprises post-traumatic stress disorder (PTSD).

[0012] Example 9. The method of any one of the above examples, wherein the trauma-related challenge is selected to upregulate activity in one or more brain regions, and the feedback is delivered responsive to the ability of the subject to downregulate the activity level.

[0013] Example 10. The method of any one of the above examples, wherein said delivering comprises delivering said feedback to said subject according to an ability of said subject to cope with said trauma-related challenge.

[0014] Example 11. A method for training a subject diagnosed with a stress disorder, comprising: Subjects diagnosed with a stress disorder are exposed to a non-specific stress challenge, assessing the subject's ability to cope with the non-specific stress challenge; providing a tailored stress-related challenge to the subject in response to the results of said assessment; The method includes:

[0015] Example 12. The method of Example 11, wherein said exposing comprises exposing said subject to a non-specific stress challenge selected to activate one or more brain regions, and said evaluating comprises evaluating the ability of said subject to cope with the activation of said one or more brain regions by said non-specific stress challenge.

[0016] Example 13. The method of Example 12, wherein said evaluating comprises evaluating the ability of said subject to affect activation of said one or more brain regions.

[0017] Example 14. The method of Example 12 or 13, wherein the non-specific stress challenge is configured to upregulate activity of the amygdala and / or amygdala-related neural circuitry.

[0018] Example 15. The method of Example 14, wherein said evaluating comprises evaluating the ability of said subject to downregulate activity of said amygdala and / or said amygdala-associated circuitry during said exposure.

[0019] Example 16. A method for training a subject diagnosed with a stress disorder, comprising: exposing a subject diagnosed with a stress disorder to a stress-related challenge; Modifying the stress-related challenge during the exposure to provide feedback to the subject. The method includes:

[0020] Example 17. The method of Example 16, further comprising determining an activity level of one or more brain regions after said exposure, and said providing comprises providing said feedback by modifying said stress-related challenge in response to said determined activity level.

[0021] Example 18. The method of Example 17, wherein said determining comprises determining that the activity level of said one or more brain regions is downregulated and said providing comprises decreasing the intensity of said stress-related channel.

[0022] Example 19. A device program configured to provide delivery of one or more of the exposures, evaluations and / or feedback as claimed above.

[0023] Further examples of some embodiments of the present invention are listed below. It should be noted that elements of any example may be used in combination with elements of other examples.

[0024] Example 1: A method for training a subject diagnosed with a traumatic stress disorder, comprising: selecting a challenge believed to induce symptoms of said stress disorder in said subject; exposing said subject to said challenge; recording, with at least one electrode, electrical signals produced by the subject's brain in conjunction with said exposure; processing the recorded electrical signals to estimate an activity level in at least one specific brain region; providing at least one indication of said estimated activity level to said subject; Repeating the recording, processing and providing. The method includes:

[0025] Example 2: The method of Example 1, wherein said exposure to said challenge affects the level of activity in said at least one particular brain region.

[0026] Example 3: The method of Example 1 or 2, further comprising identifying a relationship between at least a portion of the recorded electrical signals and an electrical fingerprint representative of an activity level of the at least one particular brain region, and wherein said generating comprises generating the at least one index based on the identified relationship.

[0027] Example 4: The method of any one of the above examples, wherein said providing comprises modifying said challenge based on said activity level in said at least one brain region.

[0028] Example 5: The method of any of the above examples, wherein the at least one brain region is a limbic brain region and has a volume of at least 20% of the limbic system volume.

[0029] Example 6: The method of any one of the above examples, wherein the challenges include challenges selected to activate the amygdala and / or brain regions connected to the amygdala by a neural network.

[0030] Example 7: The method of any one of the above examples, wherein the at least one specific brain region comprises two or more specific brain regions.

[0031] Example 8: The method of any one of the above examples, wherein the at least one specific brain region does not include the amygdala.

[0032] Example 9: The method of any one of the above examples, wherein the stress disorder comprises post-traumatic stress disorder (PTSD).

[0033] Example 10: The method of any one of the above examples, wherein the challenge is selected to upregulate the at least one specific brain region, and the at least one indicator is provided in response to the subject's ability to downregulate the activity level.

[0034] Example 11: The method of any one of the above examples, comprising instructing the subject to perform at least one exercise selected to affect the activity level of the at least one particular brain region.

[0035] Example 12: The method of Example 11, wherein said providing comprises providing said at least one indicator as a function of said subject's ability to modulate an activity level of said at least one specific brain region by performing said at least one exercise.

[0036] Example 13: The method of any one of the above examples, wherein said linking with exposure includes linking before, during, and / or after exposure.

[0037] Example 14: A method for selecting subjects for training against stress disorders, comprising: assessing a subject diagnosed with a trauma-induced stress disorder to identify at least one trauma-related challenge that is believed to induce the trauma in the subject and at least one non-specific stress challenge that is believed to not induce the trauma in the subject; exposing said subject to said at least one non-specific stress challenge; assessing the subject's ability to self-regulate the level of activity of at least one specific brain region affected by the trauma during and / or after the exposure; providing said at least one trauma-related challenge to said subject in response to a result of said assessment.

[0038] Example 15: The method of Example 14, wherein the stress disorder comprises post-traumatic stress disorder (PTSD).

[0039] Example 16: The method of Example 14 or 15, wherein the at least one non-specific stress challenge is configured to upregulate activity in the amygdala and / or brain regions connected to the amygdala by a neural network.

[0040] Example 17: The method of Example 16, wherein said evaluating comprises evaluating the ability of said subject to downregulate activity of said amygdala and / or said amygdala-associated circuitry during and / or after said exposure.

[0041] Example 18: The method of any one of the above examples, comprising recording electrical signals from the subject with at least one electrode during and / or after the exposure, at least a portion of the recorded electrical signals being indicative of an activity level of the at least one specific brain region, and wherein the evaluating comprises evaluating an ability of the subject to affect activity of the at least one specific brain region based on the recorded electrical signals.

[0042] Example 19: The method of Example 18, wherein the electrical signal comprises an EEG signal recorded by at least one EEG electrode.

[0043] Example 20: The method of any one of Examples 14 to 19, wherein the at least one specific brain region does not include the amygdala.

[0044] Example 21: A method for training a subject diagnosed with a traumatic stress disorder, comprising: selecting a challenge believed to induce said trauma in said subject; exposing said subject to said challenge; measuring the subject's response to the challenge; Modifying the challenge in response to the measured response thereby providing feedback to the subject. The method includes:

[0045] Example 22: The method of Example 21, wherein said measuring comprises determining an activity level of at least one specific brain region, and said providing comprises providing feedback to the subject by modifying the challenge in response to the determined activity level.

[0046] Example 23: The method of Example 21 or 22, comprising recording electrical signals of the subject with at least one electrode in conjunction with said exposing, at least a portion of said recorded electrical signals being indicative of an activity level of said at least one specific brain region, and said determining comprises determining said activity level of said at least one specific brain region based on said electrical signals.

[0047] Example 24: The method of Example 23, wherein the electrical signal comprises an EEG signal recorded by at least one EEG electrode.

[0048] Example 25: The method of Example 24, wherein the determining comprises identifying a relationship between at least a portion of the recorded EEG signal and at least one EEG signature or an indicator thereof stored in a recording medium, the at least one EEG signature being indicative of an activity level of the at least one particular brain region.

[0049] Example 26: The method according to any one of Examples 23 to 25, wherein said linking with exposure includes linking before, during and / or after exposure.

[0050] Example 27: The method of any one of Examples 23 to 26, wherein the at least one specific brain region comprises the amygdala.

[0051] Example 28: The method of any one of Examples 21-27, wherein the exposing comprises exposing the subject diagnosed with a stress disorder to a stress-related challenge while the subject is not confined to an imaging system.

[0052] Example 29: A method for training a subject diagnosed with a traumatic stress disorder, comprising: assessing at least one neurobehavioral process impaired in said stress disorder in said subject; Selecting a challenge in response to the identified impaired neurobehavioral process; exposing said subject to said selected challenge; recording, with at least one electrode, electrical signals produced by the subject's brain in conjunction with said exposure; processing the recorded electrical signals to estimate an activity level in at least one specific brain region; providing at least one indication of said estimated activity level to said subject; Repeating the recording, processing and providing. The method includes:

[0053] Example 30: The method of Example 29, comprising specifically designing the challenge according to the impaired neurobehavioral process.

[0054] Example 31: The method of Example 29 or 30, comprising assessing the expression of at least one symptom of the stress disorder in the subject, wherein said assessing comprises assessing the at least one impaired neurobehavioral process based on said expression of the at least one symptom.

[0055] Example 32: The method of any one of Examples 29 to 31, wherein the at least one impaired neurobehavioral process comprises at least one selected from an impaired stress detection process, an impaired emotion regulation process, and an impaired fear extinction process.

[0056] Example 33: The method of any one of Examples 29-32, wherein the stress disorder comprises post-traumatic stress disorder (PTSD).

[0057] Example 34: The method of any one of Examples 29 to 33, comprising instructing the subject to perform at least one exercise in a controlled relationship with the exposure, the at least one exercise configured to affect an activity level of the at least one specific brain region.

[0058] Example 35: The method of any one of Examples 29 to 34, comprising determining an activity level of the at least one specific brain region by identifying a relationship between at least a portion of the recorded electrical signals and at least one electrical signature or an indicator thereof stored in a recording medium, wherein the at least one electrical signature or an indicator thereof represents an activity level of the at least one specific brain region.

[0059] Example 36: The method of any one of Examples 29 to 35, wherein the at least one brain region is a limbic brain region, the at least one brain region having a volume of at least 20% of the limbic system volume.

[0060] Example 37: The method of any one of Examples 29 to 36, wherein the at least one specific brain region comprises the amygdala.

[0061] Example 38: The method of any one of Examples 29-37, wherein the exposing comprises exposing the subject diagnosed with a stress disorder to an impaired neurobehavioral process-related challenge while the subject is not confined to an imaging system.

[0062] Example 39: A method for treating a depression or anxiety disorder, comprising: Provide subjects diagnosed with PTSD and depression, or PTSD and anxiety, Training the subject using neurofeedback to control activity in at least one specific brain region to reduce the severity of PTSD and improve symptoms of depression or anxiety. The method includes:

[0063] Example 40: Evaluating the depression or anxiety disorder in the subject after the training; Modifying the neurofeedback training based on the results of the evaluation. The method of Example 39, further comprising:

[0064] Example 41: The method of Example 39 or 40, further comprising adjusting an existing dosing regimen with at least one bioactive compound for treating depression or anxiety disorder in the subject, or establishing a new dosing regimen comprising at least one bioactive compound for treating depression or anxiety disorder in the subject, based on the success of the training.

[0065] Example 42: Neurofeedback training: exposing said subject to a challenge associated with said subject's trauma; Instructing the subject to perform at least one exercise in conjunction with the exposure, the at least one exercise configured to affect an activity level of at least one specific brain region; recording electrical signals from the subject with at least one electrode during and / or after said exposure, at least a portion of said recorded electrical signals being indicative of an activity level of said at least one particular brain region; providing feedback to the subject regarding a level of activity in the at least one particular brain region in conjunction with the exposure based on the recorded electrical signals. The method of any one of Examples 39 to 41, comprising:

[0066] Example 43: The method of example 42, wherein the electrical signal comprises an EEG electrical signal.

[0067] Example 44: The method of any one of Examples 39 to 43, wherein the training is performed while the subject is not confined to an imaging system.

[0068] Example 45: A method for preparing a subject for an anticipated trigger of a stress disorder, comprising: providing a list of exercises that alter activity in at least one specific brain region; receiving the index prior to exposing the subject to a stress disorder trigger; Instructing the subject diagnosed with the stress disorder to perform at least one exercise from the list of exercises. The method includes:

[0069] Example 46: Recording EEG signals generated by the subject's brain. estimating an activity level of said at least one specific brain region based on said recorded EEG signals; providing said subject with at least one indication of said estimated activity level; The method of Example 42, comprising:

[0070] Example 47: A device for delivering training for stress disorders, comprising: A recording medium; a control circuit operatively coupled to the recording medium; Equipped with delivering to the subject a challenge configured to induce at least one symptom of the stress disorder in the subject; receiving at least one electrical signal generated by the subject's brain; using the received electrical signals to assess an effect of the challenge on at least one particular brain region and an effect of an activity level of the at least one particular brain region on the subject; Based on the results of the evaluation, a human-detectable indicator is automatically generated. An apparatus configured as follows.

[0071] Example 48: The apparatus of example 47, further comprising a user interface, configured to allow a user to select the challenge from a list of challenges stored on the recording medium using the user interface.

[0072] Example 49: The apparatus of example 47, wherein the control circuitry is configured to select the challenge from a list of challenges stored on the recording medium.

[0073] Example 50: The apparatus of any one of Examples 47 to 49, wherein the control circuitry is configured to process the effect to determine how to vary the challenge.

[0074] Example 51: The apparatus of any one of Examples 47 to 50, wherein the at least one electrical signal comprises an EEG signal.

[0075] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.Although methods and materials similar or equivalent to those described herein can be used to practice or test embodiments of this invention, exemplary methods and / or materials are described below.In case of conflict, the patent specification, including definitions, shall prevail.In addition, the materials, methods, and examples are merely illustrative and are not necessarily intended to be limiting.

[0076] As will be appreciated by those skilled in the art, some embodiments of the present invention may be implemented as a system, a method, or a computer program product. Accordingly, some embodiments of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, microcode, etc.), or an embodiment combining software and hardware aspects, all of which may be generally referred to herein as a "circuit," "module," or "system." Furthermore, some embodiments of the present invention may take the form of a computer program product embodied in one or more computer readable mediums having computer readable program code embodied therein. Implementation of the methods and / or systems of some embodiments of the present invention may include performing and / or completing selected tasks manually, automatically, or a combination thereof. Furthermore, depending on the actual equipment and apparatus of some embodiments of the methods and / or systems of the present invention, some selected tasks may be performed by hardware, by software, by firmware, and / or by a combination thereof (e.g., using an operating system).

[0077] For example, hardware performing selected tasks according to some embodiments of the present invention may be implemented as a chip or circuit. As software, selected tasks according to some embodiments of the present invention may be implemented as a number of software instructions executed by a computer using any suitable operating system. In an exemplary embodiment of the present invention, one or more tasks according to some exemplary embodiments of the methods and / or systems described herein are performed by a data processor (such as a computing platform executing a number of instructions). The data processor optionally includes volatile memory for storing instructions and / or data, and / or non-volatile storage (e.g., a magnetic hard disk and / or removable media) for storing instructions and / or data. Optionally, a network connection is also provided. Optionally, a display and / or a user input device (such as a keyboard or mouse) are also provided.

[0078] Some embodiments of the invention may utilize any combination of one or more computer readable media. The computer readable medium may be a computer readable signal medium or a computer readable storage medium. The computer readable storage medium may be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination thereof. More specific (but non-exhaustive) examples of computer readable storage media include the following: an electrical connection having one or more wires, a portable computer disk, a hard disk, a random access memory (RAM), a read only memory (ROM), an erasable programmable read only memory (EPROM or flash memory), an optical fiber, a portable compact disk read only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination thereof. In the context of this document, a computer readable storage medium may be any tangible medium that can contain or store a program for use by or in connection with a system, apparatus, or device that executes instructions.

[0079] Computer-readable signal media include propagated data signals in which computer-readable program code is embodied, for example, in baseband or as part of a carrier wave. Such propagated signals may take any of a variety of forms, including but not limited to electromagnetic, optical, or any suitable combination thereof. Computer-readable signal media are not computer-readable storage media and may be any computer-readable medium that can convey, propagate, or carry a program for use by or in connection with a system, apparatus, or device that executes instructions.

[0080] Program code embodied in a computer readable medium and / or data used by such program code may be transmitted using any suitable medium (including but not limited to wireless, wired, fiber optic cable, radio frequency, etc., or any suitable combination thereof).

[0081] Computer program code for carrying out operations of some embodiments of the present invention may be written in any combination of one or more programming languages, including object-oriented programming languages ​​(such as Java, Smalltalk, C++, etc.) and conventional procedural programming languages ​​(such as the "C" programming language or similar programming languages). The program code may run entirely on the user's computer, or parts of it may run on the user's computer as a separate software package, or parts of it may run on the user's computer and parts of it on a remote computer, or entirely on a remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network (including a local area network (LAN) or a wide area network (WAN)) or may form a connection to an external computer (e.g., through the Internet using an Internet Service Provider).

[0082] Some embodiments of the present invention are described below with reference to flowcharts and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the present invention. It will be understood that each block of the flowcharts and / or block diagrams, and combinations of blocks in the flowcharts and / or block diagrams, can be implemented by computer program instructions. These computer program instructions can be provided to a processor of a general purpose computer, a special purpose computer, or other programmable data processing apparatus forming a machine, such that these instructions (executed via the processor of the computer or other programmable data processing apparatus) form means for implementing the functions / acts specified in one or more blocks of the flowcharts and / or block diagrams.

[0083] These computer program instructions may be stored on a computer-readable medium that can direct a computer, other programmable data processing apparatus, or other device to function in a particular manner, such that the instructions stored on the computer-readable medium form an article of manufacture including instructions that implement the functions / acts specified in one or more blocks of the flowcharts and / or block diagrams.

[0084] The computer program instructions may be loaded into a computer, other programmable data processing apparatus, or other device such that a series of operational steps are performed on the computer, other programmable data processing apparatus, or other device to produce a computer-implemented process, such that the instructions, which execute on the computer or other programmable apparatus, provide a process for performing the functions / operations specified in one or more blocks of the flowcharts and / or block diagrams.

[0085] Some of the methods described herein are generally designed for computational use only and may not be suitable or practical for purely manual execution by an expert. An expert wishing to manually execute a similar task (such as determining activity levels of brain regions) would be expected to use an entirely different method (e.g., leveraging expert knowledge and / or the pattern recognition capabilities of the human brain) that is much more efficient than performing the steps of the methods described herein manually.

[0086] Certain embodiments of the present invention are described herein, by way of example only, with reference to the accompanying drawings, in which it is emphasized that the details shown hereinafter, with particular reference to the drawings, are for the purposes of illustration and for the purpose of detailed description of embodiments of the present invention. Similarly, from a reading of the description together with the drawings, it will become apparent to those skilled in the art how embodiments of the present invention may be practiced. [Brief description of the drawings]

[0087] [Figure 1] 1 is a flow chart of a stress disorder neurofeedback (NF) training process, such as an Electrical Fingerprint Neurofeedback (EFP-NF) training process, from a patient's perspective, according to some embodiments of the present invention. [Figure 2A] 1 is a flowchart of a NF training process, e.g., an EFP-NF training process, according to some embodiments of the present invention. [Figure 2B] FIG. 2 is a schematic diagram showing types of evaluations of a patient, e.g., a patient diagnosed with a stress disorder, according to some exemplary embodiments of the present invention. [Figure 2C] 1 is a schematic illustration of a matrix showing the relationship between some symptoms of stress disorders (e.g., PTSD) and impaired neurobehavioral processes, according to some exemplary embodiments of the present invention. [Figure 2D]1 is a schematic illustration of an interface generated and delivered to a trainee based on the trainee's symptoms and / or impaired neurobehavioral processes, according to some exemplary embodiments of the present invention. [Figure 2E] 1 is a schematic illustration of an interface generated and delivered to a trainee based on the trainee's symptoms and / or impaired neurobehavioral processes, according to some exemplary embodiments of the present invention. [Figure 2F] 1 is a schematic illustration of an interface generated and delivered to a trainee based on the trainee's symptoms and / or impaired neurobehavioral processes, according to some exemplary embodiments of the present invention. [Figure 2G] 1 is a flowchart of a NF training process tailored to a trainee according to the trainee's stress disorder-related symptoms and / or impaired neurobehavioral processes, according to some exemplary embodiments of the present invention. [Figure 2H] FIG. 1 is a graph showing change in stress disorder-related symptoms as measured using the CAPS-5 subscales following NF training, according to some exemplary embodiments of the present invention. [Figure 2I] FIG. 1 is a graph showing change in stress disorder-related symptoms as measured using the CAPS-5 subscales following NF training, according to some exemplary embodiments of the present invention. [Figure 2J] FIG. 1 is a graph showing change in stress disorder-related symptoms as measured using the CAPS-5 subscales following NF training, according to some exemplary embodiments of the present invention. [Figure 2K] FIG. 1 is a graph showing change in stress disorder-related symptoms as measured using the CAPS-5 subscales following NF training, according to some exemplary embodiments of the present invention. [Diagram 3] 1 is a flowchart of a process for providing feedback to a patient during a NF training process by modifying an exposure interface, e.g., a trauma-related exposure interface of a NF training, according to some embodiments of the present invention. [Figure 4]FIG. 1 is a block diagram of a system for delivery of NF training, e.g., FP-NF training, according to some embodiments of the present invention. [Diagram 5] 1 is an overview of the trial, detailing the overall process of the study, from subject recruitment to follow-up. [Figure 6] 1 is a table showing demographic and basic clinical information for the study participant group. [Figure 7] The overall sequence of intervention sessions in the intervention groups is shown. [Figure 8] 1 presents a protocol for an animation scenario-neutral interface. [Figure 9] 1 shows an auditory neutral interface. [Figure 10] We present the protocol section detailing the graded exposure of patients in the exposure group to individual traumatic content, where patients begin training in a neutral context and, once they have reached a skill level, move on to training with the individual traumatic content in the exposure sessions. [Figure 11] 13 is a graph showing an example of the change in EFP signal during the first exposure session in one patient in the exposure group. [Figure 12A] 12 is a graph showing the changes in EFP signals occurring in different sessions in an experiment with the patient appearing in FIG. 11. [Figure 12B] 12 is a graph showing the changes in EFP signals occurring in different sessions in an experiment with the patient appearing in FIG. 11. [Figure 12C] 12 is a graph showing the changes in EFP signals occurring in different sessions in an experiment with the patient appearing in FIG. 11. [Figure 12D] 12 is a graph showing the changes in EFP signals occurring in different sessions in an experiment with the patient appearing in FIG. 11. [Figure 12E] 12 is a graph showing the changes in EFP signals occurring in different sessions in an experiment with the patient appearing in FIG. 11. [Figure 12F] 12 is a graph showing the changes in EFP signals occurring in different sessions in an experiment with the patient appearing in FIG. 11. [Figure 12G]12 is a graph showing the changes in EFP signals occurring in different sessions in an experiment with the patient appearing in FIG. 11. [Figure 13] FIG. 1 is a graph showing the change in mean EFP Z-score during 13 weeks of NF training in the study. [Figure 14] A and B are graphs showing the mean change in EFP Z-score in different experimental groups. [Figure 15] 1 is a graph showing the change in CAPS-5 total score in participants in the three groups of the study after NF training. [Figure 16A] 13 is a graph showing the change in CAPS-5 total score in individual trainees who received EFP-NF in a neutral context during the experiment. [Figure 16B] 1 is a graph showing the change in CAPS-5 total score in individual trainees who received EFP-NF in an exposure context during the experiment. [Figure 16C] 1 is a graph showing the percentage of participants in each arm of the study who showed an improvement of more than 5 points on the CAPS-5 total score. [Figure 17] 1 is a graph showing the changes in different CAPS-5 subscales among the various groups of the study. [Figure 18] 1 is a graph showing the changes in PCL scores between the different groups of the experiment. [Figure 19] Represents target (e.g. amygdala) engagement after training. [Figure 20] Figure 1 shows the correlation between EFP training success index and BOLD activation during subsequent real-time fMRI neurofeedback. This positive correlation indicates that participants who were very successful in down-regulating their EFP signal during the training session (i.e., the overall optimal performing session) were also better at down-regulating their amygdala BOLD signal during real-time neurofeedback after the intervention. [Figure 21A] Schematic diagram of the experimental process. [Figure 21B] FIG. 21B is a schematic diagram of the training sessions carried out in the experiment of FIG. 21A. [Figure 22] 21B shows two graphs illustrating the learning effect of NF training, represented as amygdala EFP signal changes during NF training performed in the experiment of FIG. 21A, according to some exemplary embodiments of the present invention. [Figure 23A] FIG. 21B is a graph showing the change in total CAPS-5 score after NF training performed in the experiment of FIG. 21A. [Figure 23B] FIG. 21B is a graph showing the change in Total CAPS-5 score Percent Symptom Reduction from TP1 to TP2 following NF training performed in the experiment of FIG. 21A. [Figure 23C] FIG. 21B is a graph showing the change in total PCL assessed after NF training performed in the experiment of FIG. 21A. [Figure 23D] FIG. 21B is a graph showing the change in total PCL during the experiment and at follow-up, assessed after NF training performed in the experiment of FIG. 21A. [Figure 24A] Graph and brain diagram showing rtfMRI-NF target engagement in the experiment of FIG. 21A. [Figure 24B] FIG. 21B is a CONSORT flow chart of the experiment in FIG. [Diagram 25] Schematic diagram of the rtfMRI-NF paradigm. [Figure 26A] 1 is a graph showing the change in BDI-II score after NF training. [Figure 26B] 1 is a graph showing changes in STAI scores after NF training. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] The present invention in some embodiments relates to training for stress disorders, and more particularly, but not exclusively, to training for post-traumatic stress disorder.

[0089] Post-traumatic stress disorder (PTSD) is characterized by, for example, emotional hyper-reactivity and loss of emotional control, which correspond to changes in the activity level of at least one brain region, for example, hyperactive amygdala and hypoactive ventromedial prefrontal cortex (vmPFC). One of the problems in treating PTSD is the non-specific targeting of such abnormal processes. In some embodiments of the present invention, neurofeedback (NF) interventions, for example, electrical fingerprint (EFP)-NF for PTSD patients, are adapted to downregulate the activity of the amygdala or other stress-related regions. In some embodiments, tailored trauma-related content is adapted as learning feedback to target disorder-specific processes, allowing for personalized process-based NF. In some embodiments, electrical fingerprint (EFP) is generated, for example, as described in US Patent No. 13 / 983,419.

[0090] According to some embodiments, the brain region is a brain region that is part of different neuroanatomical layers of the brain, for example, the first layer, the second layer and the third layer of the neuroanatomical regions of the brain. In some embodiments, the brain region is a brain region located in at least one of the hindbrain, the midbrain and the forebrain, for example, the second layer or the third layer. In some embodiments, the brain region is at least one brain region of the limbic system, for example, a brain region of the limbic system having a volume of at least 20% or less, 10% or less, 5% or less, or any intermediate value, less than or greater than the total volume of the limbic system. In some embodiments, the brain region has a volume of at least 10% or less, 8% or less, 5% or less, 1% or less, or any intermediate value, less than or greater than the total volume of the brain. In some embodiments, the brain region is at least one portion of the limbic system, the salience network, the mesolimbic system, the reward circuit, the prefrontal control circuit, the ventromedial prefrontal cortex, the brainstem, the threat circuit, and the cerebellum.

[0091] According to some embodiments, the PTSD patient is evaluated after and / or before EFP-NF treatment, e.g., using CAPS-5 and / or PCL assessment methods to determine clinical severity. Optionally, the PTSD patient is evaluated for neural target engagement using amygdala fMRI-NF.

[0092] According to some embodiments, a patient diagnosed with a stress disorder treated with EFP-NF training, e.g., using EFP-NF with a personalized trauma interface, performs the exercises learned during EFP-NF and downregulates AmygEFP signals and / or activity in at least one stress-related brain region, optionally without receiving feedback.

[0093] An aspect of some embodiments of the present invention relates to training subjects suffering from stress disorders, such as post-traumatic stress disorder (PTSD), using neurofeedback (NF) training, such as electrical fingerprint-neurofeedback (EFP-NF). In some embodiments, the electrical fingerprint (EFP) is an electroencephalography (EEG) fingerprint associated with activity levels of one or more brain regions, such as those described in US20140148657A1. In some embodiments, the EFP-NF training affects activity levels of brain regions and / or neural circuits associated with stress disorders, such as memory of the trigger of the stress disorder. In some embodiments, the EFP-NF affects activity levels of brain regions and / or neural circuits associated with memory of a traumatic event, such as the traumatic event that triggered the stress disorder (e.g., PTSD). In some embodiments, the stress disorder includes agoraphobia without a history of panic disorder, social anxiety disorder, specific phobia, obsessive-compulsive disorder, depression, and substance abuse.

[0094] According to some embodiments, the electrical fingerprint (EFP) comprises an EEG electrical fingerprint of the amygdala and / or other brain regions associated with one or more stress disorders (e.g., PTSD). In some embodiments, EFP-NF training is used to selectively affect stress disorder-related brain regions and / or neural circuits. In some embodiments, EFP-NF training reduces activity levels of stress disorder-related brain regions and / or neural circuits. Alternatively or additionally, EFP-NF training increases activity levels of stress disorder-related brain regions and / or neural circuits. In some embodiments, stress disorder (e.g., PTSD) EFP-NF training is used to reduce activity of the amygdala.

[0095] According to some embodiments, EEG signals are recorded from a subject (e.g., a trainee) during EFP-NF training. In some embodiments, the trainee is a patient diagnosed with a stress disorder. In some embodiments, at least a portion of the recorded EEG signals are analyzed to determine, for example, a current activity state of a selected brain region (e.g., the amygdala). In some embodiments, a stored EEG electrical fingerprint associated with a particular activity level of a brain region is used to determine the current activity level at the brain level, for example, by correlating the recorded EEG signals with the stored EEG signals.

[0096] According to some embodiments, during EFP-NF training, the activity level of selected brain regions (e.g., amygdala) is monitored. In some embodiments, the trainee learns how to regulate the activity of the brain region, for example, how to upregulate the activity of the brain region and / or how to downregulate the activity. In some embodiments, the trainee receives feedback on the success of reaching the desired activity level.

[0097] According to some embodiments, the feedback is online, e.g., while the subject is performing one or more exercises for regulating the activity of the brain region. Alternatively or additionally, the feedback is continuous. In some embodiments, the feedback is provided to the subject and / or to a supervisor monitoring the EFP-NF process. In some embodiments, the feedback is provided by modifying an interface (e.g., a scenario) provided to the subject. In some embodiments, the feedback is provided by modifying an interface designed to upregulate and / or downregulate the activity of the brain region. In some embodiments, the feedback is provided within 10 seconds of recording the EEG signal, e.g., within 5 seconds, within 2 seconds, or any intermediate value, smaller or larger than these. Furthermore, the feedback is continuous, e.g., the feedback is delivered within a time period of at least 30 seconds and is associated with changes in the activity level of the brain region within this time period.

[0098] According to some embodiments, stress disorder EFP-NF training is combined with exposure therapy. In some embodiments of combined EFP-NF training, the interface (e.g., challenge) provided to the subject during the combined EFP-NF training is associated with a specific stress disorder, e.g., a specific trigger of the stress disorder. In some embodiments, the subject is gradually exposed to the trigger of the stress disorder during the combined EFP-NF training. In some embodiments, the interface is gradually adjusted to include more and more trauma-related factors. Alternatively or additionally, the subject's exposure time to the trauma-related factors is increased. In some embodiments, the trauma-related factors are selected to evoke the trainee's response to a specific trauma, e.g., to activate one or more brain regions and / or neural circuits.

[0099] According to some embodiments, the challenges provided to the subject are specific to a stress disorder. For example, challenges for PTSD include delivery of trigger sounds, stimuli and / or sights (e.g., via virtual reality (VR) or augmented reality (AR)), challenges for agoraphobia without a history of panic disorder include delivery of visualized spaces (e.g., via VR or AR), challenges for social anxiety disorder include images of social interactions, questioning faces, and receiving vague criticism, challenges for specific phobias include spiders, challenges for depression with suicidal impulses include suicidal prompts, and challenges for substance abuse include images of drug use paraphernalia.

[0100] According to some embodiments, NF training (e.g., EFP-NF training) is used to train subjects suffering from stress disorders (e.g., PTSD) to downregulate the activity of one or more brain regions and / or neural circuits that are selectively activated. In some embodiments, one or more brain regions and / or neural circuits (e.g., the amygdala) are selectively activated during NF training. In some embodiments, the interface delivered to the subject (e.g., a subject suffering from a stress disorder) includes one or more factors associated with the trigger of the stress disorder. In some embodiments, the one or more factors include sounds, images, odors, and / or stimuli associated with the stress disorder.

[0101] The potential advantage of receiving online and continuous feedback (e.g., during exposure to a personalized traumatic trigger) on the subject's ability to control the activation of stress-related brain regions is that it allows for an efficient and continuous training process with much higher time resolution than, for example, MRI (e.g., fMRI)-based NF training methods.Another potential advantage of receiving online and continuous feedback while the subject is exposed to a personalized traumatic trigger on the subject's ability to control the activation of brain regions is that by recording EEG signals related to undesirable activity levels, the subject's exposure to the traumatic trigger can be stopped within 10 seconds, for example, within 5 seconds, within 2 seconds, or any intermediate value, smaller or larger than these.

[0102] One aspect of some embodiments relates to testing a subject's ability to control activity levels of one or more brain regions and / or neural circuits prior to exposing the subject to a subject-specific stress-related trigger (e.g., a trauma-related trigger). In some embodiments, a subject suffering from a stress disorder (e.g., PTSD) is exposed to a non-specific stress trigger prior to exposure to the subject-specific stress trigger.

[0103] According to some embodiments, a specific (e.g., personalized) stress trigger selectively activates, e.g., selectively upregulates, activity in one or more brain regions and / or neural circuits associated with emotion regulation and / or traumatic memories. In some embodiments, a subject's ability to regulate activity (e.g., downregulate activity in one or more brain regions and / or neural circuits expected to be activated by a particular stress trigger) is tested prior to exposure to a personalized stress trigger (e.g., a personalized trauma trigger).

[0104] According to some embodiments, a supervisor, e.g., a psychologist, psychiatrist, mental health professional, monitors the subject's response, e.g., the subject's physiological and / or behavioral response, to non-specific stress triggers and / or stress-specific triggers (e.g., trauma-specific triggers). In some embodiments, the supervisor monitors the subject's response online during NF training (e.g., EFP-NF training). In some embodiments, the supervisor modifies one or more parameters of the NF training in response to the subject's response. Alternatively, one or more parameters of the NF training are automatically modified by the system's control circuitry. In some embodiments, the one or more parameters include an interface for NF training (e.g., a stress trigger interface), where the interface includes specific and non-specific stress triggers (e.g., audio and / or visual scenarios, sounds, smells and / or stimuli included in the interface. In some embodiments, the interface includes a virtual reality (VR) or augmented reality (AR) interface. In some embodiments, the one or more parameters for NF training include an overall training duration, a duration of each training session, a rest period between training sessions, content and / or type of stress trigger interface, a transition from a non-specific stress trigger interface to a specific stress trigger interface (e.g., an interface personalized to trigger a specific trauma or a subject-specific traumatic memory).

[0105] According to some embodiments, the subject is continuously exposed to a traumatic event (e.g., a traumatic event trigger) during the EFP-NF training procedure. In some embodiments, the provided exposure is adjusted according to the degree to which the subject is successful in reaching a desired activity level while exposed to the traumatic event during the EFP-NF training procedure. In some embodiments, the continuous exposure and adjustment of exposure is generated by closed-loop feedback during the NF training session.

[0106] According to some embodiments, the exposure includes traumatic content extracted for each individual through a prior detailed interview, for example an interview that is part of a diagnosis of a stress disorder (e.g., PTSD). In some embodiments, the traumatic story is provided through audio, visual and / or other types of senses. In some embodiments, the type of sense matches the traumatic emotion / stress, e.g., smell, touch, visual or audio cues. In some embodiments, the provision includes a non-immersive (natural) environment. Alternatively, the provision includes an immersive environment, e.g., a virtual or augmented reality environment.

[0107] In some embodiments, the traumatic content is introduced in a graded manner in the emotional intensity of the content, e.g., the graded introduction of the traumatic content is optionally personalized for the trainee prior to NF training. In some embodiments, the traumatic content is introduced in a graded manner using an audio interface, e.g., a voice of another person describing the traumatic event in second person, followed by the addition of certain sounds (e.g., crying or screaming) that may be part of the traumatic memory. Alternatively or additionally, the traumatic content is introduced in a graded manner using a visual interface, e.g., a pictorial presentation of a story, followed by the introduction of objects, colors or people involved in the story.

[0108] According to some embodiments, feedback is provided by continuously adjusting exposure to traumatic events and / or adjusting the traumatic content introduced in a gradual manner. In some embodiments, feedback is provided by constantly monitoring the EFP signal based on the EEG signal recorded during the EFP-NG training session. In some embodiments, feedback (e.g., sensory reward feedback) is provided in response to a change in the signal in a desired direction, e.g., down- or up-regulation relative to baseline or previous signal values.

[0109] According to some embodiments, the reward is perceived by a decrease in the intensity of exposure, e.g., a decrease in the vividness or intensity of the sensory presentation and / or a change in the narrative to be more distant from the traumatic center. In some embodiments, the feedback comprises continuous feedback. Alternatively, the feedback comprises intermittent feedback provided to the trainee in a range of every 2-30 seconds, e.g., every 2-15 seconds, every 10-20 seconds, every 17-30 seconds, or any intermediate value, smaller or larger range value. In some embodiments, the trainee perceives the traumatic content for a selected time period in a range of 5-90 seconds, e.g., 5-30 seconds, 20-60 seconds, 50-90 seconds, or any intermediate value, smaller or larger range value. In some embodiments, the trainee perceives the traumatic content while attempting to modulate the brain signals and receives feedback regarding success, e.g., from a separate screen, as described above. Alternatively or additionally, the feedback is delivered by the provision of a criterion, e.g., a scale indicating the degree of success of the change.

[0110] Without being bound by any logic, the idea of ​​a patient-specific context during NF training is thought to serve two principles: the first relates to a more precise identification of the appropriate brain circuits. Even if one or more brain regions are targeted, providing specific content while modulating these one or more brain regions may evoke the most appropriate pathogenic mechanisms. The second relates to feedback mechanisms during NF. Positive feedback usually involves reward circuits, but if the reward is a positive / desirable change in the traumatic context, it may lead to new learning linking the traumatic content to reward, contradicting the automatic meaning of the threat.

[0111] According to some embodiments, NF training (e.g., EFP-NF training) is a stepwise procedure, e.g., the trainee first establishes skills to modulate target brain signals in a neutral (non-disorder-specific) context and then is confronted with a disorder (and distressing) context, e.g., a traumatic story. In some embodiments, in a first phase of intervention, the trainee undergoes one or more NF sessions with non-specific feedback (e.g., voiced or audiovisual animated scenarios). In some embodiments, trainees who successfully reduce EFP signals during such one or more sessions continue to a second phase of NF training. In some embodiments, the second phase is conducted during exposure to disorder-specific content and context (e.g., trauma-specific content and context).

[0112] According to some embodiments, criteria are oriented to move to painful content to ensure that during the exposure session the trainee is able to use his or her already established techniques to explore appropriate brain signals and modulate them despite the challenging intervention.

[0113] Potential advantages of using EFP-NF are that it is multi-phase, multi-session, online, and allows for optional continuous feedback and close monitoring by a supervisor, whereas other brain region activation NF techniques (e.g., fMRI-NF) have significantly more limited capabilities. EFP provides both the spatial information of fMRI and the accessibility of EEG.

[0114] According to some embodiments, when the distressing content is first exposed, a supervisor (e.g., a clinician) is present in the training room to closely monitor and reassure the trainee that the trainee is able to follow the training without being overwhelmed by the situation. In some embodiments, a trained clinician is present to guide the patient when facing more distressing environments. In some embodiments, after each cycle of NF training, the clinician allows the patient to share their experience and discuss the psychological techniques that were successfully used. Additionally or alternatively, a learning graph is provided to the trainee after each session, and the successes are optionally discussed in detail with the trainee by the clinician. These safety steps are easily implemented in EEG-NF setups, but are virtually impossible in fMRI-NF.

[0115] In some embodiments, the exposure story played to the trainee as feedback is a personalized exposure story created for each individual. In some embodiments, prior to the start of NF training, a trained clinician interviews the patient and records his / her specific traumatic events. In some embodiments, the information is compiled after the interview, e.g., graded based on its intensity and proximity to a particular trauma focus. In some embodiments, the focus is defined by a set of emotional terms used to describe it and the patient's behavior in disclosing this part. In some embodiments, when unclear, a question is used to the patient to define the trauma focus, e.g., "Please indicate the most painful part of your memory."

[0116] According to some embodiments, data is collected using questions (e.g., leading questions) to characterize the emotional, sensory and physical aspects of the experience (e.g., How did it feel? Did it feel different than usual? What did you see / hear? What did you think? What did you do?). In some embodiments, the clinician obtains information about the context, such as the location, other people and time of the experience. In some embodiments, the information obtained during the interview is compiled into one or more scripts with a length in the range of 20 seconds to 10 minutes (e.g., 20 seconds to 3 minutes, 1 minute to 7 minutes, 5 minutes to 10 minutes or any intermediate value, smaller or larger value). In some embodiments, if the script includes an audio script, the audio script is provided to the trainee in a second person voice. In some embodiments, each or at least some of some NF training sessions include a debrief following each cycle in the clinic to guide each patient to find more useful techniques to promote brain regulation.

[0117] According to some embodiments, the feedback delivered to the subject is adjusted based on the subject's success in adjusting the activity of the brain region.In some embodiments, the adjusted feedback is delivered as an adjusted exposure story, for example, as described above.In some embodiments, calculation of EFP value (e.g., the average EFP value during rest for each trainee and / or the standard deviation (STD) of this average) is performed during a "rest period" of less than 5 minutes (e.g., less than 3 minutes, less than 1 minute, less than 30 minutes, or any intermediate value, smaller or larger than these).

[0118] According to some embodiments, the feedback comprises auditory feedback including brief auditory neutral context environmental feedback (e.g., feedback not specific to the trainee's trauma), for example, less than 10 minutes (e.g., less than 5 minutes, less than 3 minutes, or any intermediate value, less or greater than these). In some embodiments, the neutral context feedback comprises a piece of jazz music. Alternatively, the brief auditory feedback comprises a trauma-specific context delivered during the exposure session. In some embodiments, an increase or decrease in a statistical parameter value calculated for the measured EFP signal (e.g., a change (up or down) in one STD of the amyg-EFP value) results in a corresponding change in the volume of the auditory feedback, for example, a change of 10 dB. In some embodiments, after each NF period, the STD is reset based on the target signal value recorded during the last NF period, etc.

[0119] According to some embodiments, EFP-NF, including traumatic context, traumatic content and / or exposure to traumatic triggers, directly targets brain mechanisms while triggering mental processes involved in the consolidation / extinction of traumatic memories and experiences. Without being bound by any logic, memories are reconsolidated every time they are recalled. Thus, reconsolidation provides an opportunity to rewrite emotional memories and requires the circuits involved therein. That is, during the reconsolidation window, old traumatic experiences can be updated and recontextualized (Nader et al., 2000; Dudai et al., 2006; Schiller et al., 2010; Kandler et al., 2014). Thus, reconsolidation while manipulating the appropriate circuits allows for non-invasive interventions that not only change the experience of traumatic memories, but also modify the underlying neural mechanisms.

[0120] A potential advantage of EFP-NF training, combining training to voluntarily downregulate amygdala activity with exposure to the contents of the traumatic event during this training, is that it may favorably affect the sensitivity of the nervous system to cued provoked symptoms in PTSD. Exposure to trauma-specific challenges combined with the feedback itself in the EFP-NF training program activates and modulates (on-line) brain processes that code for traumatic experiences. Exposure to recorded stories of the trauma is a personal and challenging context that is set to activate neural processes and networks that code, maintain, and consolidate memories of the traumatic event. Participants in limbic system modulation training in the context of activation of these neural processes and networks are then able to change their behavior in the desired direction.

[0121] A further potential advantage of EFP-NF is that it is delivered at a controlled, progressive pace, with varying levels of difficulty that minimizes patient discomfort and subsequent dropout. Thus, context-related NF can also be introduced into therapeutic design structures that must incorporate multiple levels of difficulty. As the trainee is better able to control the simple, non-harmful feedback environment, the feedback itself becomes more and more relevant to the patient's pathological context, creating more emotionally evocative, progressive challenges during the treatment period.

[0122] According to some embodiments, EFP-NF is applied to various context-specific disorders (e.g., Obsessive Compulsive Disorder (OCD), specific phobias and / or social anxiety disorder). In some embodiments, feedback, e.g., positive feedback, for OCD can be related to the content of the obsession and / or compulsion, e.g., a dirty room becomes clean, a messy room becomes tidy. In some embodiments, for example, for a specific phobia of heights, it can be a descending elevator or a door that closes faster, or a scary thing or a bug is transformed into a desirable thing. In some embodiments, for example, for social anxiety disorder, the trainee needs to control while performing a task in front of others, and the verbal / facial / gesture feedback of the trainee's performance is graded from neutral / indeterminate to positive (smile, nice words, interested in the trainee).

[0123] In some embodiments, context is used to test acquired skills, in some embodiments to challenge difficulties after learning (e.g., executive function tasks for ADHD, memory tasks for mild cognitive impairment, pain induction for fibromyalgia, preference activation for depressed patients, social engagement for borderline personality disorder or related disorders (e.g., postmenstrual dysphoric disorder)).

[0124] One aspect of some embodiments relates to providing online, continuous feedback to a subject while the subject is exposed to a challenge (e.g., a stress-related challenge). In some embodiments, feedback is provided each time the subject negotiates a challenge. In some embodiments, the challenge comprises a non-specific stress challenge. Alternatively, the challenge comprises a stress disorder-specific stress challenge. In some embodiments, feedback is provided by modifying the challenge.

[0125] One aspect of some embodiments relates to exposing a subject to a challenge (e.g., a stress-related challenge) without the subject being confined within an imaging system. In some embodiments, the subject is not confined, e.g., covered, within an imaging system (e.g., an MRI or fMRI device). In some embodiments, a supervisor is located near the subject (e.g., within 10 meters of the subject) during exposure and NF, for example, to be able to quickly approach the subject if the exposure becomes too intense.

[0126] One aspect of some embodiments relates to providing feedback while modifying a stress-related challenge delivered to a subject. In some embodiments, the feedback is provided in response to the activity level of one or more brain regions affected by the challenge. In some embodiments, the feedback is provided in response to the subject's ability to modify the activation of one or more brain regions. In some embodiments, if the subject is successful in downregulating the activity of one or more brain regions, the intensity or severity of the challenge is reduced. In some embodiments, if the subject fails to downregulate the activity of one or more brain regions, the intensity or severity of the challenge is kept the same. In some embodiments, the feedback is delivered continuously and / or online.

[0127] One aspect of some embodiments relates to educating a subject to perform at least one exercise (e.g., physical or mental exercise) that regulates the activity of at least one stress-related brain region of said subject in a regulated relationship with exposure to trauma or stress disorder triggers.In some embodiments, at least one exercise is selected and / or developed during EFP-NF training, and the subject's ability to regulate the activation of at least one stress-related brain region is monitored by measuring at least one electrophysiological parameter, for example, an EEG signal that indicates the activity level of at least one particular stress-related brain region.

[0128] According to some embodiments, the subject performs at least one exercise after completing EFP-NF training, for example, one week, 14 days, one month, six months, or any intermediate value, shorter or longer than one week, 14 days, one month, six months, or any intermediate value, after completing EFP-NF training. In some embodiments, the subject performs at least one exercise outside of a clinic, for example, when the subject is at home, at work, or while traveling. In some embodiments, the subject performs at least one exercise while receiving feedback from a mobile system that measures at least one physiological parameter (e.g., EEG signal) that is indicative of the activity level of at least one stress disorder-related brain region. Alternatively, the subject performs at least one exercise without receiving feedback on the activity level of at least one stress disorder-related brain region.

[0129] According to some exemplary embodiments, the subject performs at least one exercise while being exposed to a stress-related or trauma-related interface that is tailored for the subject.In some embodiments, the interface is delivered to the subject by the user interface of the mobile device, for example, the display and / or speaker of the mobile device.Alternatively or in addition, the subject performs the exercise when receiving warning information before the occurrence of a stress disorder-related trigger or a trauma-related trigger, for example, warning information delivered by a media broadcasting organization or broadcasting station.

[0130] One aspect of some embodiments relates to the safety features when exposing a subject to stress-related challenges during NF training.In some embodiments, if the effect of the exposure is too strong, the subject is calmed down, for example, by drugs and / or training.Alternatively or additionally, NF training is stopped or modified.

[0131] One aspect of some embodiments relates to delivering NF training (e.g., EFP-NF training) while exposing the trainee (e.g., a subject diagnosed with a stress disorder) to a stress disorder-related challenge designed based on at least one impaired neurobehavioral process of the trainee. In some embodiments, the at least one impaired neurobehavioral process is identified based on an assessment of the trainee, e.g., an assessment of symptoms of a stress disorder.

[0132] According to some embodiments, the goal of the NF training includes at least one of reducing the level of expression of at least one symptom of a stress disorder and converting the trainee from an impaired neurobehavioral process to a different, less impaired, or unimpaired neurobehavioral process. Alternatively or additionally, at least one goal of the NF training includes reducing the level of impairment of the impaired neurobehavioral process in the trainee after and / or during the NF training.

[0133] According to some embodiments, the at least one impaired neurobehavioral process in stress disorders (e.g., PTSD) includes one or more of threat detection, emotion regulation, fear loss, reward consumption, salience homeostasis, episodic memory encoding and recall, and executive function. In some embodiments, NF training trains a subject diagnosed with a stress disorder to modulate the activity level of at least one brain region (e.g., limbic brain regions, deep brain regions located beneath the cortical layers of the brain, and / or neural circuits) associated with at least one impaired neurobehavioral process.

[0134] According to some embodiments, the impaired threat detection process involves one or more of the anterior insula, the ventromedial prefrontal cortex (vmPFC), the periaqueductal gray (PAG) and the locus coeruleus (LC), and the amygdala.In some embodiments, NF training is used to educate trainee to specifically adjust the activity level of one or more brain regions involved in the impaired threat detection process.In some embodiments, the trainee adjusts the activity level of at least one brain region while being exposed to a personalized interface based on the impaired threat detection process in the subject.

[0135] According to some embodiments, the impaired emotion regulation process involves one or more of the medial prefrontal cortex (mPFC), the dorsolateral prefrontal cortex (dlPFC), the left dorsomedial prefrontal cortex (dmPFC) and the amygdala. In some embodiments, NF training is used to educate the trainee to specifically adjust the activity level of one or more brain regions involved in the impaired emotion regulation process. In some embodiments, the trainee adjusts the activity level of at least one brain region while being exposed to a personalized interface based on the impaired emotion regulation process in the subject.

[0136] According to some embodiments, impaired fear extinction process involves one or more of the dorsal anterior cingulate cortex (dACC), vmPFC, hippocampus and amygdala.In some embodiments, NF training is used to teach trainee to specifically adjust the activity level of one or more brain regions involved in impaired fear extinction process.In some embodiments, trainee adjusts the activity level of at least one brain region while being exposed to a personalized interface based on impaired fear extinction process in subject.

[0137] According to some embodiments, NF treatment of stress disorder patients (e.g., PTSD patients) is enhanced by introducing a process-based approach into the design and implementation of NF training (e.g., EFP-NF training). In some embodiments, multiple stress disorder processes (e.g., PTSD stress disorder processes) are activated by context-based interfaces during neuromodulation of relevant networks. In some embodiments, different combinations of impaired processes tend to interact with each other, since they give rise to clinical phenomenology.

[0138] One aspect of some embodiments relates to the use of NF training (e.g., EFP-NF training) in treating depression in patients diagnosed with a stress disorder. In some embodiments, EFP-NF training is used to educate patients to modulate (e.g., actively modulate) the activity of at least one specific brain region (e.g., at least one specific brain region associated with a stress disorder). In some embodiments, modulating the activity of at least one specific brain region reduces the expression of depressive symptoms in the patient.

[0139] According to some embodiments, at least one parameter of the NF training is adjusted to treat depression in a patient diagnosed with a stress disorder. In some embodiments, the at least one parameter includes an interface, such as a challenge delivered to the patient and / or at least one exercise (e.g., a physical exercise and / or a mental exercise) performed by the patient. In some embodiments, the NF training is adjusted to treat depression in a patient diagnosed with a stress disorder and treated with a bioactive compound to reduce depressive symptoms.

[0140] According to some embodiments, depression is evaluated after NF training. In some embodiments, the expression level of at least one depression symptom is evaluated after NF training. In some embodiments, NF training is modified based on the evaluation result. For example, if the modulation of at least one brain region is insufficient or not in the desired direction, and / or the reduction of depression level after NF training is insufficient, instructions for other or modified training are sent to the patient.

[0141] According to some embodiments, after the NF training, the existing dosing regimen of at least one bioactive compound for treating depression is modified or a new dosing regimen is initiated, for example, based on the results of the NF training. In some embodiments, the dosage of the at least one bioactive compound is reduced when the modulation of the activity of at least one specific brain region is at a desired level and / or the NF training has been effective in reducing at least one symptom of depression in the patient. A potential advantage of reducing the dosage of the at least one bioactive compound or prescribing a new bioactive compound at a lower dosage is that it may reduce side reactions caused by the bioactive compound.

[0142] According to some embodiments, the challenges (e.g., interfaces) provided to a PTSD patient with depression include at least one environment or protocol (instructions) that induces or promotes positive autobiographical memories, reward consumption paradigms (gaining rewards for extra effort), and recall of preferred music.

[0143] One aspect of some embodiments relates to the use of NF training (e.g., EFP-NF training) to treat anxiety disorders in patients diagnosed with stress disorders. In some embodiments, EFP-NF training is used to educate patients to modulate (e.g., actively modulate) the activity of at least one specific brain region (e.g., at least one specific brain region associated with stress disorders). In some embodiments, modulating the activity of at least one specific brain region reduces the expression of anxiety disorder symptoms in the patient.

[0144] According to some embodiments, at least one parameter of the NF training is adjusted to treat anxiety disorder in a patient diagnosed with a stress disorder. In some embodiments, the at least one parameter includes an interface, such as a challenge delivered to the patient and / or at least one exercise (e.g., physical exercise and / or mental exercise) performed by the patient. In some embodiments, the NF training is adjusted to treat depression in a patient diagnosed with a stress disorder and treated with a bioactive compound to reduce anxiety disorder symptoms.

[0145] According to some embodiments, anxiety disorder is evaluated after NF training.In some embodiments, the expression level of at least one anxiety disorder symptom is evaluated after NF training.In some embodiments, NF training is modified based on the evaluation result.For example, if the modulation of at least one brain region is insufficient or not in the desired direction, and / or the reduction of anxiety disorder level after NF training is insufficient, the instruction of another or modified training is sent to the patient.

[0146] According to some embodiments, after NF training, modify the existing dosing regimen or start a new dosing regimen with at least one bioactive compound for treating anxiety disorder, for example, based on the results of NF training. In some embodiments, when the modulation of the activity of at least one specific brain region is at a desired level and / or the NF training is effective in reducing at least one symptom of the patient's anxiety disorder, reduce the dosage of the at least one bioactive compound. A potential advantage of reducing the dosage of the at least one bioactive compound or formulating a new bioactive compound at a low dosage is that it may reduce side reactions caused by the bioactive compound.

[0147] One aspect of some embodiments relates to delivering an indicator to a stress disorder patient to regulate at least one specific brain region related to the stress disorder trigger, for example, the trigger for at least one symptom of the stress disorder in the patient, before exposure to a planned stress disorder trigger.In some embodiments, the patient receives an indicator (e.g., a human detectable indicator) to perform at least one exercise selected to regulate the activation of at least one specific brain region of the subject before exposure to the stress disorder trigger.In some embodiments, the patient receives the indicator, optionally automatically, when a warning of a predicted trauma trigger is identified.

[0148] According to some embodiments, a device (e.g., a personal assistant device) located in the patient's home, on the patient, and / or in the patient's vicinity (e.g., within 20 meters of the patient, e.g., within 10 meters, within 5 meters, within 2 meters, or any intermediate distance from the patient less or greater than these) identifies at least one warning signal for the patient's anticipated exposure to a trigger for a stress disorder. In some embodiments, the device's control circuitry receives a signal directly from a microphone (e.g., the device's microphone) or from a warning signal source (e.g., a media broadcasting device that emits a warning signal) to identify the warning signal.

[0149] According to some embodiments, the device selects at least one exercise from the list of exercises based on the identified warning signal. In some embodiments, the list of exercises is stored in the device's storage medium. Alternatively, the list of exercises is stored in a remote storage medium, such as a cloud storage or a remote server. In some embodiments, the device selects at least one exercise in response to at least one of the warning signal (e.g., a stress disorder trigger expected in response to a stress disorder), at least one brain region that must be affected by the at least one exercise, the patient's time until the stress disorder trigger is expected to be exposed, and information about the patient (e.g., clinical and / or personal information). In some embodiments, the device delivers a human-detectable indication to the patient to perform the at least one selected exercise. In some embodiments, the human-detectable indication, such as an audio and / or visual indication, includes instructions to perform the at least one selected exercise.

[0150] According to some embodiments, the device monitors activity of at least one specific brain region of the patient, for example, in conjunction with (e.g., before, during and / or after) the performance of at least one exercise and / or exposure to at least one stress disorder trigger. In some embodiments, the device (e.g., control circuitry of the device) monitors activity of at least one specific brain region by receiving at least one electrical signal, for example, an electrical signal from the patient (e.g., an electrical signal generated by the patient's brain). In some embodiments, the electrical signal comprises an EEG signal. In some embodiments, the control circuitry of the device receives the EEG signal from at least one EEG electrode attached to the patient. In some embodiments, the device is wirelessly connected to the at least one EEG electrode.

[0151] According to some embodiments, the control circuitry of the device processes the at least one electrical signal to identify a relationship between at least one specific brain region's activity signature (e.g., an activity signature also named herein as EEG Electrical Fingerprint (EEG-EFP)) and at least a portion of the at least one electrical signal. In some embodiments, the processing of the received electrical signal is performed within the device by the control circuitry. In some embodiments, the storage medium of the device includes at least one EEG-EFP or a plurality of EEG-EFPs, optionally individually tailored to the patient, indicative of the activity level of at least one specific brain region of the patient. Alternatively, the at least one EEG-EFP or a plurality of EEG-EFPs, optionally individually tailored to the patient, are stored on a remote server, for example a remote server in a cloud storage. In some embodiments, the control circuitry of the device transmits the received electrical signal to the remote server, and a relationship between at least a portion of the received electrical signal and at least one stored EEG-EFP is identified in the remote server, for example by using at least one algorithm or look-up table stored on the remote server.

[0152] According to some embodiments, the device, e.g., the control circuitry of the device, delivers a human-detectable indicator to the patient in response to the activity level of at least one specific brain region. In some embodiments, the device delivers a human-detectable indicator in response to the success of modulating (e.g., upregulating or downregulating) the activity of at least one brain region in a desired direction and / or in response to the level of modulation (e.g., a score indicating the level of modulation). In some embodiments, the device, e.g., the control circuitry of the device, varies the instructions delivered to the patient and / or varies the exercises delivered to the patient based on the activity level of at least one specific brain region and / or the success of modulating the activity of at least one specific brain region using exercises by the patient.

[0153] In some embodiments of the present invention, the feedback delivered to a subject diagnosed with a stress disorder (e.g., a patient and / or a trainee of NF training) comprises information regarding the direction of modulation of at least one specific brain region, e.g., a level (e.g., a score) representing the measured degree of down- or up-regulation and / or modulation.

[0154] In some embodiments of the present invention, feedback regarding the activity level of at least one specific brain region and / or the patient's success in adjusting the activity level of at least one specific brain region is delivered online while the patient is exposed to the challenge. In some embodiments, the control circuit of the device used to deliver NF training or monitor the activity level of at least one brain region continuously and repeatedly receives electrical signals (e.g., electrical signals generated by the patient's brain), identifies a relationship between at least a portion of the received electrical signals and the stored signature (e.g., EEG-EFP signature), and delivers feedback to the patient. In some embodiments, the control circuit receives at least one electrical signal, determines the activity level of at least one specific brain region based on the signal, and generates feedback to the patient regarding the determined activity level within 30 seconds, for example, within 15 seconds, within 10 seconds, within 5 seconds, within 2 seconds, or any intermediate value, shorter or longer than these.

[0155] Before describing at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of elements and / or methods set forth in the following description and / or illustrated in the drawings and / or examples. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0156] Prologue Exposure to aversive and potentially traumatic events is pervasive in modern life. One common psychopathology following traumatic exposure is post-traumatic stress disorder (PTSD), an acute psychiatric illness with a lifetime prevalence ranging from 1.3 to 12.2% and associated with a debilitating prognosis. Functional neuroimaging studies point to limbic dysregulation as a possible neural mechanism of PTSD, optionally revealing hyperactivity in the amygdala and / or dorsal anterior cingulate cortex (dACC), alongside hypoactivity in the ventromedial prefrontal cortex (vmPFC) and / or inferior frontal gyrus (IFG).

[0157] The amygdala is involved in emotion processing, including, for example, initiating and controlling stress response, and further aids in effective emotion regulation.Therefore, it is reasonable to consider the functionality of the amygdala as an effective target for brain-guided intervention via neurofeedback (NF).According to some exemplary embodiments, NF learning is based on the self-regulation of brain activity, which is optionally induced by contingent reinforcement feedback that reflects the successful regulation of specific neural signals.

[0158] According to some exemplary embodiments, a personalized process-based EFP-NF intervention with individually tailored trauma-related feedback content is delivered to a subject diagnosed with a stress disorder (e.g., PTSD). In some embodiments, the EFP-NF intervention modulates the activity of the amygdala, a neural node of PTSD, and is optionally combined with exposure to a personalized traumatic story as a feedback interface. In some embodiments, the EFP-NF intervention allows, for example, customization of the autonomic neuromodulation of stress-related abnormal processes, thus increasing the effectiveness of treatment.

[0159] Exemplary Patient Treatment with the NF Training Process According to some exemplary embodiments, a subject diagnosed with a stress disorder (e.g., PTSD) is trained to control activation of one or more brain regions associated with the stress disorder. In some embodiments, the subject is trained to downregulate activity of one or more brain regions activated by stress disorder-related traumatic memories, e.g., traumatic events or trauma-related contexts. In some embodiments, NF training (e.g., EFP-NF training) includes training while exposed to trauma-related content. In some embodiments, the subject is trained in a sequence to achieve a reduction in stress-related symptoms, such as avoidance of traumatic cues, altered emotional experience, such as hyperarousal, intrusive thoughts and sensations, anhedonic states, re-experiencing painful memories, disruptive states, general avoidance of trauma-related cues, bodily discomfort and / or anhedonic states, and angry outbursts. Reference is now made to FIG. 1, which illustrates a process for reducing stress-related symptoms from the patient's perspective, according to some exemplary embodiments of the present invention.

[0160] According to some exemplary embodiments, at 102, the patient is exposed to a stress disorder trigger, e.g., a PTSD trigger. In some embodiments, the PTSD trigger comprises a traumatic environment and / or a traumatic interaction. In some embodiments, the PTSD trigger comprises a temporary trigger that lasts up to 24 hours (e.g., up to 12 hours, up to 1 hour, or any intermediate value, shorter or longer). In some embodiments, the trigger comprises a continuous trigger that lasts more than 24 hours (e.g., more than 2 days, more than 7 days, or any intermediate value, shorter or longer).

[0161] According to some exemplary embodiments, at 104, the subject is diagnosed with a stress disorder (e.g., PTSD). In some embodiments, the subject is diagnosed at least one day after exposure to a stress trigger (e.g., at least one week, six months, and / or years, or any intermediate, shorter or longer period after exposure to a stress trigger). In some embodiments, the subject is diagnosed based on one or more stress-related symptoms. In some embodiments, the subject is diagnosed by a psychiatrist or other clinician.

[0162] According to some exemplary embodiments, at 106, the subject (e.g., patient) is optionally treated with a bioactive compound. In some embodiments, the bioactive compound comprises one or more drugs and / or pharmaceutical substances. In some embodiments, the bioactive compound is intended to treat stress-related symptoms. Alternatively or additionally, the bioactive compound is intended to affect the activation of one or more brain regions and / or neural circuits, for example, brain regions or neural circuits associated with stress disorders (e.g., stress-impaired memory). In some embodiments, the bioactive compound comprises one or more selective serotonin reuptake inhibitors (SSRIs), i.e., new generation anti-epileptic drugs used as mood stabilizing agents (e.g., Topamax, Bupropion, Ketamine, Cannabis).

[0163] According to some embodiments, the agent is taken by the subject prior to or during NF training, e.g., to enhance the effects of NF training. Alternatively, or in addition, the agent is taken by the subject during NF training, e.g., to protect the subject from the effects of exposure to a stress-related challenge.

[0164] According to some exemplary embodiments, at 108, the patient is trained according to an EFP-NF training protocol. In some embodiments, the patient is trained while ingesting a bioactive compound. In some embodiments, the EFP-NF training protocol is individualized to a particular patient, for example, a particular stress disorder and / or a particular trauma that caused the stress disorder. Alternatively or additionally, the EFP-NF training protocol is modified depending on the particular bioactive compound ingested by the patient.

[0165] According to some embodiments, a patient (e.g., a trainee) is trained with EFP-NF to control the activity level of one or more brain regions related to stress disorder and / or trauma, for example, one or more brain regions related to traumatic memories.In some embodiments, the patient is trained to downregulate the activation of one or more brain regions, for example, the amygdala.Optionally, the patient is trained to downregulate the activity level activation of the amygdala during exposure, for example, during graded exposure, to the content and / or context related to trauma, for example, the specific trauma that affected the trainee.

[0166] According to some embodiments, at 110, the achievement of a desired outcome by the EFP-NF training is evaluated, e.g., the ability to reduce stress-related symptoms or to achieve a desired activity level in one or more brain regions. In some embodiments, the evaluation includes interviewing the patient after a selected period of time (e.g., at least one day, e.g., the next day, the next week, the next month, or any intermediate value, shorter or longer) from the EFP-NF. Alternatively or additionally, the evaluation includes recording the value of one or more clinical parameters, e.g., heart rate, blood pressure, or other clinical parameters related to stress and / or anxiety disorders. In some embodiments, the evaluation includes recording EEG and / or fMRI signals after the training. Optionally, the EEG and / or fMRI signals are recorded in a time relationship to (e.g., during and / or after) exposure to trauma-related content or context.

[0167] According to some exemplary embodiments, if the EFP-NFP training does not achieve the desired outcome, at least one parameter of the EFP-NF training is modified at 122. In some embodiments, the at least one parameter includes the number of sessions, the content of the interface delivered to the trainee during the training, the length of each session, and the EFP used during the EFP-NF training. Optionally, the bioactive compound that the trainee is taking is replaced with another bioactive compound. In some embodiments, at 108, the trainee repeats the EFP-NF training using the modified EFP-NF protocol.

[0168] According to some exemplary embodiments, when the EFP-NF training reaches a desired goal at 114, the trainee is invited to a maintenance NF session. In some embodiments, the maintenance session is configured to maintain the trainee's ability to influence the activity of one or more brain regions, for example, by using the skills the trainee acquired during the NF training at 108. In some embodiments, the NF maintenance session is performed one week, one month, one year, or any intermediate value, shorter or longer, after the NF training. In some embodiments, the maintenance training is based on recording of EEG signals or recording of one or more clinical parameter values ​​indirectly influenced by the activity of one or more brain regions. Optionally, the maintenance NF includes the EFP of one or more selected brain regions.

[0169] According to some exemplary embodiments, the maintenance sessions are performed by the subject who has undergone the EFP-NF training sessions. In some embodiments, the maintenance sessions are performed by the subject themselves, for example at home or other locations away from the clinic. In some embodiments, the maintenance sessions are performed by exposing the subject to at least one trauma trigger, for example at least one trauma trigger personalized to the trainee. In some embodiments, the personalized trauma trigger is based on personalized trauma-related scenarios provided to the subject during EFP-NF training.

[0170] According to some exemplary embodiments, the subject performs at least one exercise (e.g., physical or mental exercise) in a time relationship with exposure to the personalized trauma trigger, for example, before, during and / or after exposure.In some embodiments, the at least one exercise is performed by the subject in response to the appearance of a trauma trigger warning and / or before the expected trauma trigger.In some embodiments, the subject performs at least one exercise in the absence of feedback.

[0171] Exemplary EFP-NF Procedure Reference is now made to FIG. 2, which illustrates an EFP-NF training process according to some exemplary embodiments of the present invention.

[0172] According to some exemplary embodiments, subjects are selected for EFP-NF training at 202. In some embodiments, subjects, for example, subjects diagnosed with a stress disorder (e.g., PTSD), are selected by a clinician prior to EFP-NF training. In some embodiments, subjects are selected based on type of stress disorder, time since trigger or traumatic event for the stress disorder, medical history, and medication history.

[0173] According to some exemplary embodiments, at 204, a subject is selected by a clinician prior to EFP-NF training. In some embodiments, the subject is evaluated, for example, to tailor the EFP-NF training to a particular subject. In some embodiments, the clinician collects information from the subject by interview about the trauma (e.g., the trauma trigger and / or traumatic event that led to the stress disorder).

[0174] According to some exemplary embodiments, at 206, the subject is trained with EFP-NF in a neutral context. In some embodiments, the neutral context is a context that is non-specific to the particular subject's trauma. In some embodiments, in the neutral context EFP-NF training procedure, the subject learns how to modulate activation of one or more brain regions (e.g., the amygdala) in response to a non-specific stress trigger (e.g., noise). In some embodiments, during EFP-NF in a neural context, the subject is trained to perform one or more exercises (e.g., physical or mental exercises) to modulate (e.g., downregulate) amygdala activity.

[0175] According to some exemplary embodiments, the subject (e.g., trainee) is evaluated for success in achieving a desired activity level of one or more brain regions at 208. In some embodiments, the trainee is evaluated for success in downregulating amygdala activity levels in response to a non-specific stress trigger at 208.

[0176] According to some exemplary embodiments, if the EFP-NF does not successfully enable the trainee to achieve the desired activity level, at least one parameter of the EFP-NF in the neutral context is optionally modified at 210. In some embodiments, the at least one parameter includes the duration of training, the duration of each session, the type and / or content of non-specific stress triggers, the manner in which the non-specific stress triggers are delivered to the trainee, and an approach to find a practice that allows for effective activity adjustments in a particular subject.

[0177] According to some exemplary embodiments, if the trainee is successful in achieving the desired activation with EFP-NF in a neutral context, at 212 the trainee begins an individualized EFP-NF training protocol in a stress context. In some embodiments, the trainee performs the exercises learned with EFP-NF in a neutral context while responding to content related to a personal trauma. Optionally, the trauma-specific content is delivered to the trainee in a phased manner. In some embodiments, the trauma-specific content is delivered to the trainee under the supervision of a supervisor (e.g., a clinician). In some embodiments, the trainee and / or supervisor receive online feedback on the trainee's success in reaching the desired activation level of one or more brain regions while responding to the trauma-specific content, and optionally continues.

[0178] According to some exemplary embodiments, a post-training assessment is performed at 212. In some embodiments, the post-training assessment evaluates the progress of the trainee compared to baseline or previous activity measurements of one or more brain regions. In some embodiments, the post-training assessment is performed by measuring fMRI signals, EEG signals, or at least one clinical parameter value (e.g., a clinical parameter related to the activity level of one or more brain regions).

[0179] Illustrative symptom- or process-based NF for PTSD According to some exemplary embodiments, subjects are diagnosed with PTSD using the traditional definition of PTSD based on DSM-5, which consists of five major criteria: (A) exposure to a traumatic experience (defined as death, threat of death, actual or threatened severe disability, actual or threatened sexual assault) and experiencing distress for one month or more after the event, (B) intrusive re-experiencing of memories and emotions of the traumatic event, (C) avoidance of cues that remind one of the event, (D) altered cognition including lack of memory for the event, poor emotional cognitive processing (i.e., alexithymia), dysphoria associated with loss of pleasure, poor emotional regulation and emotional outbursts, and (E) generalized hyperarousal and insomnia. However, in some embodiments, this classification results in clinical heterogeneity, which may lead to poorly tailored management for individual patients.

[0180] According to some exemplary embodiments, in addition to or in lieu of a DSM-5 based PTSD diagnosis, various potential impairments in neurobehavioral processes are identified, such as, for example, fear learning and unlearning, threat detection, emotion regulation, etc. In some embodiments, these impairments in neurobehavioral processes are associated with amygdala activity.

[0181] According to some exemplary embodiments, when considering brain mechanisms, such as those described in, for example, Fenster RJ et al. 2018, conceptualizations, etc., emphasize the central role of the amygdala in various aspects of PTSD in relation to other limbic, salience and prefrontal regions. For example, altered fear learning, impaired loss and safety signal processing are important in PTSD symptomatology, but also depend on maladaptive top-down cortical inhibition, together with the functionality of amygdala subnuclei and various cell types. Similarly, emotional dysregulation resulting in extreme emotional reactivity, excitability and impulsivity is known to be supported by a deficit in cortical control over amygdala reactivity, as described in, for example, Etkin A. et al., 2015, and is particularly indicated by impaired connectivity patterns between the amygdala and the vmPFC and dlPFC. Furthermore, maladaptive threat detection may result in increased consideration and response to threatening or salient stimuli, with hyperarousal and associated aggressive behaviors mediated not only by the amygdala, but also by cortical regions such as the insula, vmPFC, dACC, and brainstem regions such as the PAG and locus coeruleus.

[0182] Reference is now made to FIGS. 2B-2F, which illustrate NF training based on a personalized process, according to some exemplary embodiments of the present invention.

[0183] According to some exemplary embodiments, the PTSD patient undergoes an assessment of impaired processes associated with PTSD. In some embodiments, the characterization of impaired processes is guided by putative neuroscience mechanisms that underpin the primary symptom clusters of PTSD. In some embodiments, the assessment includes a clinical assessment 220, for example, based on an interview and / or the completion of at least one questionnaire, as shown, for example, in FIG. 2B. Additionally or alternatively, the assessment includes a physiological assessment 222, for example, the measurement of at least one physiological parameter (e.g., heart rate, blood pressure, electromyogram and / or skin conductivity). Additionally or alternatively, the assessment includes a behavioral assessment 224, for example, by monitoring or visualizing the subject's response (e.g., to an external perturbation, optionally a traumatic one specific to the subject).

[0184] According to some exemplary embodiments, for example as shown in Figure 2C, the level of expression of PTSD symptoms (e.g., PTSD symptoms based on the DSM) in the subject is determined based on the assessment performed in Figure 2B. In some embodiments, the symptoms of PTSD include intrusions, avoidance, altered cognition and mood, altered arousal and reactivity.

[0185] According to some exemplary embodiments, a personalized process-related characterization of PTSD patients is possible based on behavioral and physiological assessments. In some embodiments, different processes are related to PTSD abnormalities (e.g., threat detection, emotion regulation, and fear extinction), as shown, for example, in FIG. 2C. In some embodiments, the processes are measured by administering behavioral tasks, such as the predictable and unpredictable impact task for threat detection (Schmitz A. et al., 2012), the emotion regulation task for emotion regulation (Shafir R. et al., 2015), and the aversive learning task for fear extinction (Shalev L., et al., 2018). In some embodiments, PTSD symptom clusters, such as intrusions, avoidance, cognitive and mood alterations, arousal and reactivity alterations, are represented based on their respective proposed weights in the major dysfunctional processes per patient, as shown, for example, in the table of FIG. 2C. In some embodiments, impaired processes are identified based on the respective weights or levels of expression of PTSD symptoms. Additionally or alternatively, impaired processes are identified based on the assessments performed in FIG. 2B.

[0186] According to some exemplary embodiments, processes impaired in PTSD, such as threat detection, emotion regulation and fear extinction, are linked to PTSD symptoms and, optionally, to increased severity of PTSD.

[0187] According to some exemplary embodiments, dysfunctional processes are used for delivery of NF based on personalized processes, for example as shown in Figures 2D-2F. In some embodiments, the dysfunctional process is derived from an initial assessment battery guided by the selection of a corresponding intervention interface. In some embodiments, each interface is configured to specifically target the impaired process by stimulating activity of a designated brain circuit, including the amygdala. In some embodiments, the self-regulation of the amygdala in each unique context results in a specific pattern of regulation for the underlying circuit of interest.

[0188] According to some exemplary embodiments, in the event of an impairment of the threat detection process 230, as shown, for example, in FIG. 2D, an interface including threat-related cues is delivered to the subject and amygdala activity feedback corresponds to, for example, the volume of an ambulance siren. In some embodiments, this process-specific context stimulates modulation of threat detection-related circuits, such as the anterior insula 238, the ventromedial prefrontal cortex (vmPFC) 240, the periaqueductal gray (PAG) 234 and the locus coeruleus (LC) 236, and the amygdala 232, which are involved, for example, in at least one of increased attention, reactivity to threat stimuli, and hyperarousal. In some embodiments, an electrical fingerprint (EFP) of the amygdala and one or more regions thereof is used to determine activity levels of these regions and to generate and / or modify feedback to the subject based on the determined activity levels.

[0189] According to some exemplary embodiments, in the case of impairment of emotion regulation process 242, for example as shown in FIG. 2E, an interface including emotion-related cues is delivered to the subject and amygdala activity feedback corresponds to, for example, the brightness level of the interface. In some embodiments, this process-specific context stimulates modulation of emotion regulation related circuits involving at least one of the medial prefrontal cortex (mPFC) 248, the dorsolateral prefrontal cortex (dlPFC) 246, the left dorsomedial prefrontal cortex (dmPFC) 244, and the amygdala 232. In some embodiments, an electrical fingerprint (EFP) of the amygdala and one or more regions thereof is used to determine activity levels of these regions and to generate and / or modify feedback to the subject based on the determined activity levels.

[0190] According to some exemplary embodiments, in the case of an impairment of the fear extinction process 250, for example as shown in FIG. 2F, an interface including fear-related cues is delivered to the subject, and amygdala activity feedback corresponds to, for example, the content of the interface. In some embodiments, this process-specific context stimulates modulation of fear extinction-related circuits involving at least one of the dorsal anterior cingulate cortex (dACC) 258, the vmPFC 240, the hippocampus 256, and the amygdala 232. In some embodiments, an electrical fingerprint (EFP) of the amygdala and one or more regions thereof is used to determine activity levels of these regions, and to generate and / or modify feedback to the subject based on the determined activity levels.

[0191] Example Procedure for Symptom- or Process-Based NF Training According to some exemplary embodiments, the NF training program for a subject diagnosed with a stress disorder (e.g., PTSD) is tailored to the specific subject. In some embodiments, the NF training program is tailored to the individual according to at least one trigger that caused a trauma in the past, a current trigger that causes at least one stress symptom associated with the trauma, at least one stress disorder symptom, and at least one abnormal process associated with the stress disorder. Reference is now made to FIG. 2G, which illustrates an NF training procedure for a subject diagnosed with a stress disorder (e.g., PTSD), according to some exemplary embodiments of the present invention.

[0192] According to some exemplary embodiments, in block 250, the subject is diagnosed with a stress disorder. In some embodiments, the stress disorder includes PTSD, acute stress disorder, adjustment disorder, reactive attachment disorder (RAD), disinhibited social interaction disorder (DSED), obsessive-compulsive disorder, phobia, general anxiety disorder, social anxiety disorder, borderline personality disorder. In some embodiments, the subject is diagnosed with a stress disorder based on the Diagnostic and Statistical Manual of Mental Disorders (DMS), such as a stress disorder in the category of "other traumatic and stressful or related disorders" or "nonspecific traumatic and stressful or related disorders" in the DSM 5th edition.

[0193] According to some exemplary embodiments, the subject is diagnosed with a stress disorder based on observation and / or interview by a mental health professional, e.g., a psychiatrist. Alternatively or additionally, the subject is diagnosed with a stress disorder based on measurements of at least one physiological parameter (e.g., heart rate, blood pressure, and / or skin electrical conductivity).

[0194] According to some exemplary embodiments, for example, at block 252, symptoms of stress disorder are evaluated. In some embodiments, the evaluation of symptoms is performed, for example, as shown in FIG. 2B. In some embodiments, the evaluation of symptoms is performed based on observation and / or interview by a mental health professional, for example, a psychiatrist. Alternatively or additionally, the evaluation of symptoms is performed based on measurements of at least one physiological parameter (e.g., heart rate, blood pressure, and / or skin electrical conductivity). Additionally or alternatively, the evaluation of symptoms is performed using an evaluation questionnaire, for example, the Clinical Assessment and Prediction Scale for Posttraumatic Stress Disorders (CAPS) (e.g., CAPS-DSM-5 (CAPS-5)) or a variant thereof. In some embodiments, the evaluation of symptoms is performed based on subclasses of CAPS-5. In some embodiments, the symptoms include intrusion, avoidance, cognitive and mood alterations, and alterations in arousal and reactivity. In some embodiments, the evaluation includes a determination of the intensity, for example, the level of expression of each symptom in a particular subject.

[0195] According to some exemplary embodiments, abnormal neurobehavioral processes, e.g., abnormal stress-related neurobehavioral processes, are identified in block 254. In some embodiments, abnormal neurobehavioral processes are identified based on the assessment of stress disorder symptoms performed in block 252 (e.g., based on the level of expression of each symptom in a particular subject). Alternatively, or in addition, abnormal neurobehavioral processes are identified based on a diagnosis of the subject performed in block 250.

[0196] According to some exemplary embodiments, the abnormal neurobehavioral processes include PTSD-related abnormal neurobehavioral processes (e.g., impaired threat detection processes, impaired emotion regulation processes, and / or impaired fear extinction processes).

[0197] According to some exemplary embodiments, NF training is delivered to the post-diagnosed subject (e.g., PTSD patient) at block 256. In some embodiments, the delivered NF training is Electrical Fingerprint (EFP)-NF training. In some embodiments, the EFP-NF training delivered at block 256 is in a neutral context and is not in a context related to trauma, trauma triggers, PTSD-related symptoms, or PTSD-related abnormal neurobehavioral processes.

[0198] According to some exemplary embodiments, in EFP-NF in a neutral context, the patient is instructed to perform at least one exercise (e.g., a physical or mental exercise) while interacting with (e.g., feeling, seeing and / or hearing) an interface delivered by haptic, audio and / or video signals (e.g., using virtual reality or on a display). In some embodiments, the interface is a neutral interface, e.g., one that is not related to PTSD.

[0199] According to some exemplary embodiments, performing at least one exercise modulates an activity level of at least one neural circuit or at least one brain region (e.g., at least one brain region associated with the limbic system). In some embodiments, the at least one brain region associated with the limbic system includes the amygdala. In some embodiments, the subject receives feedback in response to the activity level of the at least one neural circuit or at least one brain region. In some embodiments, the feedback is delivered by adjusting an interface.

[0200] According to some exemplary embodiments, a subject performs EFP-NF in a neutral context, for example to find exercises (e.g., physical and / or mental exercises) that are more efficient than other exercises in regulating the activity of at least one brain region in the subject. Furthermore, performing EFP-NF in a neutral context also makes it possible to determine, for example, whether the subject meets the requirements to move on to an EFP-NF session in a traumatic context.

[0201] According to some exemplary embodiments, in block 258, NF training (e.g., EFP-NF training) is delivered in a trauma context. In some embodiments, the trauma context is individualized to the trainee. In some embodiments, the trauma context includes EFP-NF training in the context of the trainee's PTSD symptoms (e.g., PTSD symptoms assessed in block 252). Alternatively or additionally, the trauma context includes EFP-NF training in the context of the trainee's PTSD-related aberrant neurobehavioral processes (e.g., aberrant processes identified in block 254).

[0202] According to some exemplary embodiments, changes in the assessed symptoms and / or identified abnormal processes are determined at block 260. In some embodiments, changes in the assessed symptoms and / or identified abnormal processes are determined during a training session, e.g., at the beginning and / or end of a training session (e.g., while the trainee is at the clinic). Alternatively or additionally, changes in the assessed symptoms and / or identified abnormal processes are determined between training sessions, e.g., when the trainee is at home rather than at the clinic, or when at the clinic.

[0203] According to some exemplary embodiments, if the determined change is a desired change, e.g., a change that reduces the onset of symptoms and / or modifies the abnormal process to a desired level, the NF training is stopped. Alternatively, if the determined change is not a desired change, e.g., a change that does not reduce the onset of symptoms and / or modifies the abnormal process to a desired level, the NF training is continued or repeated. Alternatively, the EFP-NF training is stopped.

[0204] According to some exemplary embodiments, the EFP-NF is modified at block 262. In some embodiments, at least one exercise performed by the trainee is modified. Alternatively or additionally, the trauma-related interface delivered to the trainee is modified.

[0205] According to some exemplary embodiments, after successfully completing EFP-NF, e.g., after achieving a desired goal of the training (e.g., after achieving a desired change), the trainee performs at least one additional maintenance training session in block 264. In some embodiments, the maintenance training session is performed at least one week (e.g., at least two weeks, at least one month, or any intermediate value, shorter or longer) after completing the EFP-NF training. In some embodiments, the maintenance training session is performed without receiving feedback associated with the activity level of at least one brain region and / or neural circuit. In some embodiments, the maintenance training session is performed when the trainee is not in a clinic. In some embodiments, in block 258, during the maintenance training session, the trainee performs at least one exercise, e.g., the exercise that the trainee performed during the training session. Instead, the trainee performs a different exercise, optionally selected based on the trainee's condition and / or level of PTSD symptoms.

[0206] Exemplary changes in symptoms after treatment According to some exemplary embodiments, monitoring of stress-related symptoms occurs after NF training and / or between training sessions of NF training, e.g., as shown in block 260 of FIG. 2G. Optionally, changes in stress-related abnormal neurobehavioral processes are determined in response to changes in symptoms. Reference is now made to FIGS. 2H-2K, which depict changes in stress-related symptoms (e.g., PTSD-related symptoms) following EFP-NF training according to some exemplary embodiments of the present invention.

[0207] According to some exemplary embodiments, as shown, for example, in FIG. 2H, trainees exposed to a trauma-related interface in trauma NF training 270 showed reduced levels of intrusion after training at TP2 276 (at the post-training test point) compared to levels of intrusion before training at TP1 274 (at the pre-training test point). Intrusion levels were also reduced in trainees who underwent neutral NF training 272 with a non-trauma-related neutral interface.

[0208] According to some exemplary embodiments, as shown, for example, in FIG. 2I, trainees exposed to a trauma-related interface in trauma NF training 270 showed reduced levels of cognitive and mood alterations after training at TP2 276 (at the post-training test point) compared to levels of cognitive and mood alterations before training at TP1 274 (at the pre-training test point). Trainees who underwent neutral NF training 272 with a non-trauma-related neutral interface also showed reduced levels of cognitive and mood alterations, but the reduction was smaller compared to the trauma NF training 270 group.

[0209] According to some exemplary embodiments, as shown, for example, in FIG. 2J, trainees exposed to a trauma-related interface in trauma NF training 270 showed a decrease in avoidance levels after training at TP2 276 (at the post-training test point) compared to the avoidance levels before training at TP1 274 (at the pre-training test point). Trainees who underwent neutral NF training 272 with a non-trauma related neutral interface also showed a decrease in avoidance levels, but the decrease was smaller compared to the trauma NF training 270 group.

[0210] According to some exemplary embodiments, as shown, for example, in FIG. 2K, trainees exposed to a trauma-related interface in trauma NF training 270 showed decreased arousal levels after training at TP2 276 (at the post-training test point) compared to arousal levels before training at TP1 274 (at the pre-training test point). Trainees who underwent neutral NF training 272 with a non-trauma related neutral interface also showed decreased arousal levels, but the decrease was smaller compared to the trauma NF training 270 group.

[0211] Exemplary Feedback Delivery According to some exemplary embodiments, the trainee is exposed to trauma-related content, e.g., trauma-related content tailored to the trainee's particular trauma, during training to modulate activation of one or more brain regions activated by trauma-related content. In some embodiments, the trainee is exposed to trauma-related content that upregulates amygdala activity levels during training to downregulate activity levels by one or more exercises (e.g., mental and / or physical exercises). In some embodiments, feedback regarding the trainee's success in modulating brain activity regions is delivered by modifying the trauma-related content. In some embodiments, the intensity of exposure is reduced when the trainee is successful in downregulating amygdala activity levels. In some embodiments, the trainee's level of exposure to trauma-related content follows the change in amygdala activity levels. In some embodiments, once the amygdala activity levels have decreased, the level of exposure to trauma-related content, e.g., exposure time or exposure content, is reduced. Reference is now made to FIG. 3, which illustrates a process for modifying feedback delivered to a trainee, according to some exemplary embodiments of the present invention.

[0212] According to some exemplary embodiments, trauma-related content (e.g., trauma-related challenges) is delivered to the trainee at 302. In some embodiments, the trauma-related challenges include personalized content specific to the trainee, for example, based on interviews with clinicians and / or other sources. In some embodiments, the trauma-related challenges are delivered via one or more sounds, images, smells, tactile or other interfaces.

[0213] According to some exemplary embodiments, at 304, the trainee is trained to affect activity of one or more selected brain regions. In some embodiments, the subject is trained in a time relationship with the delivery of the trauma-related challenge (e.g., during or after the delivery of the challenge). In some embodiments, the training includes predefined exercises, e.g., physical and / or mental exercises selected to affect activity of one or more brain regions. Alternatively, the subject is encouraged or asked to develop exercises or adjust known exercises, e.g., to suit his / her capabilities.

[0214] According to some exemplary embodiments, at 306, activity levels of one or more brain regions are measured. In some embodiments, the activity levels are measured based on EEG signals recorded from the trainee's head, for example, during EFP-NF training. In some embodiments, the recorded EEG signals are analyzed to generate an EFP based on the recorded EEG signals. In some embodiments, the generated EFP is associated with the activity levels of one or more brain regions.

[0215] According to some exemplary embodiments, an effect of NF training, e.g., an effect of EFP-NF training on activity of one or more brain regions, is determined at 308. In some embodiments, the effect of NF is determined based on the generated EFP and a desired EFP associated with the desired activity.

[0216] According to some exemplary embodiments, at 310, the trauma-related challenges delivered to the trainee are modified in response to the current activity level of one or more brain regions. In some embodiments, the trauma-related challenges delivered to the trainee are modified in response to the trainee's success in reaching a desired activity level in one or more brain regions. Alternatively or additionally, the trauma-related challenges are modified in response to a change in the EEG signal and / or the extracted EFP signal in a desired direction (e.g., down- or up-regulation relative to baseline or previous signal values). In some embodiments, the modification of the trauma-related challenges is delivered as a feedback of the NF training, e.g., a sensory reward feedback of the NF process.

[0217] According to some exemplary embodiments, the modified challenges are delivered to the trainee continuously or incrementally. Alternatively or additionally, feedback is delivered to the trainee online during the NF training, for example within 30 seconds, for example within 20 seconds, within 10 seconds, or any intermediate value, shorter or longer period of time from the measurement of the EEG signal.

[0218] Exemplary Systems for Delivering NF for Training Against Stress Injuries Reference is now made to FIG. 4, which illustrates a system for delivery of NF (eg, EFP-NF for training against stress disorders), according to some exemplary embodiments of the present invention.

[0219] According to some demonstrative embodiments, a system (e.g., system 400) includes a control unit 402 and an EEG measurement unit 404 electrically connected to the control unit 402. In some embodiments, the EEG measurement unit includes one or more EEG electrodes, e.g., EEG electrodes 408 and 410 attached to a scalp 412 of a subject 406. In some embodiments, the one or more EEG electrodes are configured to measure EEG signals, e.g., during EFP-NF training.

[0220] According to some exemplary embodiments, the control unit 402 includes a control circuit 416 and an EEG recording unit 414 electrically connected to the control circuit 416. In some embodiments, the EEG electrodes, e.g., EEG electrodes 408 and 410, are electrically connected to the EEG recording unit 414. In some embodiments, the EEG recording unit 414 transmits recorded EEG signals to the control circuit 416.

[0221] According to some exemplary embodiments, the control unit 402 includes a memory 418 electrically connected to the control circuitry 416. In some embodiments, the memory 418 stores the recorded EEG signals, where the stored EFP signals are, for example, general and / or personalized EFP signals associated with a particular activity level of one or more brain regions. In some embodiments, the control circuitry 416 analyzes at least a portion of the recorded EEG signals, for example, to generate an EFP associated with a current activity level of one or more brain regions. In some embodiments, the control circuitry 416 generates the EFP signal using an algorithm stored in the memory 418.

[0222] According to some exemplary embodiments, the trainee interface 424 is electrically connected to the control circuitry. In some embodiments, the trainee interface 424 includes an auditory interface and / or a display. In some embodiments, during NF training, the control circuitry delivers challenges (e.g., neutral challenges and / or trauma-specific challenges) to the trainee via the trainee interface. In some embodiments, values ​​of at least one parameter associated with the neutral challenges and / or trauma-specific challenges are stored in the memory 418. In some embodiments, the trainee interface 424 delivers the challenges by generating an auditory and / or visual signal. Alternatively or additionally, the trainee interface 424 delivers the challenges to the trainee 406 by generating an odor.

[0223] According to some exemplary embodiments, the supervisor circuitry 420 is electrically connected to the control circuitry 416. In some embodiments, the supervisor interface 420 delivers one or more indicators related to the NF training process to a supervisor, e.g., a clinician monitoring the NF training. In some embodiments, the supervisor interface is located in proximity to the trainee 406, e.g., in the same room as the trainee and / or less than 10 meters away from the trainee, e.g., less than 7 meters, less than 5 meters, less than 3 meters, or any intermediate value, less or greater than these.

[0224] According to some exemplary embodiments, the control circuitry is configured to record EEG signals from one or more EEG electrodes, for example, during delivery of a challenge to the trainee 406. Additionally, the control circuitry is configured to record EEG signals from one or more EEG electrodes when the trainee performs a practice exercise to modulate activity of one or more brain regions. In some embodiments, the control circuitry 416 is configured to analyze the recorded EEG signals during delivery of the challenge and / or after performance of the practice exercise, and generate an EFP related to activity levels of one or more brain regions.

[0225] According to some exemplary embodiments, the control circuitry 416 is configured to determine whether the EFP signal generated after the performed exercise is associated with a desired activity level of one or more brain regions based on the stored EFP signal, optionally using look-up tables and / or algorithms stored in the memory 418. In some embodiments, the control circuitry is configured to deliver feedback (e.g., an indication) to the trainee 406, optionally via the trainee interface 424. In some embodiments, the feedback is associated with the subject 406's success in altering activity of one or more brain regions in a desired direction (e.g., upregulating activity or downregulating activity).

[0226] According to some exemplary embodiments, the control circuitry 416 is configured to adjust at least one parameter of the challenge delivered to the trainee 406 in response to the level of success of the trainee in adjusting the activity level of one or more brain regions and / or in response to the activity level of one or more brain regions. In some embodiments, the control circuitry 416 adjusts the challenge delivered to the trainee 406 based on one or more parameter values ​​of the challenge stored in the memory 418 (e.g., content of the challenge, type of challenge, duration of the challenge, sound intensity, light intensity, color, color intensity, odor intensity, size of different sound sources (human or object), haptic appearance (e.g. wind or water), human avatar (with or without) in the training interface).

[0227] According to some exemplary embodiments, the supervisor monitors the performance of the trainee 406 by receiving one or more indicators from the control circuitry 416 at the supervisor interface 420. In some embodiments, the control unit is configured to measure at least one physiological parameter value of the trainee (e.g., heart rate, blood pressure, skin conductivity, pupil dilation, specific eye movements in response to exposed stimuli, electromyogram (EMG) of muscle tension, or reaction time for reaching a specific goal, or other physiological parameter related to physiological response to stress). In some embodiments, the control circuitry 416 is configured to automatically stop the NF training when the measured at least one physiological parameter and / or the recorded EEG signal indicates that the trainee's response to a challenge (e.g., a neutral challenge or a trauma-related challenge) is stronger than a predetermined value stored in the memory 418. Alternatively, or in addition, the NF training is manually stopped by a supervisor using the supervisor interface when at least one measured physiological parameter and / or recorded EEG signal indicates that the trainee's response to a challenge (e.g., a neutral challenge or a trauma-related challenge) is stronger than a predetermined value stored in memory 418.

[0228] According to some exemplary embodiments, a user of the system (e.g., system 400), e.g., a technician, nurse, doctor, introduces information and / or characteristics of a stress disorder of a patient (e.g., subject 406 diagnosed with a stress disorder) into a storage medium (e.g., memory 418 of control unit 402). In some embodiments, the user introduces the information through a user interface of the control unit (e.g., supervisor interface 420). Alternatively, the patient information and / or characteristics are delivered to memory 418 by communication circuitry of the control unit. In some embodiments, the information includes information about a traumatic event that first triggered the stress disorder in the patient, at least one symptom of the stress disorder expressed by the patient, and / or at least one impaired neurobehavioral process of the patient associated with the stress disorder.

[0229] According to some exemplary embodiments, the information added to the recording medium includes at least one challenge configured to induce at least one symptom of the patient's stress disorder. Alternatively or additionally, the information added to the recording medium includes at least one non-specific challenge configured not to induce at least one symptom of the subject's stress disorder. In some embodiments, the non-specific challenge is configured to affect activation in at least one brain region of the patient that is also affected by the patient's stress disorder, but not to induce at least one symptom of the patient's stress disorder.

[0230] According to some exemplary embodiments, the control circuit (e.g., the control circuit 416) selects a challenge from a list of challenges stored in the storage medium to provide to the patient. In some embodiments, the control circuit selects the challenge based on patient information stored in the storage medium (e.g., information about the trauma causing the stress disorder, information about at least one trigger of the stress disorder, information about at least one symptom of the patient's stress disorder, and information about at least one impaired neurobehavioral process of the patient's stress disorder). Alternatively or additionally, the control circuit selects the challenge based on a value or indicator of at least one physiological parameter (e.g., heart rate, blood pressure, skin conductivity) stored in the storage medium. Alternatively or additionally, the control circuit selects the challenge based on the results of at least one clinical assessment (e.g., CAPS-5 assessment or a variant thereof, depression assessment and / or anxiety disorder assessment) performed on the patient.

[0231] According to some exemplary embodiments, the control circuitry (e.g., control circuitry 416) provides at least one challenge selected by a user or the control circuitry, e.g., by visual and / or audio signals, to the patient, e.g., using a trainee interface (e.g., trainee interface 424). In some embodiments, the control circuitry (e.g., control circuitry 416) receives at least one electrical signal, e.g., at least one electrical signal generated by the patient's brain in association with (e.g., before, during and / or after) exposure of the patient to the at least one challenge. In some embodiments, the received electrical signal is an EEG signal. In some embodiments, the control circuitry receives the at least one electrical signal from a recording unit (e.g., EEG recording unit 414).

[0232] According to some exemplary embodiments, the control circuitry (e.g., control circuitry 416) uses the received at least one electrical signal to monitor the activity level of at least one particular brain region of the patient's brain (e.g., a limbic brain region). In some embodiments, the control circuitry processes the received at least one electrical signal to identify at least a portion of the at least one electrical signal indicative of the activity level of the at least one particular brain region, for example, as described in U.S. Patent Publication No. 13 / 983,419.

[0233] According to some exemplary embodiments, the control circuitry (e.g., control circuitry 416) identifies a relationship between at least a portion of the received electrical signals and a signature (also referred to herein as an EEG electrical fingerprint (EEG-EFP)) stored in a recording medium (e.g., memory 418). In some embodiments, the signature is an activity level signature of at least one particular brain region (e.g., the amygdala or other brain region of the limbic system).

[0234] According to some exemplary embodiments, the control circuitry (e.g., control circuitry 416) monitors the patient's ability to modulate the activation of at least one brain region, for example, using the received at least one electrical signal. In some embodiments, the control circuitry delivers instructions to the patient to perform at least one exercise (e.g., mental or physical exercise) configured to affect the activation of at least one specific brain region. In some embodiments, the control circuitry selects an exercise from a list of exercises stored in the recording medium. In some embodiments, the control circuitry selects an exercise based on patient information stored in the recording medium, and / or based on at least one specific brain region, and / or based on a desired effect on the activity of at least one specific brain region.

[0235] According to some exemplary embodiments, the control circuitry (e.g., control circuitry 416) determines how to modify, optionally automatically modify, the at least one challenge and / or instructions for an exercise to provide to the subject based on the received electrical signals. In some embodiments, the control circuitry modifies the at least one challenge and / or instructions for an exercise to provide to the subject based on the activity level of at least one particular brain region and / or the success of the patient in modulating activity of the at least one brain region.

[0236] Example demonstration experiment Various embodiments and aspects of the present invention as described above and claimed below find experimental support in the following demonstrative experiments.

[0237] Post-traumatic stress disorder (PTSD) can be characterized by excessive emotional reactivity and reduced emotional regulation. Abnormalities in these processes may correspond to an overactive amygdala and an underactive ventromedial PFC, respectively. Optionally, non-specific targeting of these processes may explain poor therapeutic efficacy in PTSD. Thus, novel process-oriented neurofeedback (NF)-targeted fMRI-evoked EEG fingerprints (EFPs) of the amygdala (Amyg-EFP) in the context of exposure to a personal traumatic story suggest that this intervention may result in a reduction of symptoms and alteration of dysfunctional neural processing in PTSD related to emotional reactivity and regulation.

[0238] Patients were randomly assigned to either Amyg-EFP-NF in a neutral context (n=14), Amyg-EFP-NF in a traumatic context (n=13) or a control group (treatment as usual, n=13). In the two study groups, patients received 15 sessions (20 min each) of NF training, before and after which they underwent clinical assessments, amygdala-fMRI-NF and emotion-reactivity fMRI tasks. The evaluation results revealed that patients in the two study groups showed reduced PTSD symptoms following the intervention, whereas control participants did not improve (sig interaction group therapy), with the traumatic context showing the greatest clinical benefit. Reduced amygdala BOLD activity following NF treatment in the study group compared to the treatment as usual group indicated target engagement.

[0239] The following examples demonstrate the role of disorder-specific context for influential NF in PTSD. Furthermore, the results suggest that amelioration of PTSD symptoms may be associated with modulation of underlying PTSD neural mechanisms.

[0240] The experiment investigated the feasibility and efficacy of amygdala-targeted NF treatment in reducing PTSD symptoms in a chronic PTSD population that had suffered from PTSD symptoms for more than 14 months. Targeting chronic patients allows the investigation of whether influencing amygdala activity (e.g. through NF) is an efficient intervention method, provided that symptoms and involved brain mechanisms are to some extent enhanced. The experiment also allows the investigation of the influence of the context of NF training.

[0241] The study includes a test group that is challenged with trauma-specific challenges followed by training in amygdala downregulation. In some embodiments and studies of the present invention, patients in the trauma context group are challenged stepwise with content from the traumatic event (in the form of audio scripts) and undergo downregulation training in the context of such challenges that are believed to increase amygdala activation.

[0242] In some embodiments and studies of the present invention, clinical outcome measures include CAPS, BDI, STAI, ERQ. Neurological outcome measures include resting-state functional connectivity sequence, amygdala reactivity task (Hariri), emotion engagement task (emotional stroop) and two short cycle amygdala rt-fMRI-NF.

[0243] Reference is now made to Figures 5 and 6 which respectively depict a general outline of the experiment and the various test groups included in the experiment.

[0244] Participants ages 18-65 who were exposed to a traumatic event at least 14 months prior were recruited from the trauma clinic at TASMC and other clinics near Tel Aviv. In some embodiments, subjects who were exposed to a traumatic event at least 6 months, e.g., at least 10 months, at least 12 months, or any intermediate value, lesser or greater period prior to EFP-NF treatment or evaluation meeting were selected for EFP-NF treatment, e.g., as described in block 202 of FIG. 2A. In some embodiments, subjects who were exposed to a traumatic event that led to a diagnosis of a stress disorder were selected for EFP-NF treatment.

[0245] Inclusion and Exclusion: In some embodiments and studies of the present invention, participants were screened (and excluded) for the presence of DSM axis-I disorders (using SCID). In some embodiments and studies of the present invention, participants who showed PTSD symptoms based on CAPS were included. In some embodiments of the present invention, the assessment method used to assess the subjects during the experiment was also used as part of the assessment in block 204 of FIG. 2A. After the assessment, participants were randomly divided into three groups, for example as shown in FIG. 6: amy-EFP-NF-neutral group (n=20), amy-EFP-NF-trauma group (n=20), and treatment as usual (TAU) group (n=20) that continued other treatment programs and did not receive NF training.

[0246] In some embodiments of the experiments and the present invention, e.g., block 204 of FIG. 2A, subject evaluations were performed as described in Timepoint 1 - Pretreatment: First Timepoint (TP1) Baseline evaluations were performed over 2-3 sessions and included clinical evaluations, psychological questionnaires, and fMRI scans.

[0247] The following training phase is an example of EFP-NF training in some embodiments of the present invention, which is performed in block 206 of FIG. 2A. Training phase: Each participant (in the two test groups) received 15 NF sessions over a 13-week period (two sessions per week for the first two weeks, then one session per week). The number of sessions is similar to that of conventional and / or common PTSD interventions, such as CPT (Resick & Schnicke, 1993) and PE (Rauch et al., 2009) that include interventions. The intervention protocol for the amy-EFP-NF-neutral group included two interleaved interfaces: the first session used an auditory interface, and the second and subsequent sessions used a waiting room scenario interface (also described above) until the last session of the intervention phase.

[0248] In some embodiments and experiments of the present invention, the protocol for the amy-EFP-NF-trauma group was similar in the first session, followed by a gradual addition of traumatic challenge NF. In the first phase, which included at least four sessions, participants were trained with the same NF sessions as the neutral group. Participants who successfully reduced their EFP signal (relative to baseline) during training in three of the last five sessions, as implemented in block 208 of FIG. 2A and in the experiment, for example, were eligible to continue training in the next phase. Participants who were unsuccessful continued training in a neutral context for the remaining sessions.

[0249] The following is an example of an individualized stress-context EFP-NF training in some embodiments of the present invention, as implemented in block 212 of FIG. 2a. In the second phase of the experiment, participants who were successful as described above were trained in the context of their own traumatic story. In the first session, participants were interviewed about the traumatic event by a trained team member to create a detailed script of a sequence of events, including thoughts, feelings, sensations, and specific information (day of the week, weather, etc.) to create the context.

[0250] After the interview that was expected to create an emotional challenge, participants received regular neutral NF training accompanied by one team member. Participants who successfully down-regulated their EFP signals during the session received training with traumatic challenge feedback in a subsequent session. In some embodiments and experiments of the present invention, each scripted event was processed into an audio file of at least 30 seconds in length (e.g., a 3-minute audio file), and was optionally recorded with a male voice narrating the event in the present tense and in the second person (i.e., "You are driving your car..."). In subsequent sessions of the experiments and some embodiments of the present invention, the feedback representing the EFP signal was the volume of the traumatic recording. That is, successful reduction of the EFP signal also reduced the volume of the traumatic recording. Participants who were not successful in down-regulating their EFP signals (in a neutral context) were re-challenged in the following NF-N session immediately after listening to the traumatic recording.

[0251] In both groups, each NF practice session consisted of five blocks of 3-min NF. During each block, a staff member reviewed with the participant the results of the previous block and asked about the strategies he or she used and his or her subjective feelings during the block. The final three sessions included two additional "transition" blocks at the beginning of the session.

[0252] During the training phase, participants in all groups completed biweekly symptom monitoring questionnaires that included questions about intrusive thoughts and feelings, avoidance, cognitive and mood symptoms, sleep disturbances, and arousals.

[0253] 7 illustrates NF sessions of a training protocol performed in an experiment, including sessions with auditory NF (blue box 702), waiting room NF (green 704), and trauma NF (purple 706), according to some exemplary embodiments of the present invention. The diagram illustrates the order of each session in the trauma-EFP-NF protocol and the neutral EFP-NF protocol.

[0254] FIG. 8 represents an NF with a multimodal interface: for example, the waiting room audiovisual animation scenario in blocks 108, 206 and 226 of FIGS. 1, 2A and 2B, respectively.

[0255] FIG. 9 illustrates a unimodal auditory interface implemented, for example, in blocks 108, 206 and 226 of FIGS. 1, 2A and 2B, respectively.

[0256] FIG. 10 depicts NF with graded exposure, for example, as performed in blocks 108, 212 and 228 of FIGS. 1, 2A and 2B, respectively.

[0257] Experimental Results Figure 11 shows the change in EFP signal over time as a subject is given a detailed description of a traumatic event. The scenario represents not only contextual information (date, weather, who was there, etc.), but also the patient's emotional, physical and cognitive experiences and how they change as the event unfolds.

[0258] 12A-12G show that as the session progressed, the patient was able to achieve more and more down-regulation of EFP signals, and that this down-regulation was evident even when faced with intense emotional challenges posed by the "peak" of the trauma script.

[0259] As shown in Figure 11 and Figures 12A-12G, subjects modulate their EFP signals while exposed to scenarios that include parts that represent "hot spots" (e.g., foci of specific trauma (yellow areas)).

[0260] Figure 13 depicts significant learning (i.e., amygdala EFP downregulation) during the training sessions. The patient successfully downregulated his amygdala (EFP) activity after 13 weeks of training. As shown in the graph, the EFP signal decreased between weeks 1 and 13 (weeks 1+2: 2 sessions per week; weeks 3-13: 1 session per week, totaling 15 sessions over 13 weeks).

[0261] Figures 14A and 14B represent NF learning by treatment type (neutral vs. exposed). Figure 14A represents the overall mean and Figure 14B shows the variability of individual scores. The graphs show that patients trained in the neutral context were successful in downregulating their EFP signal from the first part of the study to the second part of the study. On the other hand, patients in the exposed group showed a greater decrease in EFP signal during the exposure session compared to the neutral context session. This figure shows that training EFP in an individual traumatic context has an additive effect on training in the neutral context.

[0262] FIG. 15 depicts the change in CAPS-5 total score between different groups of the experiment. CAPS (PTSD Clinical Diagnostic Interview Scale) is an established and common structured clinical interview assessment for the severity of PTSD symptoms. As shown in the figure, patients who received EFP training showed a significant decrease in CAPS scores compared to patients who did not receive training. This decrease was greater in patients in the exposure group. In some embodiments, the change in CAPS-5 or other PTSD clinical diagnostic interview scales is used to evaluate the subject's condition after EFP-NF training.

[0263] Figures 16A, 16B and 16C show the individual CAPS results for patients in the neural context group (Figure 16A) and the exposed group (Figure 16B). Figure 16C shows the percentage of participants who had a greater than 5 point reduction in CAPS score after the intervention. This indicates that the majority of patients (75%) in the exposed group showed a meaningful reduction in CAPS score after the intervention.

[0264] Figure 17 shows the change in CAPS-5 subscales between different groups. These subscales are assessed separately for PTSD symptom clusters: avoidance, intrusion, arousal, and cognitive and mood changes. In some embodiments, the change in CAPS-5 subscales is used to evaluate the state or status of subjects after EFP-NF training.

[0265] FIG. 18 depicts the change in PCL scores (self-reported) between the various groups. The PCL is an established and common self-report instrument for the assessment of PTSD symptoms. The results showed that patients in both EFP groups (neutral and exposed) showed a reduction in PTSD symptoms after the intervention compared to patients not receiving the intervention (TAU group). This reduction in PTSD scores was maintained 3 and 6 months after the intervention. These results demonstrate that the effects of the EFP intervention are maintained over the long term.

[0266] Figure 19 represents the changes in fMRI measurements before (left column, denoted "before") and after (right column, denoted "after") the intervention between the various groups. On the left, the first fMRI measurement of the patient is shown. On the right, the real-time fMRI during the learning of the post-intervention session (i.e., the difference between the first and second cycle of the session) is shown. The figure shows that compared to participants trained without EFP (treatment as usual (TAU) group, who did not receive NF training), patients trained with amygdala EFP also succeeded in downregulating BOLD amygdala activity after the EEG training session. From the figure, it can be seen that patients who experienced amygdala-EFP_NF treatment performed significantly better after the treatment than before amygdala-MRI-NF. This means that after training with EFP-NF, patients in the treatment group were better at downregulating amygdala BOLD activity than the non-treatment group. In the figure, neutral (n=10) + trauma (n=8) vs. TAU. Pre: conditioning-observation, 1st cycle only. Post: Adjustment-observation, average of all 2 cycles.

[0267] Figure 20 shows the correlation between EFP training and BOLD activation during subsequent real-time fMRI neurofeedback. This positive correlation indicates that participants who were very successful in downregulating EFP signal during training sessions (i.e., those sessions that performed best overall) were also better at downregulating amygdala BOLD signal during real-time neurofeedback after the intervention. Figure 20 shows that the change in EFP-NF (regardless of the number of EFP-NF sessions) correlated with the highest change in EFP-NF.

[0268] Summary of the demonstration experiment The empirical experiment aimed to study the process modulation underlying psychiatric disorders using the neurofeedback technique fMRI-informed EEG as a reliable neurofeedback probe for limbic system modulation in PTSD.

[0269] Summary of results: Compared to control-EFP-NF, Amyg-EFP-NF led to improved amygdala-BOLD downregulation in both healthy participants (n=38) and PTSD patients (n=29). Finally, to prove its viability as an extensible NF probe, amygdala-related behavioral modification following repeated Amyg-EFP NF training was tested. In healthy participants (n=~150), results showed that Amyg-EFP-NF versus control-NF led to greater reductions in alexithymia and improved emotion regulation as measured by the affective Stroop task. Furthermore, results in PTSD patients (n=40) showed that Amyg-EFP-NF led to a reduction in PTSD ratings (~10 points on the Caps-5), and this reduction correlated with successful Amyg-EFP downregulation.

[0270] Conclusions: The results demonstrate the feasibility of using EEG in NF targeting limbic activity in healthy and patients.

[0271] Example additional demonstration experiments Exemplary Methods participants The experiment involved 59 adults, aged 18–65 years, who met DSM-5 criteria for PTSD. Forty completed the study (n=14 neutral NF, n=13 traumatic NF, n=13 no NF; see consort diagram in Appendix Fig. 24B). Recruitment sites included mental health clinics and social media advertisements. All patients underwent clinical evaluation by trained psychiatrists using the Clinical Diagnostic Interview Scale for DSM-IV axis I Disorders (SCID) and the Clinical Diagnostic Interview Scale for PTSD (CAPS-5) (see Appendix for exclusion criteria). At baseline, the groups did not differ significantly in mean age and time since trauma, nor in the proportion of women (see Table 1a,b). Patients provided written informed consent for participation and received financial compensation. The protocol was approved by the Institutional Review Board of the Tel Aviv Sourasky Medical Center and registered at ClinicalTrials.gov.

[0272] [Table 1]

[0273] [Table 2]

[0274] Table 1a. Demographic characteristics. Randomization was balanced by age (< or >40 years) and time since trauma (< or >5 years). One-way ANOVAs and chi-square tests were performed to compare groups on baseline characteristics. CAPS-5 scores at TP1: F(2,35) = 1.22, p = .306; time since trauma: F(2,36) = .16, p = .84; age: F(2,36) = 2.01, p = .14; gender, χ2(2) = 1.08, p = .58.

[0275] General Procedure In the study and in some embodiments, participants were assessed before and immediately after the interventions (TP1, TP2), as well as 3 and 6 months after their completion (see FIG. 21A). In the study and in some embodiments, the primary clinical outcome measures, as shown, for example, in FIGS. 1, 2A, and 2G, included the CAPS-5 interview and the PTSD Checklist Questionnaire (PCL) (27). Secondary clinical outcome measures included the State-Trait Anxiety Inventory (STAI) (28) and the Beck Depression Inventory-II (BDI-II) (29) to further clinically characterize patients, and the Toronto Aflexithymia Scale (TAS-20) (30) and the Emotion Regulation Scale (ERQ) (31) to assess emotion regulation abilities. Following TP1, patients were randomly assigned to one of three study arms: traumatic NF, neutral NF, and no NF. There were no differences between groups at baseline for any of the clinical measures (Total CAPS-5, PCL, STAI, BDI-II, TAS-20 and ERQ). In some embodiments, the scales and questionnaires described above were also used to assess PTSD patients prior to training to measure at least one clinical outcome, e.g., block 204 of FIG. 2A and blocks 250, 252 and 254 of FIG. 2G.

[0276] Reference is now made to Figure 21A, which illustrates the study procedure. Clinical evaluations, structural scans and rtfMRI-NF scans were performed at time point 1 (TP1) and time point 2 (TP2). Follow-up evaluations were performed via online questionnaires at 3 and 6 months after TP2.

[0277] Reference is now made to FIG. 21B, which illustrates an intervention protocol experiment in some embodiments of the present invention. The intervention phase included 15 training sessions, starting with two sessions per week for 2 weeks, followed by one session per week (total of 13 weeks). Each session lasted approximately 40 minutes, including preparation time. Patients were seated in front of a computer screen wearing headphones in a quiet room. The first five sessions were identical for both groups, alternating between two feedback interfaces: a neutral auditory interface, followed by a multimodal scenario interface in the next session. The auditory interface was a jazz piece without lyrics, and the multimodal animated scenario interface represented a virtual hospital waiting room with characters sitting or walking and facing a receptionist (see Appendix for interface description). The auditory sessions included five consecutive training blocks, each lasting 3 minutes. The volume could be increased or decreased as a function of the power of the AmygEFP signal (each in 10 dB). The multimodal scenario session type also included five consecutive blocks, each containing a 1-min activation baseline (set at 75% of the room's non-resting level and not subject to participant adjustments) and a 3-min NF during which patients were trained to adjust their brain signals and received feedback through the room scenario (see Appendix for further details on the online computation of the multimodal animated scenario). Patients were guided to reduce the auditory tones or change the animated scenario to a more relaxed one using different self-developed mental techniques. Patients in the neutral NF group continued training with these alternating interfaces until the completion of 15 intervention sessions, whereas patients in the trauma NF group who met criteria (see Appendix for trauma NF criteria) were moved to a second phase of training including the trauma-related interface.

[0278] AmygEFP-NF Training Protocol In the experiment and in some embodiments, each NF session began with a 3-minute resting recording of the baseline AmygEFP signal, followed by five 3-minute training blocks with either an auditory or multimodal feedback interface (FIG. 21B). Each training block ended with a report of the technique used by the patient during the block and a graphic illustration of their AmygEFP activity (i.e., NF success). The procedure in the traumatic NF group was also identical to the neutral NF group until the patient reached criteria for initiating traumatic story NF in the first session (approximately sessions 7-8, see accompanying traumatic NF criteria). In the trauma-related NF session, the feedback representing the AmygEFP signal was the volume of the traumatic story recording. Successful reduction of the AmygEFP signal reduced the volume of the traumatic story. Each session began with a 3-minute resting recording of the baseline AmygEFP signal, followed by one block of neutral auditory NF, followed by 3 blocks of NF with the recorded traumatic story. Each block was followed by a debrief and graphical presentation of individual performance.

[0279] AmygEFP amplitude was calculated online using an in-house algorithm based on data recorded from the Pz channel (22,23). Downregulation of the AmygEFP signal was assessed by calculating a personal NF success index for each subject for each session (i.e., the mean of the 5 NF blocks minus the mean of the baseline blocks divided by the mean baseline standard deviation) using the following formula:

[0280]

number

[0281] The desired outcome is a lower AmygEFP value during accommodation than at baseline, which results in a more negative NF Success Index (see Appendix for details of EEG data recording).

[0282] rtfMRI-NF paradigm In the experiment, MRI scans were performed on a 3.0T Siemens MRI system (MAGNETOM Prisma) with a 20-channel head coil. Preprocessing and statistical analysis were performed with Brain Voyager QX version 2.8 (Brain Innovation) (see Appendix). To represent target engagement of the AmygEFP-NF training, all patients completed rtfMRI-NF using a visual interface at TP1 and TP2 (see Appendix Fig. 2). Feedback was derived from a 6 mm sphere in Talairach space in the right amygdala (coordinates, 20, -5, -14). The level of amygdala activity was represented by the speed of the skater (based on (24,26)). Patients were instructed to slow down the speed of the skater using any mental technique that suited them. The reduced speed corresponded to reduced amygdala BOLD activity relative to baseline during NF (see Appendix Methods).

[0283] statistics R version 1.70, SPSS version 20, and STATISTICAp version 10 were used for statistical analysis. Multiple comparison corrections were performed using an FDR (≤.05) for each hypothesis.

[0284] Illustrative Results Learning effect of AmygEFP-NF To demonstrate feasibility, we investigated the ability of patients to spontaneously downregulate their AmygEFP signal. A patient repeated measures nested model analysis was adapted: fixed effects of group (neutral NF, traumatic NF) and time (13 weekly training sessions). To allow for an exploratory analysis of the impact of context on the differences in regulation between the AmygEFP groups, a fixed effect of session type was also adapted (Part 1: neutral NF sessions 1–7, traumatic NF sessions before exposure; Part 2: neutral NF sessions 8–13, traumatic NF sessions including exposure). Given the nested structure of the study, we also included patient-specific random effects, including a random effect of time nested between groups. Assessment of statistical significance was performed using likelihood ratio tests (LRT) and post hoc analyses of pairwise comparisons. Results revealed that both treatment groups showed a greater downregulation of the AmygEFP signal, as represented by smaller values ​​during regulation compared to the baseline block. Session type (part 1, 2) was tested with the LRT, and no random interactions between time and group factors were found (χ 2 (1) = 1.77, p = .18), and there was a significant fixed main effect of change in AmygEFP signal across sessions (χ 2 (1) = 4.91, p = .026). Post-hoc analyses comparing session type (Part 1 vs. Part 2) further clarified that the main effect of time was driven by greater downregulation of brain signals in the later stages of the intervention (p = .057). As hypothesized, the treatment group showed improved regulation across the intervention sessions (see Figure 22).

[0285] We now refer to Figure 22, which depicts the NF learning effect. Traumatic NF group (left panel) and neutral NF (right panel) depict individual AmygEFP-NF success as a function of intervention week. Session type is indicated in orange (traumatic NF group weekly sessions with neutral interface; neutral NF group weekly sessions 1–7) and green (traumatic NF group sessions with traumatic narratives; neutral NF group sessions 8–13). Black lines show the predictions of timepoint averages obtained by the reported nested mixed models and smoothed by locally weighted regression (Loess regression). Results showed a significant fixed main effect for session type, representing the change in AmygEFP signal across sessions (χ2(1)=4.91, p=.026) and a particularly large downregulation later in the intervention.

[0286] Further exploratory analyses aimed to assess the impact of the traumatic stories on adjustment by comparing the learning of traumatic versus neutral NFs. LRTs showed no significant differences between the two groups (χ 2 (3) = 1.64, p = .65). Post-hoc comparisons between groups conditioning by session type showed no between-group differences in either Part 1 (p = .48) or Part 2 (p = .48). Overall this exploratory analysis revealed that adjustment between treatment groups was similar both early and late in the intervention. Nevertheless, to specifically assess changes in adjustment for each group, session type was conditioned by group and then assessed with the LRT conducting post-hoc analyses. This analysis revealed a significant decrease in the AmygEFP-NF Success Index for Part 2 session types in both groups (neutral NF, p = .06; traumatic NF, p = .007). Importantly, the monotonically decreasing curves from start to finish in each group demonstrated that the improvement due to the intervention was steeper in the traumatic NF compared to the neutral NF group (see Figure 22).

[0287] AmygEFP-NF clinical efficacy In the study, changes over time (TP1, TP2) in the primary clinical outcome measures (total CAPS-5 and PCL) from TP1 to TP2 between the treatment and no NF groups were compared using 2-way repeated measures ANOVA as individual variables within subjects and between subjects within groups (neutral NF, traumatic NF, and no NF).

[0288] CAPS-5 total score analysis revealed greater improvement in the AmygEFP-NF group compared with the no NF group, and even greater improvement in the traumatic NF group (time by group interaction was F (2,35) = 3.99, p = .02, η p 2 = 0.18; the main effect of group is F (2,35) = 4.94, p = .02, η p 2 = 0.22; the main effect of time was F (1,35) = 18.20, p = .0007, η p 2 = 0.34; see Figure 23A). Planned contrasts revealed clinical improvement for treatment but not for the no NF group (simple effect of time by group: neutral NF, F = 7.22, p = .02; traumatic NF, F = 18.12, p = .0007; no NF, F = 0.13, p = .71). Further analysis showed that at TP2, greater improvement occurred with the traumatic NF compared to the no NF group (F = 14.83, p = .0001), whereas the difference between neutral NF and no NF was not significant (F = 2.39, p = .15). Treatment efficacy was further assessed by the number-needed-to-treat (NNT) index based on achieving loss of PTSD diagnosis according to CAPS-5 at TP2, comparing treatment groups with no NF: NNT=3.9 (neutral NF vs. no NF, NNT=6.5; traumatic NF vs. no NF, NNT=2.7). It further showed that the percentage symptom reduction in total CAPS-5 score differed between groups (main effect of group, F (2,35) = 6.67, p = .01, η p 2= 0.27; Figure 23B). Compared to the no NF group, which showed no improvement (-0.23%), the traumatic NF showed the greatest decrease (-35.13%; F = 13.25, p = .0008), followed by the neutral NF group (-19.48%; F = 4.203, p = .04).

[0289] Similarly, PCL analysis revealed that, as hypothesized, patients in the treatment group improved more than those in the no-NF group (F (2,34) = 4.403, p = .02, η p 2 = 0.20; the main effect of time is F (1,34) = 6.14, p = .02, η p 2 = 0.15; see Figure 23C). Planned contrasts revealed a decrease in PCL from TP1 to TP2 for the neutral NF group (Δ = -9.07; F = 9.13, p = .01) and the traumatic NF group (Δ = -7.16; F = 5.25, p = .02), but not for the no NF group (Δ = -2.84; F = 0.92, p = .36). The NNT for change in PCL scores comparing treatment groups with no NF showed an NNT = 2.4.

[0290] To investigate the long-term effects of treatment, PCL scores were analyzed 3 and 6 months after TP2. The response rate at follow-up assessment was moderate (61.2%). To ensure unbiased analysis, data from only patients with four time points of PCL were used for analysis. A two-way repeated measures ANOVA of PCL total scores against time was performed (TP1, TP2, 3 and 6 months follow-up assessments) for individual variables within subjects and between subjects within groups (AmygEFP-NF and no NF). Results showed that PTSD symptoms decreased over time, more pronounced in the treatment group than in the no NF group (time and group interaction was F-squared). (3,48)= 5.83, p = .001, ηp2 = .26). Post-hoc analysis revealed that in the treatment group, reductions in PCL occurred during the 3-month follow-up after TP1 (F = 7.9, p = .012) and the 6-month follow-up after TP1 (F = 8.34, p = .008) (Figure 23D). Taken together, these results demonstrated the second and third processes and revealed the clinical efficacy of the AmygEFP intervention for PTSD patients compared to the non-NF group.

[0291] Reference is now made to Figures 23A-23D, which show clinical outcome measures. Figure 23A: Total CAPS-5 (Clinical Diagnostic Interview for PTSD) scores reflecting severity of PTSD symptoms assessed at TP1 and TP2 for the traumatic NF, neutral NF, and no NF groups. Boxes represent the first and third quartiles, lines represent medians, "x" represents the mean, and whiskers indicate minimum and maximum values ​​outside the first and third quartiles. Results show significant reductions in CAPS-5 scores after the intervention in the neutral and traumatic NF groups, but not in the no-NF control group (time x group interaction F(2,35) = 3.99, p = .02, ηp2 = .18; time main effect F(1,35) = 18.20, p = .0007, ηp2 = .34; simple effects of time per group: neutral NF F = 7.22, p = .02; traumatic NF F = 18.12, p = .0007; no-NF F = 0.13, p = .71). At TP2, there was a greater improvement in traumatic NF compared to no-NF (F = 14.83, p = .0001), whereas the difference between neutral NF and no-NF was not significant (F = 2.39, p = .15).

[0292] Figure 23B: Percentage reduction in total CAPS-5 score symptoms from TP1 to TP2. Results show a significant difference in percent reduction in total symptoms based on CAPS-5 between groups (main effect of group, F(2,35) = 6.67, p = .01, ηp2 = .27). Traumatic NF showed the largest reduction (-35.13%; F = 13.25, p = .0008) compared to the No NF group (-0.23%) which showed no improvement, followed by the Neutral NF group (-19.48%; F = 4.203, p = .04).

[0293] Figure 23C: Total PCL (PTSD Checklist) assessed at TP1 and TP2. Results showed a significant decrease in subjective PTSD severity after the intervention in both treatment groups compared to subjects without NF (time × group interaction F(2,34) = 4.403, p = .02, ηp2 = .20; time main effect F(1,34) = 6.14, p = .02, ηp2 = .15). Planned contrasts revealed a decrease in PCL from TP1 to TP2 in the neutral NF group (Δ = -9.07; F = 9.13, p = .01) and the traumatic NF group (Δ = -7.16; F = 5.25, p = .02), but not in the no NF group (Δ = -2.84; F = 0.92, p = .36).

[0294] Figure 23D: Total PCL throughout the study. TP1, TP2, 3 and 6 months after intervention. Results showed a reduction in subjective PTSD severity after intervention throughout the study in both treatment groups compared to no NF controls (time x group interaction F(3,48) = 5.83, p = .001, ηp2 = .26). Post hoc analyses revealed PCL reductions in the treatment groups at 3 months follow-up from TP1 (F = 7.9, p = .012) and 6 months follow-up from TP1 (F = 8.34, p = .008).

[0295] rtfMRI-NF To test the target engagement of AmygEFP-NF in exploring the amygdala, we evaluated rtfMRI-NF, which successfully down-regulated amygdala BOLD signal. Amygdala activity was compared between patients in the AmygEFP-treated and no-NF groups by a random-effects general linear model of amygdala signal change (modulation vs. observation, see Fig. 24A and Appendix 1.4 for model details). A two-way repeated measures ANOVA was performed with right amygdala beta values ​​as dependent variables and group (AmygEFP-NF, no-NF) and time (TP1, TP2) as independent variables. Six patients were not included in the fMRI study from the start due to incompatibility with MR, three more patients were excluded due to missing data at one TP, and two more patients were excluded due to excessive head motion, resulting in n=20 for AmygEFP-NF group and n=11 for no-NF group in the rtfMRI analysis. Results were as expected, with a greater decrease in amygdala-BOLD signal after the intervention in the treatment group compared to the control group (F (1,29) = 10.31, p = .004, η p 2 = .26). Planned comparisons of change over time for each group showed the desired NF effect in the treatment group (F = 10.85, p = .004) but not in the no-NF control group (F = 2.41, p = .13) (see Figure 4). This finding supports the targeted engagement of AmygEFP-NF treatment in the right amygdala.

[0296] Reference is now made to FIG. 24A, which depicts rtfMRI-NF target engagement. Mean beta values ​​obtained from the right amygdala used as a target for modulation during rtfMRI-NF. The model included six regressors for each condition in each cycle (baseline, NF, and dropouts) at TP1 and TP2, respectively. The regressors were convolved with a standard hemodynamic response function. Additional confounding variables included head movement recalibration parameters. Modulation is represented by the difference in modulation vs. attend trials shown for the AmygEFP-NF and No NF groups at TP1 (first cycle) and TP2 (average of the two cycles). The interaction between time and group was F(1,29)=10.31, p=.004, ηp2=.26; simple main effects of time for AmygEFP-NF, F=10.85, p=.004, and No NF, F=2.41, p=.13.

[0297] Consideration The current study provides a randomized controlled test of a process-based NF intervention aimed at scalable downregulation of the amygdala in PTSD patients. In line with our first hypothesis, patients in the treatment group showed neuromodulation learning throughout the NF sessions, with more profound improvements in the traumatic NF compared to the neutral NF. In line with our second and third hypotheses, patients in the treatment group showed clinical improvement, as represented by declines in CAPS-5 and PCL measures after the intervention, compared to the no-NF group, with the traumatic NF group showing the greatest decline. Interestingly, follow-up at 3- and 6-month PCL points pointed to further symptom reductions only in the treatment group. Finally, we demonstrated the target engagement of the AmygEFP-NF intervention, as represented by a greater downregulation of patients' amygdala BOLD signal in the treatment group compared to the no-NF group in a single session of rtfMRI-NF. This is the first demonstration of clinical efficacy in PTSD using fMRI-inspired EEG-NF training, targeting trauma-related processes in an individualized format.

[0298] Learning outcomes Patients learned to downregulate AmygEFP signals through repeated training sessions with either disorder-specific or non-specific feedback. Learning occurred mainly in the later part of training (Figure 2). Interestingly, the personalized traumatic story feedback may not have interfered with learning, but rather accelerated it. It is possible that the gradual removal of more aversive cues (i.e., decreasing the volume of the traumatic story) could have led to increased reward and more rapid learning (32). Future studies could test this option by successfully introducing more exposure or by decoupling exposure from reward using intermittent feedback. Although our protocol used 15 NF sessions designed to fit other common psychotherapy protocols, it is possible that other numbers of sessions could achieve good or better learning and clinical effects. Given the large heterogeneity of learning abilities, it may be advantageous to tailor protocols to individual patients or to try to predict clinical benefits from initial NF success (33-35).

[0299] Clinical Efficacy Results showed large clinical benefits for chronic PTSD, with changes in total CAPS-5 scores showing large effect sizes in the traumatic NF group (Cohen's D 1.229; Hedges' g 0.828), medium effect sizes in the neutral NF group (Cohen's D 0.636; Hedges' g 0.4306), and large effect sizes when combining treatment groups (Cohen's D 0.853; Hedges' g 0.591). Importantly, clinical benefits were driven by large symptom reductions following treatment (traumatic NF -35.13%; neutral NF -19.48%) compared with no NF (-0.23%; Fig. 3b). The AmygEFP intervention demonstrated clinical utility similar to commonly used cognitive behavioral therapies. Illustrative are meta-analyses (21) showing that Prolonged Exposure Therapy (PE) in PTSD exerts effects over control conditions with a large effect size (Hedges' g = 1.08, 95% CI 0.69-1.46), and Watts et al. (2013) showing an overall effect size of g = 0.81 (95% CI 0.71-0.91) in 112 randomized clinical trials including psychotherapy (g = 1.14, 95% CI 0.97-1.3) and physical treatments (g = 1.24, 95% CI 0.35-2.13). Our results further showed that both treatment groups obtained an NNT = 3.9 (and total PCL score 2.4) for loss of PTSD diagnosis based on CAPS-5 at TP2 compared to no NF. These results are consistent with reports of an NNT ≤ 4 for achieving loss of PTSD diagnosis following psychotherapy (37). Interestingly, at follow-up assessments 3 and 6 months after the intervention, patients showed sustained improvements in PTSD severity, as expressed by the PCL (Figure 3d). This is in line with accumulating reports of continued improvements several weeks after the end of NF interventions (25, 38). One explanation is to equate NF with skill learning that is implemented (intentionally or automatically) in patients' daily lives. Another possibility is that consolidation and reconsolidation processes typical of NF learning occur through the entrainment of targeted brain circuits after training is completed.Taken together, the clinical results of our study demonstrate the feasibility and efficacy of processing traumatic content while targeting one of the limbic-related mechanisms underlying it.

[0300] In line with the known effects of exposure-based psychotherapy, one could argue that the large effect found for trauma-NF is due to the combination of NF treatment with repeated exposure to traumatic content (21). However, we argue that this theory cannot explain the magnitude of our results, since trauma-NF does not follow the common practice of prolonged exposure therapy, and is relatively low-dose (seven sessions), short-duration (3-minute segments vs. 40-60 minutes), and limited in content (only the gist of the trauma record, not an extended narrative), and not self-created. Of note, dropout rates during AmyEFP-NF were 10% and 15.7% for trauma-NF and neutral-NF, respectively (see the CONSORT diagram in Appendix Figure 1), whereas exposure-based treatments often have higher dropout rates of up to 40% (39). AmygEFP interventions do not require verbal and interpersonal interaction or repeated prolonged exposure, yet still demonstrate similar clinical benefits and low dropout rates.

[0301] Consideration of NF mechanism Notably, not only PTSD symptoms, but also anxiety and depression symptoms improved over time in the treatment group and were maintained during follow-up (see Appendix 2.2). Mainly major depression, anxiety and substance use disorders are associated with a high probability of dependent disorders in PTSD (40, 41). These findings not only highlight the importance of assessing dependent disorders in PTSD, but also support our idea that AmygEFP-NF explores transdiagnostically relevant emotion regulation as a mechanism underlying the disorder. Further studies could delineate the clinical effects of other processes underlying PTSD and its comorbidities, such as reward processes (by upregulating mesolimbic circuits) or cognitive control (by upregulating attention circuits), all related to depression, substance use disorders and / or PTSD.

[0302] The results demonstrated the target engagement of the AmygEFP-NF intervention by showing improved amygdala BOLD signal downregulation during rtfMRI-NF in patients in the treatment group versus the no NF group. It could be advantageous to clarify the association between AmygEFP-NF intervention and rtfMRI-NF target engagement. However, the complexity of obtaining data from this clinical population and the high research costs slowed the present study to find such an association. Another way to study the specificity of the mechanism is to prove the correlation between the AmygEFP intervention and clinical outcomes. Similar to Goldway et al. (2018), the present study did not show a correlation between AmygEFP learning and clinical outcomes (see Appendix 2.3). This is contrary to our findings found in a priori healthy warriors who underwent similar training to improve stress resilience (26). One explanation is that the clinical changes in patients do not correlate linearly with the level of NF proficiency. Rather, skills are acquired and added to the behavioral inventory (42). Thus, skill acquisition, not level of progress, is the driver of clinical change. Evidence for a preference for mechanism specificity can also be found in our findings, with patients trained with the traumatic story interface versus those trained with the neutral NF showing improvements on several symptom clusters of the CAPS-5 (intrusions, avoidance and arousal, see Appendix 2.1). Future studies with larger sample sizes could explore specific process-related outcome measures (e.g. cognitive tests, emotional challenges, etc.) and pursue learning-specific signs, especially as indicators of further patient success.

[0303] conclusion We showed that PTSD patients successfully down-regulated their AmygEFP signal by exposure to personalized traumatic content. In the randomized control condition, we demonstrated a moderate effect of clinical improvement following AmygEFP-NF treatment in PTSD patients compared to no-NF controls. Interestingly, the effect of clinical improvement was greater in patients trained with traumatic stories as feedback interface, supporting a process-based NF approach. Importantly, for target engagement and generalizability, treated patients showed a greater down-regulation of amygdala BOLD signal to different interfaces during rtfMRI compared to no NF. Finally, the study demonstrated the feasibility and clinical efficiency of an extended neurofeedback intervention based on the neural mechanisms underlying PTSD, which broadens the horizon of more brain-directed treatments in psychiatry inspired by neuroscience.

[0304] References

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Paret C, Goldway N, Zich C, et al.: Current progress in real-time functional magnetic resonance-based neurofeedback: Methodological challenges and achievements. NeuroImage 2019; 202:116107 35. Kadosh KC, Staunton G: A systematic review of the psychological factors that influence neurofeedback learning outcomes. Neuroimage 2019; 185:545-555 36. Watts BV, Schnurr PP, Mayo L, et al.: Meta-analysis of the efficacy of treatments for posttraumatic stress disorder. J Clin Psychiatry 2013; 74:e541-50 37. Jonas DE, Cusack K, Forneris CA, et al.: Psychological and pharmacological treatments for adults with posttraumatic stress disorder (PTSD)2013; 38. Rance M, Walsh C, Sukhodolsky DG, et al.: Time course of clinical change following neurofeedback. Neuroimage 2018; 181:807-813 39. Imel ZE, Laska K, Jakupcak M, et al.: Meta-Analysis of Dropout in Treatments for Posttraumatic Stress Disorder. J Consult Clin Psychol 2013; 81:394-404 40. Kessler RC, Sonnega A, Bromet E, et al.: Posttraumatic Stress Disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995; 52:1048-1060 41. Campbell DG, Felker BL, Liu CF, et al.: Prevalence of Depression-PTSD Comorbidity: Implications for Clinical Practice Guidelines and Primary Care-based Interventions. J Gen Intern Med 2007; 22:711-718 42. Ramos-Murguialday A, Broetz D, Rea M, et al.: Brain-Machine Interface in Chronic Stroke Rehabilitation: A Controlled Study. Ann Neurol 2013; 74:100-108

[0306] Exemplary appendix for further study 1. Method 1.1. Participants Reference is now made to Figure 24B, which shows the CONSORT flow chart. Dropout rates for each group were as follows: Neutral NF, 26.3%, Traumatic NF, 25%, and No NF, 10%. One additional participant randomly assigned to the traumatic NF group was excluded from the traumatic NF group analysis because he did not meet the criteria described in "Trauma-Related NF Interface and Procedures."

[0307] In some embodiments of the experiment and the present invention, exclusion criteria included current pregnancy, major medical or neurological illness, psychotic disorders, major depression, schizophrenia, and severe suicidal ideation. Patients currently receiving psychotherapeutic and / or pharmacological treatment were included in the study, provided there was no change in treatment plan for at least the past 3 months and the period up to the completion of the study.

[0308] 1.2. General Procedure [Table 3]

[0309] Table 1. Clinical outcome measures. Table 1 presents the results of each clinical measure used to assess clinical change at the four time points (TP1, TP2, 3-month and 6-month follow-up) by group. To examine differences at TP1 between groups, a one-way ANOVA was performed with group (traumatic NF, neutral NF, no NF) as the independent variable. The analysis did not show differences between groups at baseline in any clinical measure: CAPS-5 (F (2,35) = 1.22, p = .306, η p 2 = .06), PCL(F (2,35) = 1.13, p = .33, η p 2 = .06), STAI(F (2,34) = 1.12, p = .33, η p 2 = .06), BDI-II (F (2,34) = .76, p = .47, η p 2 = .04), TAS-20 (F (2,31)= .71, p = .49, η p 2 = .04), ERQ reassessment (F (2,34) = 1.15, p = .32, η p 2 =.06), ERQ suppression (F (2,34) = 1.74, p = .19, η p 2 =.09).

[0310] Experiments and on-line computation of an exemplary multimodal animated scenario in some embodiments. The scenario includes sounds of chatter and commotion in a busy emergency room. The scenario can be graded between a quiescent state (everyone seated, low volume) to an excited state (people crowding the reception desk, complaining loudly) and back again. The overall level of anxiety in the room is determined by the power of the EFP signal. The ratio of characters seated to those complaining at the reception desk is considered to be in a two-state Boltzmann distribution, whose occurrence is driven by a "virtual temperature" whose temperature is derived from the instantaneous value of the target signal power (AmygEFP). The scenario uses a probability (P value) of the instantaneous signal value at the time of adjustment sampled under the previous participation distribution. This P value is used to determine the probability of the virtual characters moving in the virtual room, and the distribution of the characters is updated sequentially. A matching soundtrack recorded in the real hospital complements the output of the system. Three alternative soundtracks with different levels of excitement were produced and switched depending on the signal value. In the participating state, 75% of the characters rush to the front desk, expressing their dissatisfaction through gestures and words. The system is powered by the Unreal Development Kit game engine, which controls not only the appropriate animations (walking, sitting, standing, getting angry) but also the transitions of the individual characters.

[0311] Exemplary trauma NF criteria in some embodiments and experiments of the present invention. Patients who successfully lowered their AmygEFP signal during training in three of the last five sessions or four of the total six sessions continued. Patients who were not successful continued training in the neutral context for the remaining sessions. In the second phase of training, patients in the trauma NF group were trained while receiving feedback in the context of their traumatic story. In the first session, patients were interviewed using a common method (Shalev, Orr & Pitman, 1993; Rauch. 1996) about a traumatic event that met DSM-5 criteria A to create a script of a sequence of events that included thoughts, feelings, impacts and contextual information. The interview was edited and recorded as a 3-minute syllable (present tense, second person male voice). After the interview, patients were again trained in the neutral NF interface. Patients who successfully lowered their AmygEFP signal in this session continued training with traumatic story feedback in the following session. ·Shalev AY, Orr SP, Pitman RK: Psychophysiologic assessment of traumatic imagery in Israeli civilian patients with posttraumatic stress disorder. Am J Psychiatry 1993; 150:620-624 ·Rauch SL: A Symptom Provocation Study of Posttraumatic Stress Disorder Using Positron Emission Tomography and Script-Driven Imagery. Arch Gen Psychiatry 1996; 53:380

[0312] 1.3 Exemplary EEG Data Recording Methods EEG data is stored in a V-Amp TM EEG amplifier (Brain Products, Munich, Germany) TM) and Brain Cap with Ag / AgCI sintered ring electrode TM Electrode caps (Falk-Minow Services, Herrsching-Breitburnn, Germany) TM ) were used. Electrodes were positioned according to the standard 10 / 20 system. The reference electrode was between Fz and Cz. Raw EEG signals were sampled at 250 Hz and recorded using the Brain Vision Recorder. TM Recordings were made using software (Brain Products). The baseline for the auditory session was the first rest period, and the baseline for the multimodal animation scenario was the active baseline block of each training cycle.

[0313] 1.4 Exemplary fMRI Data Acquisition and Processing To enable high-resolution structural images, a T1-weighted three-dimensional (3D) sagittal MPRAGE pulse sequence (repetition time / echo time = 1,860 / 2.74 ms, flip angle = 8°, pixel size = 1 × 1 mm, field of view = 256 × 256 mm) was used. Functional whole-brain scans were performed in an interleaved top-to-bottom order using a T2*-weighted phased echo-planar imaging pulse sequence (repetition time / echo time = 2,500 / 30 ms, flip angle = 82°, pixel size = 2.3 mm, field of view = 220 × 220 mm, slice thickness = 3 mm, 42 slices per volume). Slice scan time correction was performed with cubic spline interpolation. Head motion was corrected with a shape-preserving transformation with three translation and three rotation parameters, with the central image serving as the reference constant volume. Trilinear interpolation was applied for head motion detection and sinc interpolation was used for its correction. The temporal smoothing process included linear trend removal and the use of a 1 / 128H high-pass filter. Functional maps were manually co-registered to the corresponding structural maps and together introduced into the 3D dataset through trilinear interpolation. The complete dataset was transformed into Talairach space and spatially smoothed with an isotropic 6 mm full width at half-maximum Gaussian kernel.

[0314] Exemplary rtfMRI-NF paradigm Reference is now made to FIG. 25, which illustrates the rtfMRI-NF paradigm of the present study and some embodiments. The visualization feedback interface consists of 2D monomodal flash-based graphics, including an animated figure skating on a road. The NF paradigm includes five conditions. In the "global baseline" condition (54 seconds), which appears only in the first block of each session, the patient is instructed to fixate his / her gaze on a cross. In the "active baseline" condition (60 seconds), the skateboarder skates at an average fixed speed, and no speedometer is provided. The patient is instructed to simply watch the skateboarder and not to participate in any mental activity other than watching. The patient is instructed not to consider any mental strategies or past successes or failures in this condition, emphasizing the importance of developing meaningful mental differences from condition to condition. During the "neurofeedback" condition (90 seconds), the patient is provided with continuous feedback on his / her right amygdala BOLD activity, which is implicit in the runner's changing speed, accompanied by a speedometer speed display (online feedback calculation is described in detail below). The instructions were to slow down the skateboarder by practicing any mental strategy that the patient thought would work. In the "bar" condition (9 s), the subject was told his average speed of the last NF block, which represents the success of the previous baseline block, helping him decide whether to continue practicing the successful strategy or to replace the failed one with another. In the "failure" condition (15 s), the subject was instructed to stop all deliberation and self-reflection and to prepare for the next baseline block. The paradigm consisted of two cycles including all four conditions (active baseline, neurofeedback, bar, failure) in addition to a "global baseline" that appeared once at the beginning.

[0315] Online computation of an exemplary rtfMRI-NF paradigm Instantaneous beta weights of the defined amygdala ROI (averaged over all voxels of the ROI) were extracted online using Turbo Brain voyager 3.0 (Brain Innovation). The beta weights were then analyzed using MATLABTM For each TR, right amygdala activity was first converted to a standardized score.

[0316]

number

[0317] where B(t) is the right amygdala BOLD activity at time point t, and μ(B_BL) is the mean BOLD value during the previous "baseline activity". Values ​​ranged from -4 std. from the baseline mean to 4 std. above the mean. Each value was then converted to a rate-based value using the following formula:

[0318]

number

[0319] This formula results in the fact that the right amygdala BOLD value equal to the previous "baseline" mean value was set to 60km / h, and an increase or decrease of 1std. resulted in a change of 15km / h. The limits from -4 to 4 were translated into a possible speed scale of 0 to 120km / h. Furthermore, to make the NF paradigm more interactive and flexible to adjustments and trials, an update principle was introduced. In the NF block, the representative values ​​were limited by an interval of 4 std., resulting in a 60km / h interval of the speed scale. In the first block of the first run, the intervals provided were symmetric around the mean speed (60km / h): -2 to 2 (30km / h to 90km / h). In each successive run, the intervals were updated based on the patient's success during the previous run by the following steps: 1. In the first cycle, the NF screen interval was set from -2 to 2. 2. When the NF screen finishes the current block, calculate the success index of the current block as follows (n represents the cycle ordinal number):

[0320]

number

[0321] By dividing the standardized value of the mean NF by the pooled mean, we introduced an index of the ability of subjects not only to successfully regulate their right amygdala activity during the NF blocks, but also to keep it as constant as possible during the "baseline activity" blocks. 3. The interval [Lower Limit Upper Limit] for the next cycle (n+1) is updated to [Lower Limit = (Success_Index(n)-Learning_Rate) Upper Limit = (Success_Index(n)-Learning_Rate+4)]. The learning rate parameter is preset to learning rate = 1.

[0322] This process aims to enable significant control in one run and achieve more control in subsequent runs, making the NF paradigm more challenging, dynamic, and encouraging maximum control.

[0323] 2. Results 2.1 AmygEFP-NF clinical efficiency Reference is now made to Figures 2H-2K, which depict the subscales of the CAPS-5, changes across experiments and in some embodiments.

[0324] The clinical effect of feedback type (traumatic vs. neutral) was explored by examining changes in CAPS-5 subscales (i.e., intrusions, avoidance, cognitive and mood changes, and arousal) in the treatment group. For each CAPS-5 subscale by time (TP1, TP2), a two-way repeated measures ANOVA was performed for individual variables within subjects and between subjects within groups (neutral NF and traumatic NF). All scales showed similar improvement over time and there were no interactions between time and group (main effect of time: avoidance was F (1,23) = 15.75, p = .0006, ηp2 = .406; intrusion is F (1,23) = 9.73, p = .004, ηp2 = .29; cognitive and mood alterations were F (1,23) = 15.43, p = .0004, ηp2 = .41; Arousal F (1,23)= 16.54, p = .004, ηp2 = .41, see Figures 2H-2K). Although no significant interactions were found, further post hoc tests revealed smaller symptom reductions in the neutral NF group relative to the traumatic NF group for all subscales (simple main effects of time: intrusion: Δ = -1.5 for traumatic NF, F = 6.34, p = .01; Δ = -1.07 for neutral NF, F = 3.54, p = .072; avoidance: Δ = -2.75 for traumatic NF, F = 2.06, p = .021). (F = 12.46, p = .001; neutral NF Δ = -1.54, F = 4.22, p = .051; cognition and mood changes: traumatic NF Δ = -4.25, F = 10.204, p = .004; neutral NF Δ = -3.23, F = 6.38, p = .01; arousal: traumatic NF Δ = -3.42, F = 16.11, p = .0005; neutral NF Δ = -1.39, F = 2.86, p = .103).

[0325] Figures 2H-2K represent the CAPS-5 subscales in the experiment and in some embodiments: intrusion (Figure 2H), avoidance (Figure 2J), cognitive and mood alterations (Figure 2I), and arousal (Figure 2K). Scores reflect the change in severity of PTSD symptoms subscales between TP1 and TP2 in the traumatic NF and neutral NF groups. Boxes represent the first and third quartiles, lines represent the median, "x" represents the mean, and whiskers indicate the minimum and maximum values ​​outside the first and third quartiles.

[0326] 2.2 Illustrative Secondary Clinical Outcomes We used secondary clinical assessments based on self-scored questionnaires: alexithymia: TAS-20 (n=33), depression: BDI-II (n=35), anxiety: STAI (n=35) and emotion regulation: ERQ (n=35). Two-way repeated measures ANOVAs were performed with time (TP1, TP2) as a separate variable within subjects and between subjects within group (neutral NF, traumatic NF and no NF).

[0327] Results showed improvement in BDI-II scores over time in the treatment group compared with the no NF group (F (2,32) = 3.48, p = .04, ηp2 = .17; the main effect of time was F(1,32) = 7.28, p = .01, ηp2 = .18, Figure 26A). Post hoc analyses revealed a reduction in depressive symptoms in the neutral NF group (simple main effect of time; F = 11.14, p = .002; Δ = -11.92), and a slight reduction in the traumatic NF group (F = 3.47, p = .07; Δ = -5.16), but no change in the no NF group (F = .19, p = .66; Δ = -4.08). Analysis of change in the STAI scales showed a reduction in anxiety symptoms over time in the treatment group but not in the control group (slight time × group interaction F (2,32) = 3.28, p = .0504, ηp2 = .17, and the main effect of time was F (1,32) = 4.69, p = .03, ηp2 = .12, Figure 26B). Post-hoc analyses revealed reductions in anxiety symptoms for the neutral NF group (simple main effect of time; F = 6.8, p = .01; Δ = -9.91) and traumatic NF group (F = 4.24, p = .04; Δ = -7.83), whereas the no NF group remained unchanged (F = .67, p = .41; Δ = 3.27). Analyses of change in alexithymia and emotion regulation did not reveal differences between treatment and no NF groups: the TAS-20 showed no interaction of time and group (F (2,30) = .66, p = .52, η p 2 = 0.04), ERQ scores were split into two scales, reappraisal and suppression, and a significant time-group interaction was found for reappraisal (F (2,32) = 5.03, p = .01, η p 2 = .23), but not for inhibition (F (2,32) = .11, p = .89, η p 2 = .007).

[0328] Figures 26A and 26B demonstrate secondary clinical outcomes. Scores reflect changes in symptoms of depression (Figure 26A) and anxiety (Figure 26B) between TP1 and TP2 in the traumatic NF, neutral NF and no NF groups, respectively. Boxes represent the first and third quartiles, lines represent the median, "x" represents the mean and whiskers indicate minimum and maximum values ​​outside the first and third quartiles.

[0329] 2.3 Exemplary AmygEFP Learning and Clinical Improvement Correlations We investigated whether the clinical improvements seen in the treatment group corresponded to NF learning effects. Pearson correlation coefficients were calculated to evaluate the relationship between clinical change (reduction in total CAPS-5 and PCL scores) and AmygEFP learning (measured by mean and minimum NF success index). One patient was excluded due to a value 2.5 std lower than the minimum AmygEFP NF success index. The results showed that only the mean and minimum AmygEFP NF success index could be correlated (see Table 2).

[0330] [Table 4]

[0331] It is expected that suitable EEG electrodes will be developed during the life of the patent arising from this application, and thus the term EEG electrode is intended a priori to encompass all such new technology.

[0332] As used herein, the term "about" in reference to an amount or value refers to ±10%.

[0333] The terms "comprises," "comprising," "includes," "including," "having" and conjugations thereof mean "including but not limited to."

[0334] The term "consisting of" means "including and limited to."

[0335] The term "consisting essentially of" means that a composition, method, or structure may include additional ingredients, steps, and / or moieties, provided that the additional ingredients, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0336] As used herein, the singular forms "a," "an," and "the" include the plural unless the context clearly indicates otherwise. For example, "a compound" or "at least one compound" includes a plurality of compounds, and may also include mixtures thereof.

[0337] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and is not an inflexible limitation of the scope of the invention. Thus, the description of a range should be considered to specifically disclose all of the possible subranges, as well as each individual numerical value within that range. For example, the description of a range such as "1-6" specifically discloses not only subranges such as "1-3", "1-4", "1-5", "2-4", "2-6", "3-6", etc., but also each individual numerical value within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the size of the range.

[0338] When a numerical range is recited herein (e.g., "10-15," "10 to 15," or any pair of numbers joined by another such range designator), it is intended to include any number (fractional or integer) within the boundaries of the recited range (including the boundaries of the range unless otherwise indicated). The terms "range between" a first recited number and a second recited number, and "range from" "up to" "until" or "through" a first recited number (or other terminology denoting such a range) are used interchangeably herein and are intended to include the first recited number and the second recited number, and all fractional and integer numbers therebetween.

[0339] As will be understood by one of ordinary skill in the art, the numerical values ​​used herein and numerical ranges based thereon are approximations within the precision of reasonable measurement errors and rounding errors, unless otherwise specified.

[0340] As used herein, the term "method" means manner, means, techniques, and procedures for accomplishing a given task, including, but not limited to, those known to practitioners in the chemical, pharmacological, biological, biochemical, and medical fields or that can be readily developed by practitioners from known manners, means, techniques, and procedures.

[0341] The term "treating" as used herein in connection with abnormal activity, disease or condition includes arresting, substantially inhibiting, slowing or reversing the progression of the condition, substantially ameliorating the clinical or cosmetic symptoms of the condition, or substantially preventing the worsening of the clinical or cosmetic symptoms of the condition.

[0342] It will be understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in a single embodiment in any combination of those features. Conversely, several features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or with respect to other described embodiments as appropriate. Certain features described in the context of various embodiments should not be construed as essential to that embodiment, unless the particular embodiment is inoperable without that element.

[0343] While the present invention has been described in conjunction with specific embodiments thereof, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0344] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, and patent application was specifically and individually incorporated herein by reference. In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. Nor should it be necessarily construed as limiting, to the extent that section headings are used.

[0345] Additionally, any priority document to this application is incorporated herein by reference.

Claims

1. 1. An apparatus for delivering training for stress disorders for training a subject to modify activity of at least one specific subcortical deep brain region, comprising: a recording medium storing a stress disorder training protocol specific to the stress disorder; a control circuit operatively coupled to the recording medium and configured to deliver training for the stress disorder according to the stress disorder training protocol stored on the recording medium; Equipped with The control circuit, in delivering training to the stress disorder, presenting a challenge configured to induce at least one symptom of a stress disorder in the subject; delivering instructions to the subject to apply a mental strategy to modify the displayed exercise; receiving at least one electrical signal, said at least one electrical signal being received during said indication of said challenge; processing the at least one electrical signal to identify at least a portion of the at least one electrical signal representative of an activity level of at least one particular deep subcortical brain region; the device is configured to modify the displayed challenge based on an activity level of the at least one particular deep subcortical brain region represented by at least a portion of the identified at least one electrical signal, and to deliver human-detectable feedback to the subject.

2. 2. The device of claim 1, wherein modifying the challenge by the control circuitry comprises reducing the intensity or severity of the challenge when the activity level of the at least one particular deep subcortical brain region is downregulated.

3. 3. The device of claim 1 or 2, wherein the control circuitry is configured to provide the feedback continuously and / or during delivery of the challenge.

4. The apparatus according to any one of claims 1 to 3, wherein the challenge is a stress-related challenge.

5. 5. Apparatus according to any one of claims 1 to 4, wherein the control circuitry is configured to process the at least one electrical signal to determine how to modify the challenge.

6. The apparatus of any one of claims 1 to 5, wherein the at least one electrical signal is an electroencephalography (EEG) signal.

7. 7. The apparatus of claim 6, wherein the control circuitry is configured to deliver the feedback within 10 seconds of receiving the EEG signal.

8. The apparatus of any one of claims 1 to 7, wherein the stress disorder comprises post-traumatic stress disorder (PTSD).

9. An apparatus according to any one of claims 1 to 8, wherein the stress disorder training protocol stored on the recording medium comprises at least two separate sessions.

10. 10. The apparatus of claim 9, wherein each training session of the at least two separate training sessions includes at least one baseline signal recording portion and at least one training portion, and the control circuitry is configured to determine a baseline activity level of the at least one particular deep subcortical brain region in the at least one baseline signal recording portion.

11. The apparatus of claim 10 , wherein the control circuitry is configured to repeat the displaying, the processing, and the delivering in at least one training portion of the at least two separate training sessions.

12. An apparatus according to any one of claims 1 to 11, wherein the storage medium stores the challenges, the stored challenges comprising non-specific neutral challenges and / or trauma-specific challenges.

13. The apparatus of claim 12, wherein the challenges stored on the recording medium include challenges selected to activate the amygdala and / or amygdala-associated neural circuits.

14. The device of any one of claims 1 to 13, wherein the control circuitry is configured to automatically stop training against a stress disorder when processing of the at least one electrical signal indicates a stronger response to the challenge than a predetermined value stored in the recording medium.

15. An apparatus according to any one of claims 1 to 14, wherein the recording medium stores information and / or characteristics of a subject diagnosed with a stress disorder.

16. The device of claim 15, wherein the information comprises information regarding at least one symptom of a stress disorder that has developed and / or information regarding at least one neurobehavioral process that is impaired in the subject in association with a stress disorder.

17. 16. The apparatus of claim 15, wherein the information stored on the recording medium includes a clinical assessment of at least one stress disorder.

18. 18. The device of claim 17, wherein the clinical assessment for the at least one stress disorder comprises the Clinical Interview for PTSD Scale for DSM-5 (CAPS-5) and / or the Post-Traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5).

19. 19. An apparatus according to any one of claims 1 to 18, comprising a trainee interface electrically connected to the control circuitry, the control circuitry displaying the challenge via the trainee interface.

20. 20. The apparatus of claim 19, wherein the control circuitry is configured to provide instructions for performing at least one exercise with the trainee interface, the at least one exercise being configured to affect an activity level of the at least one particular deep subcortical brain region.

21. 21. The device of claim 20, wherein the control circuitry is configured to vary the instructions based on an activity level of the at least one particular deep subcortical brain region.

22. 22. The apparatus of claim 1, wherein the recording medium stores at least one EEG electrical fingerprint of the at least one specific deep subcortical brain region, and the control circuitry is configured to process the at least one electrical signal using the at least one EEG electrical fingerprint to identify at least a portion of the at least one electrical signal representative of an activity level of the at least one specific deep subcortical brain region.

23. 23. The apparatus of claim 22, wherein the at least one EEG electrical fingerprint is an EEG electrical fingerprint of the amygdala.

24. 24. Apparatus according to any one of claims 1 to 23, comprising at least one EEG electrode located at the Pz position in the EEG coordinate system.

25. A method for operating the device of claim 1, comprising the steps of: receiving an indication that the subject has been diagnosed with a stress disorder; Subsequent to said receiving, delivering stress disorder training according to said stress disorder training protocol stored on said storage medium of said device. A method comprising:

26. 1. A method of operation of an apparatus for delivering a stress disorder training protocol to a subject diagnosed with a stress disorder for training the subject to modify activity of at least one specific subcortical deep brain region, comprising: presenting a challenge configured to induce at least one symptom of the stress disorder; delivering instructions to the subject to apply a mental strategy to modify the displayed exercise; receiving at least one electrical signal, the at least one electrical signal being received during the indication of the challenge; processing the at least one electrical signal to identify at least a portion of the at least one electrical signal representative of an activity level of at least one particular deep subcortical brain region; modifying the displayed challenge based on an activity level of the at least one particular deep subcortical brain region representative of the at least one identified electrical signal and delivering human-detectable feedback to the subject. A method comprising:

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