EP3890603A1 - Entraînement contre des troubles de stress - Google Patents

Entraînement contre des troubles de stress

Info

Publication number
EP3890603A1
EP3890603A1 EP19896188.0A EP19896188A EP3890603A1 EP 3890603 A1 EP3890603 A1 EP 3890603A1 EP 19896188 A EP19896188 A EP 19896188A EP 3890603 A1 EP3890603 A1 EP 3890603A1
Authority
EP
European Patent Office
Prior art keywords
subject
training
challenge
trauma
brain region
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP19896188.0A
Other languages
German (de)
English (en)
Other versions
EP3890603A4 (fr
Inventor
Talma Hendler
Tom FRUCHTMAN-STEINBOK
Avihai COHEN
Gal Raz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medical Research Infrastructure and Health Services Fund of the Tel Aviv Medical Center
Original Assignee
Medical Research Infrastructure and Health Services Fund of the Tel Aviv Medical Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Medical Research Infrastructure and Health Services Fund of the Tel Aviv Medical Center filed Critical Medical Research Infrastructure and Health Services Fund of the Tel Aviv Medical Center
Publication of EP3890603A1 publication Critical patent/EP3890603A1/fr
Publication of EP3890603A4 publication Critical patent/EP3890603A4/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/16—Devices for psychotechnics; Testing reaction times ; Devices for evaluating the psychological state
    • A61B5/165—Evaluating the state of mind, e.g. depression, anxiety
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/369—Electroencephalography [EEG]
    • A61B5/375—Electroencephalography [EEG] using biofeedback
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
    • A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/369—Electroencephalography [EEG]
    • A61B5/377—Electroencephalography [EEG] using evoked responses

Definitions

  • the present invention in some embodiments thereof, relates to stress disorders training and, more particularly, but not exclusively, to post traumatic stress disorder training.
  • Example 1 A method for training a subject diagnosed with a stress disorder, comprising: exposing a subject diagnosed with a stress disorder to a trauma-related challenge;
  • Example 2 A method according to example 1, wherein said exposing to said trauma-related challenge affects activation of said one or more brain regions and/or neural circuits.
  • Example 3 A method according to example 1, comprising:
  • an electrical finger print based on at least a portion of said recorded electrical signals, which relates to a current activation level of said one or more brain regions and/or neural circuits;
  • said delivering comprises delivering a feedback according to said current activation level of said one or more brain regions and/or neural circuits.
  • Example 4 A method according to example 3, wherein said delivering a feedback comprises modifying said trauma-related challenge according to said current activation level.
  • Example 5 A method according to any one of examples 3 or 4, wherein said electrical signals are EEG and/or EMG electrical signals.
  • Example 6 A method according to any one of the previous examples, wherein said trauma- related challenge comprises a challenge selected to activate an amygdala and/or an amygdala related neural circuit.
  • Example 7 A method according to any one of the previous examples, wherein said trauma- related challenge comprises a challenge personalized to a specific trauma of said subject and/or to a specific stress disorder.
  • Example 8 A method according to any one of the previous examples, wherein said stress disorder comprises post-traumatic stress disorder (PTSD).
  • PTSD post-traumatic stress disorder
  • Example 9 A method according to any one of the previous examples, wherein said trauma-related challenge is selected to upregulate activation of said one or more brain regions, and wherein said feedback is delivered according to an ability of said subject to downregulate said activation level.
  • Example 10 A method according to any one of the previous 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.
  • Example 11 A method for training a subject diagnosed with a stress disorder, comprising: exposing a subject diagnosed with a stress disorder to a non-specific stress challenge;
  • Example 12 A method according to example 11, wherein said exposing comprises exposing said subject to a non-specific stress challenge selected to activate one or more brain regions, and wherein said evaluating comprises evaluating said subject to cope with activation of said one or more brain regions by said non-specific stress challenge.
  • Example 13 A method according to example 12, wherein said evaluating comprises evaluating said subject ability to affect the activation of said one or more brain regions.
  • Example 14 A method according to any one of example 12 or 13, wherein said non-specific stress challenge is configured to upregulate an activity of an amygdala and/or an amygdala-related neural circuit.
  • Example 15 A method according to example 14, wherein said evaluating comprises evaluating an ability of said subject to downregulate the activity of said amygdala and/or said amygdala- related circuit during said exposing.
  • 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;
  • Example 17 A method according to example 16, comprising: determining an activity level of one or more brain regions following said exposing, and wherein said providing comprises providing said feedback by modifying said stress -related challenge according to said determined activity level.
  • Example 18 A method according to example 17, wherein said determining comprises determining that an activity level of said one or more brain regions is downregulated, and wherein said providing comprises reducing an intensity of said stress-related channel.
  • Example 19 An apparatus program configured to provide one or more of exposing, evaluating and/or delivering feedback according to any one of the previous claims.
  • Example 1 A method for training a subject diagnosed with a stress disorder caused by a trauma, comprising:
  • Example 2 A method according to example 1, wherein said exposing to said challenge affects an activation level of said at least one specific brain region.
  • Example 3 A method according to any one of examples 1 or 2, comprising:
  • identifying a relation between at least a portion of said recorded electrical signals and an electrical fingerprint indicating an activation level of said at least one brain region and wherein said generating comprises generating said at least one indication based on said identified relation.
  • Example 4 A method according to any one of the previous examples, wherein said presenting comprises modifying said challenge according to said activation level of said at least one brain region.
  • Example 5 A method according to any one of the previous examples, wherein said at least one brain region is a brain region of the limbic system that has a volume of less than 20% from the volume of the limbic system.
  • Example 6 A method according to any one of the previous examples, wherein said challenge comprises a challenge selected to activate an amygdala and/or brain regions connected to the amygdala by a neural network.
  • Example 7 A method according to any one of the previous examples, wherein said at least one specific brain region comprises two or more specific brain regions.
  • Example 8 A method according to any one of the previous examples, wherein said at least one specific brain region does not comprise the Amygdala.
  • Example 9 A method according to any one of the previous examples, wherein said stress disorder comprises post-traumatic stress disorder (PTSD).
  • PTSD post-traumatic stress disorder
  • Example 10 A method according to any one of the previous examples, wherein said challenge is selected to upregulate activation of said at least one specific brain region, and wherein said at least one indication is presented according to an ability of said subject to downregulate said activation level.
  • Example 11 A method according to any one of the previous examples, comprising:
  • Example 12 A method according to example 11, wherein said presenting comprises presenting said at least one indication according to an ability of said subject to modulate an activation level of said at least one specific brain region by performing said at least one exercise.
  • Example 13 A method according to any one of the previous examples, wherein said in conjunction with said exposing comprises before, during and after said exposing.
  • Example 14 A method for selecting a subject for a stress disorder training, comprising:
  • evaluating a subject diagnosed with a stress disorder caused by a trauma to identify at least one trauma-related challenge expected to trigger said trauma in said subject and at least one non specific stress challenge not expected to trigger said trauma in said subject;
  • Example 15 A method according to example 14, wherein said stress disorder comprises post- traumatic stress disorder (PTSD).
  • Example 16 A method according to any one of examples 14 or 15, wherein said at least one non specific stress challenge is configured to upregulate an activity of an amygdala and/or an amygdala- related neural circuit.
  • Example 17 A method according to example 16, wherein said evaluating comprises evaluating an ability of said subject to downregulate the activity of said amygdala and/or said amygdala- related circuit during and/or following said exposing.
  • Example 18 A method according to any one of examples 14 to 17, comprises:
  • Example 19 A method according to example 18, wherein said electrical signals comprises EEG signals recorded by at least one EEG electrode.
  • Example 20 A method according to any one of examples 14 to 19, wherein said at least one specific brain region does not comprise the Amygdala.
  • Example 21 A method for training a subject diagnosed with a stress disorder caused by a trauma, comprising:
  • Example 22 A method according to example 21, wherein said measuring comprises determining an activation level of at least one specific brain region, and wherein said providing comprises providing said feedback to said subject by modifying said challenge according to said determined activation level.
  • Example 23 A method according to any one of examples 21 or 22, comprising:
  • Example 24 A method according to example 23, wherein said electrical signals comprises EEG signals recorded by at least one EEG electrode.
  • Example 25 A method according to example 24, wherein said determining comprises identifying a relation between at least a portion of said recorded EEG signals and a least one EEG signature or indication thereof stored in a memory, wherein said at least one EEG signature indicates an activity level of at said at least one specific brain region.
  • Example 26 A method according to any one of examples 23 to 25, wherein said in conjunction with said exposing comprises before, during and/or after said exposing.
  • Example 27 A method according to any one of examples 23 to 26, wherein said at least one specific brain region comprises the Amygdala.
  • Example 28 A method according to any one of examples 21 to 27, wherein said exposing comprises exposing said subject diagnosed with a stress disorder to a stress-related challenge while said subject is not confined by an imaging system.
  • Example 29 A method for training a subject diagnosed with a stress disorder caused by a trauma, comprising:
  • Example 30 A method according to example 29, comprising specifically designing said challenge according to said impaired neurobehavioral process.
  • Example 31 A method according to any one of examples 29 or 30, comprising evaluating an expression of at least one symptom of said stress disorder in said subject, and wherein said assessing comprises assessing said at least one impaired neurobehavioral process based on said expression of said at least one symptom.
  • Example 32 A method according to any one of examples 29 to 31, wherein said at least one impaired neurobehavioral process comprises at least one of an impaired stress detection process, an impaired emotion regulation process, and an impaired fear extinction process.
  • Example 33 A method according to any one of examples 29 to 32, wherein said stress disorder comprises post-traumatic stress disorder (PTSD).
  • Example 34 A method according to any one of examples 29 to 33 comprising, instructing said subject to perform at least one exercise in a timed relation with said exposing, wherein said at least one exercise is configured to affect an activation level of said at least one specific brain region.
  • Example 35 A method according to any one of examples 29 to 34, comprises determining an activation level of said at least one specific brain region by identifying a relation between at least a portion of said recorded electrical signals and at least one electrical signature or indication thereof stored in a memory, wherein said at least one electrical signature or said indication thereof, indicate an activation level of said at least one brain region.
  • Example 36 A method according to any one of examples 29 to 35, wherein said at least one specific brain region comprises a brain region of the limbic system having a volume which is less than 20% of the volume of the limbic system.
  • Example 37 A method according to any one of examples 29 to 36, wherein said at least one specific brain region comprises the Amygdala.
  • Example 38 A method according to any one of examples 29 to 37, wherein said exposing comprises exposing said subject diagnosed with a stress disorder to said impaired neurobehavioral process-related challenge while said subject is not confined by an imaging system.
  • Example 39 A method for treating depression or anxiety, comprises:
  • Example 40 A method according to example 36, comprising:
  • Example 41 A method according to any one of claims 39 or 40, comprising:
  • Example 42 A method according to any one of examples 39 to 41, wherein neurofeedback training comprises:
  • Example 43 A method according to example 42, wherein said electrical signals comprise EEG electrical signals.
  • Example 44 A method according to any one of examples 39 to 43, wherein said training is performed while said subject is not confined by an imaging system.
  • Example 45 A method for preparing a subject for an expected stress disorder trigger, comprising:
  • Example 46 A method according to example 42, comprising:
  • Example 47 A device for delivery of a stress disorder training, comprising:
  • control circuitry functionally coupled to said memory, configured to:
  • Example 48 A device according to example 47, comprising a user interface, wherein a user selects said challenge using said user interface from a list of challenges stored in said memory.
  • Example 49 A device according to example 47, wherein said control circuitry is configured to select said challenge from a list of challenges stored in said memory.
  • Example 50 A device according to any one of examples 47 to 49, wherein said control circuitry is configured to process said effect to determine how to modulate said challenge.
  • Example 51 A device according to any one of claims examples 47 to 50, wherein said at least one electrical signal comprises an EEG signal.
  • some embodiments of the present invention may be embodied as a system, method or 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, micro-code, etc.) or an embodiment combining software and hardware aspects that may all generally be 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 medium(s) having computer readable program code embodied thereon. Implementation of the method and/or system of some embodiments of the invention can involve performing and/or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of some embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware and/or by a combination thereof, e.g., using an operating system.
  • a data processor such as a computing platform for executing a plurality of instructions.
  • the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data.
  • a network connection is provided as well.
  • a display and/or a user input device such as a keyboard or mouse are optionally provided as well.
  • the computer readable medium may be a computer readable signal medium or a computer readable storage medium.
  • a 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 of the foregoing.
  • a computer readable storage medium may be any tangible medium that can contain, or store a program for use by or in connection with an instruction execution system, apparatus, or device.
  • a computer readable signal medium may include a propagated data signal with computer readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electro magnetic, optical, or any suitable combination thereof.
  • a computer readable signal medium may be any computer readable medium that is not a computer readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.
  • Program code embodied on a computer readable medium and/or data used thereby may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, RF, etc., or any suitable combination of the foregoing.
  • Computer program code for carrying out operations for some embodiments of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages.
  • the program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server.
  • 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 the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).
  • LAN local area network
  • WAN wide area network
  • Internet Service Provider for example, AT&T, MCI, Sprint, EarthLink, MSN, GTE, etc.
  • These computer program instructions may also be stored in a computer readable medium that can direct a computer, other programmable data processing apparatus, or other devices to function in a particular manner, such that the instructions stored in the computer readable medium produce an article of manufacture including instructions which implement the function/act specified in the flowchart and/or block diagram block or blocks.
  • the computer program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions/acts specified in the flowchart and/or block diagram block or blocks.
  • Some of the methods described herein are generally designed only for use by a computer, and may not be feasible or practical for performing purely manually, by a human expert.
  • a human expert who wanted to manually perform similar tasks, such as determine activation level of a brain region might be expected to use completely different methods, e.g., making use of expert knowledge and/or the pattern recognition capabilities of the human brain, which would be vastly more efficient than manually going through the steps of the methods described herein.
  • Fig. 1 is a flow chart of a process for a stress disorder neurofeedback (NF) training, for example an electrical fingerprint neurofeedback (EFP-NF) training process from a patient perspective, according to some embodiments of the invention
  • NF stress disorder neurofeedback
  • EFP-NF electrical fingerprint neurofeedback
  • Fig. 2A is a flow chart of a NF training process, for example an EFP-NF training process, according to some embodiments of the invention
  • Fig. 2B is a schematic illustration showing types of assessment of a subject, for example a subject diagnosed with a stress disorder, according to some exemplary embodiments of the invention.
  • Fig. 2C is a schematic representation of a matrix showing a relation between some symptoms of a stress-disorder, for example PTSD, and impaired neurobehavioral processes, according to some exemplary embodiments of the invention
  • Figs. 2D-2F are schematic representations of interfaces delivered to a trainee generated based on a trainee’s symptoms and/or impaired neurobehavioral processes, according to some exemplary embodiments of the invention.
  • Fig. 2G is a flow chart of a NF training process personalized according to a trainee’s stress disorder related symptoms and/or impaired neurobehavioral processes, according to some exemplary embodiments of the invention
  • Figs. 2H-2K are graphs showing changes in stress disorder-related symptoms measured using CAPS-5 subscales following NF training, according to some exemplary embodiments of the invention.
  • Fig. 3 is a flow chart of a process for providing a feedback to a patient during a NF training process by modifying an exposure interface, for example a trauma related exposure interface of the NF training, according to some embodiments of the invention
  • Fig. 4 is a block diagram of a system for delivery of NF training, for example EFP-NF training, according to some embodiments of the invention.
  • Fig. 5 is an outline of a validation experiment which details the overall procedure of the trial from recruitment to follow up;
  • Fig. 6 is a table showing demographic and baseline clinical information about the group of participants in the experiment;
  • Fig. 7 describes an overall order of intervention sessions by intervention group
  • Fig. 8 describes a protocol for an animated scenario neutral interface
  • Fig. 9 describes an auditory neutral interface
  • Fig. 10 describes a protocol section detailing a gradual exposure of patients in the exposure group to the content of their individual trauma; Patients begin with training in a neutral context and upon reaching a skill criterion they move on to train using their individual trauma in the exposure sessions;
  • Fig. 11 is a graph showing an example of changes in EFP signal during the first exposure session of one patient in the exposure group
  • Figs. 12A-12G are graphs showing changes in EFP signals between different sessions during the experiment of the patient appearing in Fig. 11;
  • Fig. 13 is a graph showing changes in EFP Z score average during 13 weeks of NF training in the experiment
  • Figs. 14A-14B are graphs showing changes in EFP Z score average between the different groups in the experiment.
  • Fig. 15 is a graph showing changes in CAPS-5 total score in three groups of participants in the experiments following the NF training;
  • Fig. 16A is a graph showing changes in CAPS-5 total score in individual trainees received EFP-NF in a neutral context during the experiment;
  • Fig. 16B is a graph showing changes in CAPS-5 total score in individual trainees received EFP-NF in an exposure context during the experiment;
  • Fig. 16C is a graph showing percentage of participants in each group of the experiment showing an improvement in CAPS-5 total score which is larger than 5 points;
  • Fig. 17 describes changes in different CAPS 5 subscales between different groups of the experiment
  • Fig. 18 is a graph describing changes in PCL score between different groups of the experiment.
  • Fig. 19 shows target, for example amygdala engagement following the training
  • Fig. 20 is a graph showing correlation between EFP training success index and subsequent BOLD activation during real-time fMRI neurofeedback. This positive correlation demonstrates that participants who were very successful at down regulating their EFP signal during training sessions (i.e. overall best performance session) were also better at down regulating their amygdala BOLD signal during real-time neurofeedback following intervention;
  • Fig. 21A is a schematic representation of a process of an experiment
  • Fig. 21B is a schematic representation of training sessions performed in the experiment of FIG. 21 A;
  • Fig. 22 shows two graphs describing a learning effect of the NF training demonstrated as changes in the Amygdala EFP signal during the NF training performed in the experiment of FIG. 21 A, according to some exemplary embodiments of the invention
  • Fig. 23A is a graph showing changes in Total CAPS-5 scores following the NF training performed in the experiment of FIG. 21 A;
  • Fig. 23B is a graph showing changes Total CAPS-5 Score Percent Symptom Reduction from TP1 to TP2 following NF training performed in the experiment of FIG. 21 A;
  • Fig. 23C is a graph showing changes in total PCL assessed following NF training performed in the experiment of FIG. 21 A;
  • Fig. 23D is a graph showing changes in total PCL through the experiment and in follow up meeting as assessed following NF training performed in the experiment of FIG. 21 A;
  • Fig. 24A is a graph and a schematic representation of a brain showing rtfMRI-NF Target Engagement in the experiment of FIG. 21 A;
  • Fig. 24B is a CONSORT flow chart of the experiment of FIG. 21 A;
  • Fig. 25 is a schematic representation of an rtfMRI-NF paradigm
  • Fig. 26A is a graph showing changes in BDI-II score following NF training.
  • Fig. 26B is a graph showing changes in STAI score following NF training.
  • the present invention in some embodiments thereof, relates to stress disorders training and, more particularly, but not exclusively, to post traumatic stress disorder training.
  • Post-traumatic stress disorder is characterized, for example, by excessive emotion reactivity and diminished emotion regulation, corresponding to changes in activation levels of at least one brain region, for example, hyperactive amygdala and hypoactive ventro-medial pre frontal cortex (vmPFC).
  • a neurofeedback (NF) intervention for example an electrical finger print (EFP)-NF for PTSD patients is applied, aimed at down regulating amygdala activity or other stress-associated regions.
  • an electrical finger print (EFP) is generated for example as described in US Patent Application No. 13/983,419.
  • a brain region is a region of the brain which is part of the different neuroanatomical hierarchies of the brain, for example a first hierarchy, a second hierarchy and a third hierarchy of neuroanatomical regions in the brain.
  • the brain region is a region of the brain located in at least one of the hindbrain, the midbrain, and the forebrain, for example in a second hierarchy or a third hierarchy.
  • a brain region is at least one brain region of the limbic system, for example a brain region of the limbic system having a volume which is less than 20%, less than 10%, less than 5% or any intermediate, smaller or larger percentage value of the total volume of the limbic system.
  • a brain region has a volume which is less than 10%, less than 8%, less than 5%, less than 1% or any intermediate, smaller or larger percentage value of the total volume of the brain.
  • the brain region is part of at least one 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.
  • PTSD patients are assessed before and/or after the EFP- NF treatment for example, to determine clinical severity using CAPS-5 and/or PCL assessment methods.
  • the PTSD patients are assessed for neural-target engagement using amygdala fMRI-NF.
  • stress-disorder diagnosed patients treated with the EFP- NF training for example using an EFP-NF with a personalized trauma interface, down-regulate the AmygEFP signal, and/or activity of at least one stress-related brain region by performing exercises learned during the EFP-NF, optionally without receiving feedback.
  • An aspect of some embodiments of the invention relates to training a subject suffering from stress disorders, for example post-traumatic stress disorders (PTSD) using neurofeedback (NF) training, for example electrical finger print- neuro feedback (EFP-NF).
  • NF neurofeedback
  • the electrical finger print (EFP) is an electroencephalography (EEG) fingerprint related to an activity level of one or more brain regions, for example as described in US20140148657A1.
  • EFP-NF training affects activation levels of brain regions and/or neural circuits related to the stress disorders, for example to a memory of the stress-disorders trigger.
  • the EFP-NF affects activation levels of brain regions and/or neural circuits related to a memory of a traumatic event, for example a traumatic event that was a trigger of the stress disorder, for example a PTSD.
  • the stress disorders comprise Agoraphobia Without History of Panic Disorder, Social Phobia, Specific Phobia, Obsessive-Compulsive Disorder, Depression, Substance Abuse.
  • the electrical fingerprint comprises an EEG electrical fingerprint of the amygdala and/or other brain regions related to one or more stress disorders, for example PTSD.
  • the EFP-NF training is used to selectively affect the stress disorders-related brain regions and/or neural circuits.
  • the EFP-NF training reduces activation levels of the stress disorders-related brain regions and/or neural circuits.
  • the EFP-NF training increases activation levels of the stress disorders-related brain regions and/or neural circuits.
  • the stress disorders for example PTSD
  • EFP-NF training is used to reduce activation of the amygdala.
  • EEG signals are recorded from a subject, for example a trainee.
  • a trainee is a patient diagnosed with a stress disorder.
  • at least a portion of the recorded EEG signals is analysed, for example to determine a current activity state of a selected brain region, for example the amygdala.
  • a stored EEG electrical fingerprint associated with a specific activity level of the brain region is used to determine a current activity level of the brain level, for example by associating a recorded EEG signal with a stored EEG signal.
  • an activity level of a selected brain region for example the amygdala is monitored.
  • the trainee learns how to modulate the activity of the brain regions, for example how to upregulate the activity and/or how to downregulate the activity of the brain region.
  • the trainee receives a feedback on his success to reach a desired activity level.
  • the feedback is online, for example while the subject performs one or more exercises to modulate 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 which monitors the EFP-NF process. In some embodiments, the feedback is provided by modifying an interface, for example a scenario, presented to the subject. In some embodiments, the feedback is provided by modifying an interface that is designed to upregulate and/or downregulate the activation of the brain region. In some embodiments, the feedback is delivered to the subject in less than 10 seconds, for example less than 5 seconds, less than 2 seconds, or any intermediate, smaller or larger value from recording the EEG signals.
  • the feedback is a continuous feedback, for example the feedback is delivered during a time period of at least 30 seconds and related to changes in the activation levels of the brain region during this time period.
  • the stress disorders EFP-NF training is combined with exposure therapy.
  • an interface for example a challenge is provided to the subject during the EFP-NF training is related to a specific stress disorder, for example to a specific trigger of the stress disorder.
  • a subject is gradually exposed to a trigger of the stress disorder during the combined EFP-NF training.
  • an interface is gradually modulated to include an increasing number of features related to the trauma. Alternatively or additionally, an exposure time of a subject to the trauma- related features increases.
  • the trauma-related features are selected to evoke a response of a trainee to a specific trauma, for example activation of one or more brain regions and/or neural circuits.
  • the challenge provided to the subject is specific to a stress disorder, for example: for PTSD the challenge comprises sounds, sensations and/or scenes that cause triggering, delivered for example by virtual reality (VR) or augmented reality (AR); for Agoraphobia Without History of Panic Disorder the challenge comprises visualization of open space, delivered for example by VR or AR; for Social Phobia, the challenge comprises social interaction, images of faces asking questions, getting vague critic; for Specific Phobia the challenge comprises spiders; for depression which involves suicide obsession, the challenge comprises features related to suicide; for Substance Abuse, the challenge comprises image of drug paraphernalia.
  • VR virtual reality
  • AR augmented reality
  • the challenge comprises visualization of open space, delivered for example by VR or AR
  • the challenge comprises social interaction, images of faces asking questions, getting vague critic
  • Specific Phobia the challenge comprises spiders
  • depression which involves suicide obsession the challenge comprises features related to suicide
  • for Substance Abuse the challenge comprises image of drug paraphernalia.
  • the NF training for example the EFP-NF training is used to train a subject suffering from stress disorders, for example PTSD, to down regulate activation of one or more brain regions and/or neural circuits that are selectively activated.
  • the one or more brain regions and/or neural circuits for example the amygdala, are selectively activated during the NF training.
  • an interface delivered to the subject for example a subject suffering from a stress-disorder comprises one or more features related to a trigger of the stress disorder.
  • the one or more features comprise sound, visual, smell and/or a sensation related to the stress disorder.
  • a potential advantage of receiving online and continuous feedback on the ability of a subject to control the activation of stress-related brain regions, for example during an exposure to a personalized trauma trigger is that it allows an efficient and continuous training process with much higher temporal resolution, compared to, for example NF training methods which are based on MRI, for example fMRI.
  • An additional potential advantage of receiving online and continuous feedback on a subject ability to control activation of brain regions, while exposing the subject to a personalized trauma trigger is that it allows to stop the exposure of the subject to the trauma trigger in less than 10 seconds, for example in less than 5 seconds, in less than 2 seconds or any intermediate, smaller or larger value, from recording EEG signals related to an undesired activity level.
  • An aspect of some embodiments relates to examining an ability of a subject to control an activation level of one or more brain regions and/or neural circuits before exposing the subject to a stress-related trigger, for example a trauma-related trigger, specific to the subject.
  • a stress-related trigger for example a trauma-related trigger
  • a subject suffering from a stress disorder for example PTSD, is exposed to a non specific stress trigger prior to an exposure to a stress-trigger specific to the subject.
  • the specific, for example personalized, stress-trigger selectively activates, for example selectively upregulates, the activation of one or more brain regions and/or neural circuits related to emotion control and/or trauma memory.
  • an ability of the subject to control the activation for example to downregulate the activation of the one or more brain regions and/or neural circuits expected to be activated by the specific stress trigger, is examined prior to the exposure to the personalized stress trigger, for example a personalized trauma trigger.
  • a supervisor monitors reactions of the subject, for example physiological and/or behavioral reactions of the subject to the non-specific stress trigger and/or to the stress specific trigger, for example the trauma- specific trigger.
  • the supervisor monitors online the reactions of the subject during the NF training, for example during the EFP-NF training.
  • the supervisor modifies one or more parameters of the NF training according to the reactions of the subject.
  • a control circuitry of a system automatically modifies the one or more parameters of the NF training.
  • the one or more parameters comprise an interface, for example a stress trigger interface, of the NF training which delivers the specific and non-specific stress trigger to the subject, for example an audio and/or visual scenario, sound, smell, and/or sensation included in the interface.
  • the interface comprises a virtual reality (VR) or an augmented reality (AR) interface.
  • the one or more parameters of the NF training comprises overall training duration, duration of each training session, intermission period between training sessions, content and/or type of the stress trigger interface, moving from a non-specific stress trigger interface to a specific stress trigger interface, for example an interface that is personalized to trigger a specific trauma event or a trauma memory specific to the subject.
  • a subject is continuously exposed to a traumatic event, for example to a trigger of the traumatic event, during an EFP-NF training procedure.
  • the provided exposure is modulated according to the success of the subject to reach a desired activity level while being exposed to the traumatic event.
  • a continuous exposure and exposure modulation is generated by a closed-loop feedback during the NF raining session.
  • the exposure comprises traumatic contents extracted for each individual through a prior detailed interview, for example an interview which is part of the diagnosis of the stress disorder, for example PTSD.
  • a trauma narrative is presented via auditory, visual and/or other sensory modalities.
  • the sensory modalities are relevant to the emotionality/stress of the trauma, for example smell, touch, visual or auditory cue.
  • the presentation comprises not immersive (natural) environments.
  • the presentation comprises immersive environments, for example virtual or augmented reality environments.
  • the traumatic content is introduced gradually in terms of an emotional intensity of the content, for example the gradual introduction of the traumatic content is personalized per trainee, optionally prior to the NF training.
  • the traumatic content is introduced gradually by using an auditory interface, for example a voice of another person describing a traumatic event in a second person manner, then specific sounds are added that could be part of the traumatic memory, for example crying, yelling etc.
  • the traumatic content is introduced gradually by using a visual interface, for example showing graphic presentations of the narrative, then introduce personal cues related to objects, colors or people involved in the story.
  • feedback is provided by continuous modulation of the exposure to the traumatic event and/or modulation of the gradual introduction of the traumatic content.
  • the feedback is provided by constantly monitoring EFP signals based on recorded EEG signals during a EFP-NG training session.
  • the feedback for example a sensory rewarding feedback, is provided according to a change of the signals in a desired direction, for example down or up regulation relative to a baseline or previous signals values.
  • reward is perceived through decreased exposure intensity, for example by reducing clarity of sensory presentations or intensity of content, and/or changing the narrative to become more distant to a trauma focus.
  • the feedback comprises a continuous feedback.
  • the feedback comprises an intermittent feedback presented to a trainee every 2-30 seconds, for example every 2-15 seconds, every 10-20 seconds, every 17-30 seconds or any intermediate, smaller or larger range of values.
  • the trainee perceives the traumatic content for a selected time period in a range of 5- 90 seconds, for example 5-30 seconds, 20-60 seconds, 50-90 seconds or any intermediate, smaller or larger range of values.
  • the trainee perceives the traumatic content while trying to modulate brain signals and gets the feedback about success on a separate screen, for example as described above.
  • the feedback is delivered by presenting a scale, for example a metric scale showing degree of success in change.
  • the idea of patient specific context during NF training may serve two principles: one is related to better identification of the relevant brain circuit. Even though one or more brain regions are targeted, by providing the specific content while modulating these one or more brain regions, the most relevant pathological mechanism may be recruited. The second is related to the feedback mechanism during NF.
  • a positive feedback usually involves a reward circuitry, but when the reward is a positive/desirable change in the traumatic context, it leads to new learning that attach traumatic content with a reward, thus contradict its threat automatic meaning.
  • the NF training for example the EFP-NF training is a gradual procedure, for example a trainee first establishes its skill to modulate a target brain signal in a neutral (not disease specific) context, and only then confronted with the disease (and distressing) context, for example a trauma narrative or other.
  • the trainee receives one or more NF sessions with a non-specific feedback, for example an audio or an audio-visual animated scenario.
  • trainees who succeed in lowering their EFP signal during these one or more sessions continue to a second phase of the NF training.
  • the second phase is performed during exposure to diseases specific contents and contexts, for example trauma specific content and context.
  • a criterion for when moving to the distressing content is set in order to ensure that during exposure sessions trainees will be able to use their already established techniques to probe the relevant brain signal and modulate it despite the challenging interference.
  • EFP-NF provides both the spatial information from the fMRI and the accessibility of the EEG.
  • a supervisor for example a clinician attends the training room, closely monitor and reassures that the trainee is not overwhelmed with the situation and is able to handle the training.
  • a trained clinician is present also to guide the patient when confronting the distressing environment.
  • the clinician after each cycle of NF training, the clinician allows the patient to share their experience and discuss the mental strategy that was used successfully. Additionally or alternatively, at the end of each session, a learning graph is presented to the trainee and optionally, the clinician discusses with the trainee the success points in details. These safety steps are easily implemented in an EEG-NF set up, but are practically impossible with fMRI-NF.
  • an exposure narrative which is played back to the trainee as the feedback is a personalized exposure narrative generated for each individual subject.
  • a trained clinician interviews and records the patient about his/her particular traumatic event.
  • the information is edited, for example graded, according to the intensity and proximity to a specific trauma focal point.
  • a focal point is defined by number of emotional terms used to describe it or the behavior of the patient when disclosing this part.
  • a confronted question to the patient for example "please indicate what is the most distressing part of your memory", is used to define the trauma focal point.
  • data is collected by using questions, for example guiding questions, in order to characterize emotional, sensory and physical aspects of the experiences (e.g. how did you feel, was your feeling different than usual? what did you see/ hear, what did you think, what did you do?).
  • the clinician receives contextual information, for example about location, other people and time experience.
  • the information received during the interview is edited into one or more scripts having a duration in a range of 20 seconds- 10 minutes, for example 20 seconds-3 minutes, 1 minutes-7 minutes, 5 minutes- 10 minutes or any intermediate, smaller or larger range of values.
  • the script comprises an audio script
  • the audio script is delivered to the trainee in a second person voice.
  • each or at least some NF training sessions include debriefing following each cycle in the clinic, in order to guide each patient in finding the most useful techniques in order to promote brain modulation.
  • the feedback delivered to the subject is modulated according to the subject success in modulating the activity of the brain region.
  • the modulated feedback is delivered as a modulated exposure narrative, for example as described above.
  • a "rest period" of less than 5 minutes, for example less than 3 minutes, less than 1 minute, less than 30 minutes or any intermediate, smaller or larger value
  • calculation of an EFP value for example each trainee mean EFP value during rest and/or a standard deviation (STD) across this average is performed.
  • the feedback for example an auditory feedback comprising a short auditory neutral context feedback, for example a feedback not specific to a trauma of the trainee, of less than 10 minutes, for example less than 5 minutes, less than 3 minutes or any intermediate, smaller or larger value.
  • the neutral context feedback comprises a jazz music piece.
  • the short auditory feedback comprises a trauma specific context delivered during exposure sessions.
  • an increase or decrease in a value of a statistical parameter calculated for a measured EFP signal for example a change of one STD in amyg-EFP value (either up or down), causes a respective change in the loudness of the auditory feedback, for example a change of lOdB.
  • the STD is reset in accordance to the target signal values recorded during the last NF period and so on.
  • the EFP-NF which comprises an exposure to a trauma context, trauma content and/or trauma trigger, directly targets brain mechanism while provoking mental processing that is involved in the consolidation/extinction of the traumatic memory and experience.
  • memories are re-consolidated each time they are retrieved. Accordingly, re consolidation opens a window of opportunity to rewrite emotional memories and require the involved circuity. That is, old traumatic experiences can be updated and recontextualized during the reconsolidation window (Nader et ak, 2000, Dudai et ak, 2006, Schiller et ak, 2010, Kandler et ak, 2014). Therefore, re consolidation while manipulating the relevant circuit, enables non-invasive intervention that not only alter the experience of the traumatic memory but also modify its underlying neural mechanism.
  • Exposure to a recorded narrative of the trauma is an individual and challenging context that is set to activate the neural processes and networks that are used to code and retain and consolidate the memory of the traumatic event. Training participants to modulate limbic activity while these neural processes and networks are activated could hopefully alter its operation and drive it in a positive direction.
  • EFP-NF EFP-NF
  • it is performed in a controlled, gradual pace, with varied level of difficulty that minimizes patient discomfort and subsequent dropout. Therefore, context-related NF could also be recruited to constructing a therapeutic design which includes several difficulty levels built into it. As the trainee manages to regulate successfully in a simple, non-aversive feedback environment, the feedback itself could become more and more related to the patient’s pathology context and more emotionally evoking, creating a gradient challenge across the treatment period.
  • the EFP-NF is applied to different context- specific disorders, for example Obsessive Compulsive Disorders (OCD), specific phobia and/or social anxiety.
  • OCD Obsessive Compulsive Disorders
  • the feedback for example a positive feedback could be related to the content of the obsessions and/or compulsion, for example, a dirty room that becomes clean, disorganized room that become organized.
  • the elevator is going down or the doors closed faster, or a frightening object or insect transformed into a pleasant one.
  • the trainee is required to regulate while performing a task in front of other people and their verbal/facial/gesture feedback about the performance changes gradually from neutral/ambiguous to positive (smile, nice words, leaning towards the trainee with interest).
  • context is used to test an acquired skill.
  • it is used after learning to challenge the difficulty for example; executive function task for ADHD, memory task for mild cognitive impairment, pain induction for fibromyalgia, hedonic cue for depressive patients, social interaction for borderline personality disorder or related disorders (e.g. Post menstrual dysphoric disorder.
  • An aspect of some embodiments relates to providing online and continuous feedback to a subject while the subject is exposed to challenge, for example a stress related challenge.
  • the feedback is provided as the subject negotiates the challenge.
  • the challenge comprises a non-specific stress challenge.
  • the challenge comprises a stress disorder specific stress challenge.
  • the feedback is provided by modifying the challenge.
  • An aspect of some embodiments relates to exposing a subject to a challenge, for example a stress-related challenge during a NF procedure while the subject is not confined by an imaging system.
  • the subject is not confined, for example surrounded by the imaging system, for example an MRI or an fMRI device.
  • a supervisor is located near the subject during the exposure and the NF, for example at a distance of up to 10 meters from the subject, for example to allow fast access to the subject in case that the exposure is too intensive.
  • An aspect of some embodiments relates to providing feedback to a subject by modifying a stress-related challenge delivered to the subject. In some embodiments, the feedback is provided according to an activation level of one or more brain regions affected by the challenge.
  • the feedback is provided according to an ability of the subject to modify the activation of the one or more brain regions. In some embodiments, if the subject is successful in down regulating the activity of the one or more brain regions then the challenge intensity or severity is lowered. In some embodiments, if the subject is not successful in down regulating the activity of the one or more brain regions, then the challenge intensity or severity remains the same. In some embodiments, the feedback is delivered continuously and/or online.
  • An aspect of some embodiments relates to teaching a subject to perform at least one exercise, for example a physical or a mental exercise, shown to modulate an activity of at least one stress-related brain region in said subject in a timed relation with an exposure to a trauma or a stress-disorder-trigger.
  • the at least one exercise is selected and/or developed during an EFP- NF training, in which the ability of the subject to modulate an activation of the at least one stress-related brain region is monitored by measuring at least one electrophysiological parameter, for example EEG signals indicating an activation level of the specific at least one stress- related brain region.
  • the subject performs the at least one exercise after the completion of the EFP-NF training, for example a week, 14 days, a month, 6 months or any intermediate, shorter or longer time period from the completion of the EFP-NF training.
  • the subject performs the at least one exercise outside the clinic, for example when the subject is at his home, at his workplace or traveling.
  • the subject performs the at least one exercise while getting feedback from a mobile system that measures at least one physiological parameter indicating an activity level of at least one stress disorder-related brain region, for example an EEG signal.
  • the subject performs the at least one exercise without receiving a feedback regarding the activity level of the at least one stress disorder-related brain region.
  • the subject performs the at least one exercise while being exposed to a stress-related or a trauma-related interface personalized to the subject.
  • the interface is delivered to the subject by a user interface of a mobile device, for example a display and/or a speaker of the mobile device.
  • the subject performs the exercise when receiving an alert indication prior to an appearance of a stress disorder related trigger or a trauma-related trigger, for example an alert indication delivered by a media broadcasting organization or channel.
  • An aspect of some embodiments relates to safety features while exposing a subject to a stress-related challenge during NF training.
  • the subject is calmed down, for example by a drug and/or exercises if an effect of the exposure is too intensive.
  • the NF training is stopped or modified.
  • An aspect of some embodiments related to delivering a NF training for example an EFP- NF training while exposing the trainee to a stress disorder-related challenge designed according to at least one impaired neurobehavioral process in the trainee, for example a subject diagnosed with a stress disorder.
  • the at least one impaired neurobehavioral process is identified based on an assessment of the trainee, for example assessment of symptoms of the stress disorder.
  • At least one of the NF training goals comprises one or more of reduction in the expression level of at least one symptom of the stress disorder and shifting the trainee from the impaired neurobehavioral process towards a less impaired different neurobehavioral process or a non-impaired neurobehavioral process.
  • the at least one of the NF training goals comprises reducing the level of impairment of the impaired neurobehavioral process in the trainee following and/or during the NF training.
  • the at least one impaired neurobehavioral process in a stress disorder comprises one or more of threat detection, emotion regulation, fear extinction, reward consumption, saliency homeostasis, episodic memory encoding and reinstatement, executive function.
  • the NF training trains a subject diagnosed with a stress disorder to modulate an activation level of at least one brain region, for example a brain region of the limbic system, a deep brain region located under the cortex layer of the brain, and/or a neural circuit related to the at least one impaired neurobehavioral process.
  • an 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.
  • the NF training is used to teach a trainee to specifically modulate an activation level of one or more of the brain regions involved in the impaired threat detection process.
  • the trainee modulates an activation level of the at least one brain region while being exposed to an interface personalized based on the impaired threat detection process in the subject.
  • an impaired emotion regulation process involves one or more of the medial prefrontal cortex (mPFC), the dorsolateral prefrontal cortex (dlPFC), the dorsomedial prefrontal cortex (dmPFC), and the Amygdala.
  • the NF training is used to teach a trainee to specifically modulate an activation level of one or more of the brain regions involved in the impaired emotion regulation process.
  • the trainee modulates an activation level of the at least one brain region while being exposed to an interface personalized based on the impaired emotion regulation process in the subject.
  • an impaired fear extinction process involves one or more of the dorsal anterior cingulate cortex (dACC), the vmPFC, the Hippocampus, and the Amygdala.
  • the NF training is used to teach a trainee to specifically modulate an activation level of one or more of the brain regions involved in the impaired fear extinction process.
  • the trainee modulates an activation level of the at least one brain region while being exposed to an interface personalized based on the impaired fear extinction process in the subject.
  • the NF treatment of stress-disorder patients in enhanced by implementing a Process-Based approach to the design and practice of the NF training, for example an EFP-NF training.
  • multiple stress- disorder processes for example PTSD stress-disorder processes are activated via a context based interface during the neuromodulation of related networks.
  • various combinations of impaired processes are likely to interact as they give rise to the clinical phenomenology.
  • An aspect of some embodiments relates to treating depression in patients diagnosed with a stress disorder using NF-training, for example EFP-NF training.
  • the EFP- NF training is used to teach the patient to modulate, for example to actively modulate an activity of at least one specific brain region, for example at least one specific brain region which is related to the stress disorder.
  • modulation of the activity of the at least one specific brain region reduces the expression of depression symptoms in the patient.
  • At least one parameter of the NF training is adjusted in order to treat depression in the stress disorder diagnosed patient.
  • the at least one parameter comprises an interface, for example a challenge, delivered to the patient, and/or at least one exercise performed by the patient, for example a physical exercise and/or a mental exercise.
  • the NF-training is adjusted to treat depression in a stress disorder diagnosed patient treated with a bioactive compound for reducing depression symptoms.
  • the depression is evaluated following the NF training.
  • the expression level of at least one depression symptom is evaluated following the NF training.
  • the NF training is modified based on the evaluation results, for example instructions of a different exercise or a modified exercise are delivered to the patient if the modulation of the at least one brain region is not sufficient or is not is a desired direction and/or if the reduction in depression levels following the NF training is not sufficient.
  • an existing drug regime of at least one bioactive compound for treating depression is modified or a new drug regime is initiated following the NF training, for example based on the results of the NF training.
  • a dosage of the at least one bioactive compound is reduced if the modulation of the activity of the at least one specific brain region is in a desired level and/or if the NF training was effective in reducing at least one symptom of depression in the patient.
  • a potential advantage of reducing a dosage of the at least one bioactive dosage or the prescribing a new bioactive compound with a low dosage may be to reduce side effects in the patient caused by the bioactive compound.
  • An aspect of some embodiments relates to treating anxiety in patients diagnosed with a stress disorder using NF-training, for example EFP-NF training.
  • the EFP- NF training is used to teach the patient to modulate, for example to actively modulate an activity of at least one specific brain region, for example at least one specific brain region which is related to the stress disorder.
  • modulation of the activity of the at least one specific brain region reduces the expression of anxiety symptoms in the patient.
  • At least one parameter of the NF training is adjusted in order to treat anxiety in the stress disorder diagnosed patient.
  • the at least one parameter comprises an interface delivered to the patient, and/or at least one exercise performed by the patient, for example a physical exercise and/or a mental exercise.
  • the NF-training is adjusted to treat anxiety in a stress disorder diagnosed patient treated with a bioactive compound for reducing anxiety symptoms.
  • the anxiety is evaluated following the NF training.
  • the expression level of at least one anxiety symptom is evaluated following the NF training.
  • the NF training is modified based on the evaluation results, for example instructions of a different exercise or a modified exercise are delivered to the patient if the modulation of the at least one brain region is not sufficient or is not is a desired direction and/or if the reduction in anxiety levels following the NF training is not sufficient.
  • an existing drug regime of at least one bioactive compound for treating anxiety is modified or a new drug regime is initiated following the NF training, for example based on the results of the NF training.
  • a dosage of the at least one bioactive compound is reduced if the modulation of the activity of the at least one specific brain region is in a desired level and/or if the NF training was effective in reducing at least one symptom of anxiety in the patient.
  • a potential advantage of reducing a dosage of the at least one bioactive dosage or the prescribing of a new bioactive compound with a low dosage may be to reduce side effects in the patient caused by the bioactive compound.
  • An aspect of some embodiments relates to delivering an indication to a stress disorder patient to modulate at least one specific brain region related to a trigger of said stress disorder, for example a trigger of at least one symptom of said stress disorder in the patient, prior to an expected exposure to a stress disorder trigger.
  • the patient receives an indication, for example a human detectable indication to perform at least one exercise selected to modulate an activation of at least one specific brain region in the subject, prior to an exposure to a stress disorder trigger.
  • the patient receives the indication, optionally automatically, when an alert of an expected trauma trigger is identified.
  • a device for example a personal assisting device located in the home of the patient, on the patient, and/or near the patient, for example at a distance of up to 20 meters from the patient, for example up to 10 meters, up to 5 meters, up to 2 meters or any intermediate, smaller or larger distance from the patient, identifies at least one alert signal for an expected exposure to a trigger of the stress disorder of the patient.
  • a control circuitry of the device identifies the alert signal by receiving a signal from a microphone, for example a microphone of the device, or directly from the alert signal source, for example a media broadcasting device generating the alert signal.
  • the devise selects at least one exercise of a list of exercises, according to the identified alert signal.
  • the list of exercises is stored in a memory of the device.
  • the list of exercises is stored in a remote memory storage, for example a cloud storage, or a remote server.
  • the device selects the at least one exercise according to at least one of, the alert signal, for example according to the expected trigger of the stress disorder, according to the stress disorder, the at least one brain region that needs to be affected by the at least one exercise, the time the patient has until the expected exposure to the stress disorder trigger, and information on the patient, for example clinical and/or personal information.
  • the device delivers a human detectable indication to the patient to perform the at least one selected exercise.
  • the human detectable indication for example an audio and/or a visual indication, comprises instructions how to perform the at least one selected exercise.
  • the device monitors the activity of at least one specific brain region of the patient, for example in conjunction, for example before, during and/or following, with the performance of the at least one exercise and/or with the exposure to the at least one stress disorder trigger.
  • the device for example a control circuitry of the device, monitors the activity of the at least one specific brain region by receiving at least one electrical signal for example electrical signals from the patient, for example electrical signals generated by the brain of the patient.
  • the electrical signals comprise EEG signals.
  • the control circuitry of the device receives the EEG signals from at least one EEG electrode attached to the patient.
  • the device is wirelessly connected to the at least one EEG electrode.
  • the control circuitry of the device processes the at least one electrical signal to identify a relation between an activity signature of the at least one specific brain region, for example an activity signature also termed herein as an EEG electrical fingerprint (EEG-EFP), and at least a portion of the at least one electrical signal.
  • EEG-EFP EEG electrical fingerprint
  • the processing of the received electrical signals is performed in the device by the control circuitry.
  • a memory of the device comprises at least one EEG-EFP, or a plurality of EEG-EFPs, which are optionally personalized to the patient, and indicate an activation level of at least one specific brain region in the patient.
  • the at least one EEG-EFP or the plurality of EEG-EFPs, optionally personalized to the patient, are stored in a remote server, for example a remote server of a cloud storage.
  • the control circuitry of the device transmits the received electrical signals to the remote server and the identified relation between the at least a portion of the received electrical signals and the at least one stored EEG- EFP is performed in the remote server, for example using at least one algorithm or at least one lookup table stored in the remote server.
  • the device for example a control circuitry of the device delivers a human detectable indication to the patient according to the activation level of the at least one specific brain region.
  • the device delivers the human detectable indication according to a success of the patient to modulate an activation of the at least one brain region is a desired direction, for example upregulate or downregulate, and/or according to a modulation level, for example based on a score indicating a level of modulation.
  • the device for example a control circuitry of the device changes the instructions delivered to the patient, and/or changes an exercise delivered to the patient, based on the activation level of the at least one specific brain region and/o a success of the patient in modulating the activity of the at least one specific brain region using an exercise.
  • a feedback delivered to a subject diagnosed with a stress disorder for example a patient and/or a trainee of the NF training, comprises information regarding a direction of modulation of at least one specific brain region, for example downregulation or upregulation, and/or a level, for example a score, indicating a measured degree of modulation.
  • the feedback regarding an activation level of the at least one specific brain region and/or a success of the patient in modulating the activity level of the at least one specific brain region is delivered online while the patient is exposed to the challenge.
  • a control circuitry of a device that is used to deliver the NF training or to monitor an activation level of the at least one brain region, continuously and repeatedly receives electrical signals, for example electrical signals generated by the brain of the patient, identifies a relation between at least a portion of the received electrical signals and a stored signature, for example an EEG-EFP signature, and delivers a feedback to the patient.
  • control circuitry receives the at least one electrical signal, determines an activation level of at least one specific brain region based on the signals, and generates a feedback to patient regarding the determined activation level in less than 30 seconds, for example less than 15 seconds, less than 10 seconds, less than 5 seconds, less than 2 seconds or any intermediate, shorter or longer time period.
  • PTSD Post-Traumatic Stress Disorder
  • dACC dorsal anterior cingulate cortex
  • IGF inferior frontal gyrus
  • amygdala is involved, for example, in emotional processing including initiation and regulation of stress response and is also instrumental in effective emotion regulation. It is therefore reasonable to assume that amygdala functionality could be an effective target for brain-guided intervention through Neurofeedback (NF).
  • NF learning is based on self-modulation of brain activity, guided optionally, by contingent reinforcing feedback that reflects success in modulating a specific neural signal.
  • a personalized process-based EFP-NF intervention using individually-tailored trauma-related feedback content is delivered to subjects diagnosed with a stress disorder, for example PTSD.
  • the EFP-NF intervention modulated the amygdala activity, which is a neural node for PTSD, and is optionally coupled with exposure to personalized trauma-narrative as a feedback interface.
  • the EFP-NF intervention allows, for example to customize self-neuromodulation of a stress-related abnormal process and therefore increase treatment effectiveness.
  • a subject diagnosed with a stress disorder is trained to control activation of one or more brain regions related to the stress disorder.
  • the subject is trained to downregulate activation of one or more brain regions that are activated by a memory of a trauma related to the stress disorder, for example a traumatic event or a trauma-related context.
  • the NF training for example an EFP-NF training comprises training while exposure to content related to the trauma.
  • the subject is trained in order, for example, to reduce stress-related symptoms such as avoidance from trauma cues, hyper arousal, intrusion of thoughts and sensations, alterations in emotional experiences like anhedonia, re-experiencing of distressing memories, dissociative states, generalized avoidance from trauma related cues, dysphoria and/or anhedonia, anger bursts.
  • stress-related symptoms such as avoidance from trauma cues, hyper arousal, intrusion of thoughts and sensations, alterations in emotional experiences like anhedonia, re-experiencing of distressing memories, dissociative states, generalized avoidance from trauma related cues, dysphoria and/or anhedonia, anger bursts.
  • stress-related symptoms such as avoidance from trauma cues, hyper arousal, intrusion of thoughts and sensations, alterations in emotional experiences like anhedonia, re-experiencing of distressing memories, dissociative states, generalized avoidance from trauma related cues, dys
  • a subject is exposed to a stress disorder trigger, for example to a trigger of a PTSD, at 102.
  • a PTSD trigger comprises a traumatic environment and/or a traumatic interaction.
  • the PTSD trigger comprises a transient trigger that lasts for up to 24 hours, for example up to 12 hours, up to 1 hour, or any intermediate, smaller or larger time duration.
  • the trigger comprises a continuous trigger that lasts for more than 24 hours, for example more than 2 days, more than 7 days or any intermediate, smaller or larger time duration.
  • the subject is diagnosed with a stress disorder, for example PTSD, at 104.
  • a stress disorder for example PTSD, at 104.
  • the subject is diagnosed after a time period of at least 1 day from the exposure to the stress trigger, for example after a time period of at least 1 week, after a time period of 6 months and/or after a time period of several years from the exposure to the stress trigger, or any intermediate, shorter or longer time period.
  • the subject is diagnosed based on one or more stress-related symptoms.
  • the subject is diagnosed by a psychiatrist or any other clinician.
  • the subject for example, a patient is optionally treated with a bioactive compound at 106.
  • the bioactive compound comprises one or more drugs and/or pharmaceutical substances.
  • the bioactive compound is directed to treat the stress-related symptoms.
  • the bioactive compound is directed to affect activation of one or more brain regions and/or neural circuits, for example brain regions or neural circuits related to the stress disorder, for example stress disorder memory.
  • the bioactive compound comprises one or more of a Selective Serotonin Reuptake Inhibitor (SSRI), new generation of antiepileptic drugs that are used as mood stabilizers; e.g. Topamax, Bupropion, Ketamine, Cannabis.
  • SSRI Selective Serotonin Reuptake Inhibitor
  • the drug is taken by the subject prior to or during the NF training, for example to enhance the effect of the NF training.
  • the drug is taken to protect the subject during the NF training, for example from the effects of an exposure to stress-related challenges.
  • the patient is trained by the EFP-NF training procedure at 108.
  • the patient is trained while receiving the bioactive compound.
  • the EFP-NF training procedure is personalized for a specific patient, for example to the specific stress disorder and/or to a specific trauma caused the stress disorder. Alternatively or additionally, the EFP-NF training procedure is modified according to a specific bioactive compound taken by the patient.
  • the patient for example a trainee is trained using the EFP-NF to control the activation levels of one or more brain regions related to a stress disorder and/or to a trauma, for example, one or more brain regions related to a memory of the trauma.
  • the patient is trained to downregulate activation of the one or more brain regions, for example the amygdala.
  • the patient is trained to downregulate activation levels of the amygdala during an exposure, for example gradual exposure, to content and/or context related to the trauma, for example a specific trauma that affected the trainee.
  • the ability of the EFP-NF training to reach a desired outcome is evaluated at 110.
  • the evaluation comprises an interview with the patient after a selected period of time following the EFP-NF, for example after at least one day, for example after a day, after a week, after a month or any intermediate, shorter or longer time period.
  • the evaluation comprises recording values of one or more clinical parameters, for example heart rate, blood pressure or any other clinical parameter related to stress and/or anxiety.
  • the evaluation comprises recording of EEG signals and/or fMRI signals following the EFP-NF training.
  • the EEG signals and/or fMRI signals are recorded in a time relationship to exposure to a trauma-related content or context, for example during the exposure and/or following the exposure.
  • At least one parameter of the EFP-NF training is modified at 122.
  • the at least one parameter comprises the number of sessions, content of an interface delivered to the trainee during the training, duration of each session, an EFP used during the EFP- NF training.
  • a bioactive compound taken by the trainee is replaced to a different bioactive compound.
  • the trainee repeats the EFP-NF training using the modified EFP-NF protocol at 108.
  • the trainee is invited to maintenance NF sessions at 114.
  • the maintenance sessions are configured to maintain the ability of the trainee to affect the activation of the one or more brain regions, for example using the skills the trainee acquired during the NF training at 108.
  • the NF maintenance sessions are performed a week, a month, a year or any intermediate, smaller or larger time period following the NF training.
  • the maintenance training is based on recordings of EEG signals or recordings of one or more clinical parameter values indirectly affected by the activation of the one or more brain regions.
  • the maintenance NF comprises an EFP of the selected one or more brain regions.
  • the maintenance sessions are performed by a subject that underwent the EFP-NF training session.
  • the maintenance sessions are performed by the subject himself, for example in his home or in any other location away from a clinic.
  • 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.
  • the personalized trauma trigger is based on a personalized trauma-related scenario presented to the subject during the EFP-NF training.
  • the subject applies at least one exercise, for example a physical or a mental exercise in a timed relation with the exposure to the personalized trauma trigger, for example before, during and/or after the exposure.
  • the at least one exercise is applied by the subject in response to an appearance of a trauma-trigger warning, and/or prior to an expected trauma-trigger.
  • the subject performs applies the at least one exercise in an absence of feedback.
  • a subject is selected for an EFP-NF training at 202.
  • the subject for example a subject diagnosed with a stress disorder, for example PTSD, is selected by a clinician prior to the EFP-NF training.
  • the subject is selected based on the stress disorder type, time that passed from a stress disorder trigger or a traumatic event, clinical history, medication history.
  • the subject is evaluated by a clinician prior to the EFP-NF training at 204.
  • the subject is evaluated, for example to personalize the EFP-NF training to a specific subject.
  • the clinician collects information from the subject, for example in an interview about the trauma, for example about the trauma trigger and/or the traumatic event that caused the stress disorder.
  • the subject is trained using the EFP-NF in a neutral context at 206.
  • a neutral context is a context that is non-specific to a trauma of the specific subject.
  • the subject learn how to modulate the activation of one or more brain regions, for example the amygdala while reacting to non-specific stress triggers, for example loud noise.
  • the subject is trained to perform one or more exercises, for example physical or mental exercises to modulate, for example to downregulate, amygdala activity.
  • a success of the subject for example a trainee to reach a desired activation level of the one or more brain regions is evaluated at 208.
  • a success of the trainee to downregulate an activity level of the amygdala while reacting to the non-specific stress triggers is evaluated at 208.
  • At least one parameter of the neutral context EFP-NF is modified at 210.
  • the at least one parameter comprises training duration, duration of each session, type and/or content of the non-specific stress trigger, the way the non-specific stress trigger is delivered to the trainee, strategy to find an exercise that allows efficient activity modulation in the specific subject.
  • the trainee if the trainee demonstrated a success in reaching a desired activation by the neutral context EFP-NF, then the trainee initiates an EFP-NF training protocol in a personalized stress context at 212.
  • the trainee performs the exercises learned in the neutral context EFP-NF while reacting to content relating to his personal trauma.
  • the trauma- specific content is delivered to the trainee gradually.
  • the trauma- specific content is delivered to the trainee under a supervision of a supervisor, for example a clinician.
  • the trainee and/or the supervisor receive online and optionally continues feedback on the success of the trainee to reach a desired activity level of the one or more brain regions while reacting to the trauma- specific content.
  • a post-training evaluation is performed at 212.
  • the post-training evaluation evaluates a progress of the trainee compared to a baseline or previous activation measurements of the one or more brain regions.
  • the post-training evaluation is performed by measuring fMRI signals, EEG signals or values of at least one clinical parameter, for example a clinical parameter associated with activation levels of the one or more brain regions.
  • a subject is diagnosed with PTSD using a traditional definition of PTSD according to DSM-5, which consists of five main criteria: (A) exposure to a traumatic experience (defined as death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence), and experiencing subsequent suffering for more than a month from the time of the event (B) intrusive re-experiencing of memories and feelings of the traumatic event (C) avoidance of cues that remind the individual of the event (D) altered cognition, including deficient memory of the event, poor cognitive processing of emotions (i.e.
  • alexithymia and mood dysregulation related to loss of pleasure, poor emotion regulation and emotional outbursts, and (E) general hyper arousal and vigilance.
  • this categorization results in clinical heterogeneity that can lead to poorly tailored management for individual patients.
  • various underlying impairments in neurobehavioral processes for example, fear learning and extinction, threat detection, emotion regulation and others are identified.
  • these impairments in neurobehavioral processes are related to amygdala activity.
  • such a conceptualization emphasizes a pivotal role of the Amygdala in different aspects of PTSD, with respect to its relation with other limbic, salience and prefrontal regions, for example as described in Monica RJ et al. 2018.
  • altered fear learning, impaired extinction and safety signal processing are important for PTSD symptomatology, but also depend on the Amygdala functionality of its subnuclei and various cell types, as well as on maladaptive top-down cortical inhibition.
  • emotion dysregulation resulting in intense emotional reactivity, irritability, and impulsivity are known to be underlined by a lack of cortical control over Amygdala reactivity, specifically manifested by impaired connectivity patterns between the Amygdala and the vmPFC and dlPFC, for example as described in Etkin A. et al.,2015.
  • maladjusted threat detection may give rise to increased attention and reactivity to threatening or salient stimuli and is accompanied by hypervigilance and related aggressive behavior, mediated by the Amygdala as well as cortical regions such as the insula, vmPFC, dACC, as well as brain stem areas such as the PAG and locus coeruleus.
  • a PTSD patient undergoes assessment of impaired processes related to PTSD.
  • the impaired process characterization is guided by assumed neuroscientific mechanism that underlie the main symptom clusters in PTSD.
  • the assessment comprises clinical assessment 220, for example based on an interview and/or filling at least one questionnaire.
  • the assessment comprises physiological assessment 222, for example measurements of at least one physiological parameter, for example heart rate, blood pressure, electromyography and/or skin conductivity.
  • the assessment comprises behavioral assessment 224, for example by monitoring or visualizing the subject response, for example to external perturbation which are optionally trauma- specific for the subject.
  • the expression level of PTSD symptoms for example PTSD symptoms according to the DSM, in the subject is determined based on the assessment performed in fig. 2B.
  • the PTSD symptoms comprise intrusion, avoidance, altered cognition and mood, and altered arousal and reactivity.
  • based on behavioral and physiological assessments it is possible to establish an individually-tailored process-related characterization of PTSD patients.
  • different processes are related to PTSD abnormalities, for example threat detection, emotion regulation and fear extinction.
  • the processes are measured by administering behavioral tasks, for example predictable and unpredictable shock task for threat detection (Schmitz A. et, al., 2012), emotional regulation task for emotion regulation (Shafir R. et, al., 2015), and an aversive learning task for fear extinction (Shalev L., et, al., 2018).
  • behavioral tasks for example predictable and unpredictable shock task for threat detection (Schmitz A. et, al., 2012), emotional regulation task for emotion regulation (Shafir R. et, al., 2015), and an aversive learning task for fear extinction (Shalev L., et, al., 2018).
  • PTSD symptom clusters for example intrusion, avoidance, altered cognition and mood, and altered arousal and reactivity, are depicted, for example as shown in the table shown in fig. 2C, according to their suggested weights in each of the major dysfunctional processes per patient.
  • the impaired processes are identified, based on the weight or level of expression of each of the
  • the impaired processes in PTSD for example threat detection, emotion regulation, and fear extinction are linked to PTSD symptoms, and are optionally related to an increase in PTSD severity.
  • the dysfunctional processes are used for delivery of individually tailored process based NF.
  • the dysfunctional processes derived from the initial assessment battery guide the selection of the corresponding intervention interface.
  • each interface is configured to specifically target an impaired process by provoking activity in a designated brain circuitry including the Amygdala.
  • self-modulation of the Amygdala in each unique context results in specific modulation patterns of the underlying circuit of interest.
  • an interface with threat related cues is delivered to the subject, and the Amygdala activity feedback corresponds, for example to the volume of an ambulance siren.
  • this process- specific context provokes modulation of threat detection related circuits involved in, for example, at least one of increased attention, reactivity to threatening stimuli and hypervigilance, 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.
  • electrical fingerprints (EFP) of the Amygdala, and one or more of these regions are used to determine the activation level of these regions, and to generate and/or modify a feedback to the subject based on the determined activation level.
  • an interface with emotion related cues is delivered to the subject, and the Amygdala activity feedback corresponds, for example, to a brightness level of the interface.
  • this process-specific context provokes modulation of emotion regulation related circuits involving at least one of the medial prefrontal cortex (mPFC) 248, the dorsolateral prefrontal cortex (dlPFC) 246, the dorsomedial prefrontal cortex (dmPFC) 244, and the Amygdala 232.
  • electrical fingerprints (EFP) of the Amygdala, and one or more of these regions are used to determine the activation level of these regions, and to generate and/or modify a feedback to the subject based on the determined activation level.
  • an interface with fear related cues is delivered to the subject, and the Amygdala activity feedback corresponds, for example, to the content of the interface.
  • this process-specific context provokes 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.
  • electrical fingerprints (EFP) of the Amygdala, and one or more of these regions are used to determine the activation level of these regions, and to generate and/or modify a feedback to the subject based on the determined activation level.
  • a NF training program for a subject diagnosed with a stress disorder is personalized to the specific subject.
  • the NF training program is personalized, according to at least one of a trigger that caused a trauma in the past, a current trigger that causes at least one stress symptom related to the trauma, at least one stress-disorder symptom, and at least one abnormal process related to the stress disorder.
  • a trigger that caused a trauma in the past a current trigger that causes at least one stress symptom related to the trauma, at least one stress-disorder symptom, and at least one abnormal process related to the stress disorder.
  • a subject is diagnosed with a stress disorder, at block 250.
  • the stress disorder comprises PTSD, Acute Stress Disorder, Adjustment disorder, Reactive attachment disorder (RAD), Disinhibited social engagement disorder (DSED), Obsessive compulsive disorder, phobia, general anxiety, social anxiety, borderline personality disorder.
  • the subject is diagnosed with a stress disorder according to the diagnostic and statistical manual of mental disorders (DMS), for example a stress disorder in the categories "other Trauma and Stressor-Related Disorders” or“unspecified Trauma- and Stressor-Related Disorder” in the DSM, 5 th edition.
  • DMS mental disorders
  • the subject is diagnosed with the stress disorder based on an observation and/or an interview with a mental health professional, for example a psychiatrist.
  • the subject is diagnosed with the stress disorder based on measurement results of at least one physiological parameter, for example heart rate, blood pressure and/or skin electrical conductivity.
  • symptoms of the stress-disorder are assessed at block 252.
  • the symptom assessment is performed as described for example in fig. 2B.
  • the symptoms are assessed based on an observation and/or an interview with a mental health professional, for example a psychiatrist.
  • the symptoms are assessed based on measurement results of at least one physiological parameter, for example heart rate, blood pressure and/or skin electrical conductivity.
  • the symptoms are assessed using an assessment questionnaire, for example a Clinician-Administered PTSD Scale (CAPS), for example CAPS- DSM-5 (CAPS-5) or variations thereof.
  • the symptoms are assessed based on subclasses of the CAPS-5.
  • the symptoms comprise one or more of Intrusion, Avoidance, Altered Cognition and Mood, and Altered Arousal and Reactivity.
  • the assessment comprises determining a strength, for example an expression level of each of the symptoms in the specific subject.
  • abnormal neurobehavioral processes for example abnormal stress-related neurobehavioral processes are identified at block 254.
  • the abnormal neurobehavioral processes are identified based on the assessment of the stress-disorder symptoms performed at block 252, for example based on an expression level of the symptoms in a specific subject.
  • the abnormal neurobehavioral processes are identified based on the subject diagnosis performed at block 250.
  • the abnormal neurobehavioral processes comprise PTSD-related abnormal neurobehavioral processes, for example an impaired threat detection process, an impaired emotion regulation process, and/or an impaired fear extinction process.
  • a NF training is delivered to the diagnosed subject, for example a PTSD patient, at block 256.
  • the delivered NF training is an electrical finger print (EFP)-NF training.
  • the delivered EFP-NF training at block 256 is in a neutral context, and not in a context related to the trauma, a trigger of the trauma, a PTSD-related symptom or a PTSD-related abnormal neurobehavioral process.
  • the patient in the neutral context EFP-NF, is instructed to perform at least one exercise, for example a physical or a mental exercise while interacting, for example sensing, watching and/or listening to an interface delivered to him by tactile sensation, audio and/or video signals, for example using virtual reality or on a display.
  • the interface is a neutral interface, for example non-related to the PTSD.
  • performing the at least one exercise modulates an activation level of at least one neural circuitry, or at least one brain region, for example at least one brain region related to the limbic system.
  • the at least one brain region related to the limbic system comprises the Amygdala.
  • the subject receives a feedback according to the activity level of the at least one neural circuitry or the at least one brain region. In some embodiments, the feedback is delivered by modulating the interface.
  • the subject performs the EFP-NF in a neutral context, for example to find the exercise, for example the physical and/or mental exercise that show high efficiency relative to other exercises in modulation of the activity of the at least one brain region in the subject. Additionally, performing the EFP-NF in a neutral context also allows, for example, to determine whether the subject qualifies for moving to EFP-NF sessions in a trauma context.
  • an NF training for example an EFP-NF training is delivered in a trauma context, at block 258.
  • the trauma context is personalized to the trainee.
  • the trauma context comprises EFP-NF training in context of PTSD symptoms in the trainee, for example PTSD symptoms assessed at block 252.
  • the trauma context comprises EFP-NF training in context of PTSD-related abnormal neurobehavioral processes in the trainee, for example abnormal processes identified at block 254.
  • changes in the assessed symptoms and/or identified abnormal processes are determined at block 260.
  • the changes in the assessed symptoms and/or identified abnormal processes are determined during a training session, for example in the beginning and/or in an end of a training session, for example while the trainee is in the clinic.
  • changes in the assessed symptoms and/or identified abnormal processes are determined between training sessions, for example while the trainee is in his home and not in the clinic or in a clinic.
  • the NF training is stopped.
  • the determined changes are desired changes, for example changes that reduce the expression of symptoms and/or modified the abnormal process in a desired level.
  • the NF training is stopped.
  • the determined changes are not desired changes, for example changes that did not reduce the expression of symptoms and/or modified the abnormal process in a desired level.
  • the EFP-NF is continued or repeated.
  • the EFP-NF training is stopped.
  • the EFP-NF is modified at block 262.
  • the at least one exercise performed by the trainee is modified.
  • the trauma-related interface delivered to the trainee is modified.
  • the trainee after a successful completion of the EFP-NF, for example after reaching the desired goals of the training, for example after reaching the desired changes, the trainee perform at least one additional maintenance training session at block 264.
  • the maintenance training session is performed at least 1 week, for example at least 2 weeks, at least 1 month, or any intermediate, shorter or longer time duration after completing the EFP-NF training.
  • the maintenance training session is performed without receiving feedback in relation to the activity level of the at least one brain region and/or neural circuitry.
  • the maintenance training session is performed while the trainee is not in the clinic.
  • the trainee perform at least one exercise, for example the exercise the trainee performed during the training session, at block 258. Alternatively, the trainee performs a different exercise, which is optionally selected based on the clinical condition of the trainee and/or PTSD symptom levels.
  • changes in stress-related symptoms are monitored following the NF training and/or between training sessions of the NF training, for example as described at block 260 in fig. 2G.
  • changes in stress-related abnormal neurobehavioral processes are determined.
  • figs. 2H-2K depicting changes in stress-related symptoms, for example PTSD-related symptoms, following EFP-NF training, according to some exemplary embodiments of the invention. According to some exemplary embodiments, for example as shown in fig.
  • trainees that were exposed to a Trauma-related interface in a Trauma-NF training 270 exhibited reduction in alterations in cognition and mood following the training, in a TP2 276 (post-training test point), compared to levels in alterations in cognition and mood prior to the training at TP1 274 (pre training test point). Alterations in cognition and mood levels were also reduced in trainees that performed Neutral-NF training 272 with a neutral interface not related to the Trauma, but the reduction was smaller compared to the Trauma-NF training 270 group.
  • trainees that were exposed to a Trauma-related interface in a Trauma-NF training 270 exhibited reduction in avoidance levels following the training, in a TP2 276 (post-training test point), compared to levels of avoidance prior to the training at TP1 274 (pre-training test point). Avoidance levels were also reduced in trainees that performed Neutral-NF training 272 with a neutral interface not related to the Trauma, but the reduction was smaller compared to the Trauma-NF training 270 group.
  • trainees that were exposed to a Trauma-related interface in a Trauma-NF training 270 exhibited reduction in arousal levels following the training, in a TP2 276 (post-training test point), compared to levels of arousal prior to the training at TP1 274 (pre-training test point).
  • Arousal levels were also reduced in trainees that performed Neutral-NF training 272 with a neutral interface not related to the Trauma, but the reduction was smaller compared to the Trauma-NF training 270 group.
  • the trainee is exposed to trauma-related content, for example trauma-related content personalized to a specific trauma of the trainee, while training to modulate activation of one or brain regions that are activated by the trauma-related content.
  • the trainee is exposed to trauma-related content which upregulates the activation levels of the amygdala while training to downregulate the activation levels by one or more exercises, for example mental and/or physical exercises.
  • a feedback regarding a success of the trainee in modulating the brain activity region is delivered by modifying the trauma-related content.
  • the intensity of the exposure decreases.
  • the exposure level of the trainee to the trauma-related content follows a change in the activity level of the amygdala. In some embodiments, if the amygdala activity level decreases, then the exposure level to the trauma content decreases, for example exposure time or exposure content.
  • fig. 3 depicting a process for modifying a feedback delivered to a trainee, according to some exemplary embodiments of the invention.
  • a trauma-related content for example a trauma-related challenge is delivered to a trainee at 302.
  • the trauma-related challenge comprises content personalized to a specific trainee, for example based on interviews with a clinician and/or based other information sources.
  • the trauma-related challenge is delivered by one or more of sound, visual, smell, sensation or any other interface.
  • a trainee is trained to affect activity of selected one or more brain regions at 304.
  • the subject is trained in a time relationship to the delivery of the trauma-related challenge, for example during the delivery of the challenge or following the delivery of the challenge.
  • the training comprises performing predetermined exercises, for example physical and/or mental exercises selected to affect the activation of the one or more brain regions.
  • the subject is encouraged or directed to generate the exercises or to modulate know exercises, for example to fit his own abilities.
  • an activity level of the one or more brain regions is measured at 306.
  • the activity level is measured based on EEG signals recorded from the head of the trainee, for example during the EFP-NF training.
  • the recorded EEG signals are analyzed and an EFP is generated based on the recorded EEG signals.
  • the generated EFP is related to an activation level of the one or more brain regions.
  • an effect of the NF training for example EFP- NF training on the activity of the one or more brain regions is determined at 308.
  • the effect of the NF is determined based on the generated EFP and a desired EFP, which relates to a desired activity.
  • the trauma-related challenge delivered to a trainee is modified according to a current activity level of the one or more brain regions at 310.
  • the trauma-related challenge delivered to the trainee is modified according to a success of a trainee to reach the desired activity level of the one or more brain regions.
  • the trauma-related challenge is modified according to a change of the EEG signals and/or the extracted EFP signals in a desired direction, for example down or up regulation relative to a baseline or previous signals values.
  • the modification in the trauma-related challenge is delivered as a feedback of NF training, for example a sensory rewarding feedback of the NF process.
  • the modified challenge is delivered to the trainee continuously or incrementally.
  • the feedback is delivered to the trainee online during the NF training, for example in less than 30 seconds from measuring the EEG signals, for example in less than 20 seconds, in less than 10 seconds or any intermediate, shorter or longer time duration.
  • a system for example system 400 comprises a control unit 402, and an EEG measuring unit 404 electrically connected to the control unit 402.
  • the EEG measuring unit comprises one or more EEG electrodes, for example EEG electrodes 408 and 410 which are attached to a scalp 412 of a subject 406.
  • the one or more EEG electrodes are configured to measure EEG signals, for example during the EFP-NF training.
  • control unit 402 comprises a control circuitry 416 and an EEG recording unit 414, electrically connected to the control unit 416.
  • EEG electrodes for example EEG electrodes 408 and 410 are electrically connected to the EEG recording unit 414.
  • the EEG recording unit 414 transmits the recorded EEG signals to the control circuitry 416.
  • the control unit 402 comprises a memory 418 electrically connected to the control circuitry 416.
  • the memory 418 stores recorded EEG signals, and stored EFP signals, for example generic EFP signal and/or a personalized EFP signal which relates to a specific activation level of one or more brain regions.
  • the control circuitry 416 analyzes at least a portion of the recorded EEG signals, for example to generate an EFP which relates to a current activity level of one or more brain regions.
  • the control circuitry 416 generates the EFP signal using an algorithm stored in the memory 418.
  • the control circuitry is electrically connected to a trainee interface 424.
  • the trainee interface 424 comprises an audio interface and/or a display.
  • the control circuitry delivers a challenge, for example a neutral challenge and/or a trauma- specific challenge to the trainee by the trainee interface.
  • values of at least one parameter related to the neutral challenge and/or to the trauma-related challenge are stored in the memory 418.
  • the trainee interface 424 delivers the challenge, by generating audio and/or visual signals. Alternatively or additionally the trainee interface 424 delivers the challenge to the trainee 406 by generating smell.
  • control circuitry 416 is electrically connected to a supervisor circuitry 420.
  • the supervisor interface 420 delivers one or more indications regarding the NF training process to a supervisor, for example a clinician monitoring the NF training.
  • the supervisor interface is located near the trainee 406, for example in the same room of the trainee and/or at a distance of less than 10 meters from the trainee, for example at a distance of less than 7 meters, less than 5 meters, less than 3 meters or any intermediate, smaller or larger distance from the trainee 406.
  • control circuitry is configured to record EEG signals from the one or more EEG electrodes, for example during the delivery of the challenge to the trainee 406. Additionally, the control circuitry is configured to record EEG signals from the one or more EEG electrodes when the trainee performs exercises to modulate the activity of one or more brain regions. In some embodiments, the control circuitry 416 is configured to analyse the recorded EEG signals and to generate an EFP signal which relates to an activity level of the one or more brain regions during the delivery of the challenge and/or following the performed exercises.
  • control circuitry 416 is configured to determine whether a generated EFP signal following the performed exercises relates to a desired activity level of the one or more brain regions based on stored EFP signals, optionally using a lookup table and/or an algorithm stored in the memory 418.
  • control circuitry is configured to deliver feedback, for example an indication to the trainee 406, optionally by the trainee interface 424.
  • the feedback relates to a success of the subject 406 in modifying the activity of the one or more brain regions in a desired direction, for example activity upregulation or activity downregulation.
  • control circuitry 416 is configured to modulate at least one parameter of the challenge delivered to the trainee 406 according to a success level of the trainee in modulating the activity level of the one or more brain regions and/or according to an activity level of the one or more brain regions.
  • control circuitry 416 modulates the challenge delivered to the trainee 406 based on values of one or more parameters of the challenge, for example content of the challenge, challenge type, challenge duration, sound intensity, light intensity, colors, colors intensity, smell intensity, different sound sources volume (human and or objects), appearance of touch (e.g. wind or water), a person avatar in the training interface (with or without), stored in the memory 418.
  • a supervisor monitors the performance of the trainee 406 by receiving one or more indications to the supervisor interface 420 from the control circuitry 416.
  • the control unit is configured to measure values at least one physiological parameter of the trainee, for example heart rate, blood pressure, skin conductance, pupil dilation, specific eye movement towards an exposure stimuli, Electromyography (EMG) for muscle tension or reaction time for specific goal reach, or any other physiological parameter that is associated with a physiological response to stress.
  • EMG Electromyography
  • control circuitry 416 is configured to automatically stop the NF training if measurements of the at least one physiological parameter and/or recorded EEG signals indicate that a trainee response to the challenge, for example a neutral challenge or a trauma-related challenge is stronger than a predetermined value stored in the memory 418.
  • a supervisor using the supervisor interface manually stops the NF training, if measurements of the at least one physiological parameter and/or recorded EEG signals indicate that a trainee response to the challenge, for example a neutral challenge or a trauma-related challenge is stronger than a predetermined value stored in the memory 418.
  • a user inserts information and/or characteristics of a stress-disorder patient, for example subject 406 diagnosed with the stress disorder, into a memory, for example memory 418 of the control unit 402.
  • the user inserts the information via a user interface of the control unit, for example supervisor interface 420.
  • the information and/or characteristics of the patient are delivered by a communication circuitry of the control unit into the memory 418.
  • the information comprises information regarding a trauma event initially triggered the stress disorder in the patient, at least one symptom of the stress disorder expressed in the patient, and/or at least one impaired neurobehavioral process in the patient which is linked to the stress disorder.
  • the information inserted into the memory comprises at least one challenge configured to trigger at least one symptom of the stress disorder in the patient.
  • the information inserted into the memory comprises at least one non-specific challenge, configured not to trigger at least one symptom of the stress disorder in the subject.
  • a non-specific challenge is configured to affect an activation of at least one brain region in the patient which is also affected by the stress disorder in the patient, without triggering at least one symptom of the stress disorder in the patient.
  • control circuitry selects a challenge from a list of challenges stored in the memory, to present to the patient.
  • the control circuitry selects the challenge based on information on the patient stored in the memory, for example information regarding a trauma that triggered the stress disorder, information on at least one trigger of the stress disorder, information on at least one symptom of the stress disorder expressed in the patient and information on at least one impaired neurobehavioral process of the stress disorder in the patient.
  • the control circuitry selects the challenge based on values or indications thereof of at least one physiological parameter, for example heart rate, blood pressure, skin conductivity, stored in the memory.
  • the control circuitry selects the challenge based on results of at least one clinical assessment performed to the patient, for example CAPS-5 assessment or variations thereof, depression assessment and/or anxiety assessment.
  • control circuitry for example control circuitry 416 presents, for example by visual and/or audio signals, at least one challenge, selected by a user or aby the control circuitry, to the patient, for example using a trainee interface, for example trainee interface 424.
  • the control circuitry receives at least one electrical signal, for example at least one electrical signal generated by the brain of the patient, in conjunction with the exposure of the patient to the at least one challenge, for example before, during and/or following the exposing.
  • the received electrical signals are EEG signals.
  • the control circuitry receives the at least one electrical signal from a recording unit, for example an EEG recording unit 414.
  • control circuitry for example control circuitry 416 monitors an activation level of at least one specific brain region in the brain of the patient, for example a brain region of the limbic system, using the received at least one electrical signal.
  • control circuitry processes the received at least one electrical signal to identify at least a portion of the at least one electrical signal that indicates an activity level of the at least one specific brain region, for example as described in in US Patent Application No. 13/983,419.
  • control circuitry identifies a relation between the at least a portion of the received electrical signal to a signature, also termed herein as an EEG electrical fingerprint (EEG-EFP), stored in the memory, for example memory 418.
  • a signature also termed herein as an EEG electrical fingerprint (EEG-EFP)
  • the signature is an activity level signature of at least one specific brain region, for example the amygdala or any other brain region of the limbic system.
  • control circuitry monitors an ability of the patient to modulate the activation of the at least one brain region, for example using the received at least one electrical signal.
  • control circuitry delivers instructions to said patient to perform at least one exercise, for example a mental or a physical exercise configured to affect the activation of the at least on specific brain region.
  • the control circuitry selects the exercise from a list of exercises stored in the memory.
  • the control circuitry selects the exercise based on the patient information stored in the memory, and/or based on the at least one specific brain region, and/or a based on a desired effect on the activity of the at least one specific brain region.
  • control circuitry determines how to modify, optionally automatically modifies, at least one of the challenge presented to the subject, and/or instructions of the exercise, based on received electrical signals.
  • control circuitry modifies the at least one of the challenge presented to the subject, and/or instructions of the exercise based on an activation level of the at least one specific brain region and/or a success of the patient in modulating the activity of the at least one brain region.
  • Post-traumatic stress disorder may be characterized by excessive emotion reactivity and diminished emotion regulation. These process abnormalities may correspond to hyper-active amygdala and hypo-active ventro-medial PFC, respectively.
  • nonspecific targeting of these processes might explain low treatment efficacy in PTSD.
  • NF process-oriented neurofeedback
  • EEG-finger-print EEG-finger-print
  • This intervention may result in symptom reduction and in altering dysfunctional neural processing in PTSD related to emotion reactivity and regulation.
  • the study includes a test group that trains amygdala down regulation following a challenge that is trauma specific.
  • patients in the trauma context group are gradually challenged with content from their traumatic event (in form of an auditory script) and train on down regulation in this challenging context that is assumed to increase amygdala activation.
  • clinical outcome measures include CAPS, BDI, STAI, ERQ.
  • Neural outcome measures include a resting state functional connectivity sequence, an amygdala reactivity task (Hariri), an emotional interference task (Emotional Stroop) and two short cycles of amygdala rt-fMRI-NF.
  • Participants between the ages of 18-65, who have been exposed to a traumatic event at least 14 months ago were recruited from the trauma clinic at TASMC and from other clinics at the area of Tel Aviv.
  • subjects exposed to a traumatic event at least 6 months, for example at least 10 months, at least 12 months or any intermediate, smaller or larger time duration, prior to the NF-treatment or an evaluation meeting are selected for the EFP-NF treatment, for example as described at block 202 shown in fig. 2A.
  • subjects that were exposed to a traumatic event that lead to a diagnosis of a stress disorder are selected for the EFP- NF treatment.
  • Inclusion and exclusion in some embodiments of the invention and in the study participants were screened (and excluded) for the presence of DSM axis-I disorders (using SCID). In some embodiments of the invention and in the study, participants who are exhibiting PTSD symptoms according to CAPS were included. In some embodiments of the invention, the methods that are used for the evaluation of subjects during the experiment are used as part of the subject evaluation at block 204 shown in fig. 2A.
  • TAU Treatment as usual
  • subject assessment is performed as described in time point 1 - pre-treatment:
  • the first time point (TP1) baseline assessments was performed in two to three sessions and included the clinical evaluation, psychological questionnaires and fMRI scan.
  • Training phase is an example to the EFP-NF training performed at block 206 in fig. 2A, in some embodiments of the invention.
  • Training phase Each participant (in the two test groups) received 15 NF sessions in a duration of 13 weeks (two sessions per week in the first two weeks followed by one weekly session). The number of sessions is similar to the custom duration and or session amounts of common PTSD intervention such as CPT (Resick & Schnicke, 1993) and PE (Rauch et ah, 2009) that include exposure.
  • CPT Resick & Schnicke, 1993
  • PE Raster et ah, 2009
  • the intervention protocol for the amy-EFP-NF- neutral group included two types of interfaces in an interleaved manner: the first session will use the auditory interface; the second session will use the Waiting Room scenario interface (also described above) and so on until the last session in the intervention period.
  • the protocol for the amy- EFP-NF-trauma group was similar in the first session and then gradually included the traumatic challenge NF.
  • the participants were trained in NF sessions identical to those of the neutral group.
  • each scripted event was processed to an audio file of at least 30 seconds, for example a three-minute audio file, optionally recorded in a male voice, narrating the event in present-time and second-person (i.e. "you are driving your car... ").
  • the feedback indicating the EFP signal was the volume of the trauma-recording. That is, a successful reduction of EFP signal reduced the volume of the trauma recording. Participants that did not succeed in down regulating their EFP signal (with the neutral context) immediately after listening to the trauma-recording tried again in the following NF-N session.
  • each NF practice session consisted of 5 blocks of 3 minutes of NF. Following each block the staff member reviewed with the participant the results of the previous block and asked about the strategies he or she used and their subjective feeling during the block. The last three sessions included two additional "transfer" blocks at the beginning of the session.
  • Fig. 7 describes an NF session in a training protocol, according to some exemplary embodiments of the invention and as performed in the experiment, which comprises sessions with auditory NF (blue boxes 702), waiting room NF (green 704) and Trauma NF (purple 706).
  • the figure describes the order of each of the sessions in a Trauma-EFP-NF protocol and in a Neutral EFP-NF protocol.
  • Fig. 8 describes a NF with a multimodal interface: audiovisual animated scenario of a Waiting Room, for example as performed at blocks 108, 206, and 226 in figs. 1, 2A, and 2B respectively.
  • Fig. 9 describes a NF with a single modal auditory interface, for example as performed at blocks 108, 206, and 226 in figs. 1, 2A, and 2B respectively.
  • Fig. 10 describes a NF with gradual exposure, for example as performed at blocks 108, 212, and 228 in figs. 1, 2A, and 2B respectively.
  • Fig. 11 describes changes in EFP signal in time, while the subject is exposed to a detailed account of the traumatic event.
  • the scenario details contextual information (date, weather, who was there and so on) as well as the emotional, physical and cognitive experience of the patient and the manner in which it changes as the event unfolds.
  • Figs. 12A-12G demonstrate that a patient is able to down regulate EFP signal more so as the sessions progress and that this down regulation is evident even in the face of intense emotional challenge caused by the "peaks" in the trauma script.
  • a subject modulates an EFP signal while exposed to a scenario having sections that describe a "hot spot", for example a focal point of a specific trauma (yellow sections).
  • Fig. 13 demonstrates significant learning (i.e. amygdala EFP down regulation) throughout training sessions. Patients were successful at down regulation their amygdala (EFP) activity after 13 weeks of training. As shown in the graph the EFP signal is reduced between week 1 and week 13 (week 1 + 2 - two sessions a week, week 3-13 - one session a week, in total: 15 sessions in 13 weeks.
  • EFP amygdala
  • Figs. 14A and 14B demonstrate NF learning per treatment type, neutral vs exposure).
  • Fig. 14A demonstrates overall means while Fig. 14B shows variability in individual scores.
  • These graphs show that patients that trained in a neutral context were successful at down regulating their EFP signal from the first part of the trial to the second part of the trial.
  • patients in the exposure group showed a larger reduction of EFP signal during exposure sessions, compared to neutral context sessions.
  • This figure shows that training EFP in an individual trauma context has an additive effect over neutral context training.
  • Fig. 15 demonstrates changes in CAPS 5 total score between the different groups of the experiment.
  • CAPS clinically administered PTSD scale
  • CAPS is an established and common structured clinical interview assessing for PTSD symptom severity.
  • patients who received EFP training demonstrated a significant reduction in their CAPS scores, compared to patients who were not trained. This reduction is larger for patients in the exposure group.
  • changes in CAPS 5 or other clinically administered PTSD scales are used to evaluate a condition of a subject following the EFP-NF training.
  • Figs 16 A, 16B and 16C show individual CAPS results of patients in the neural context group (Fig. 16A) and the exposure group (Fig. 16B).
  • Fig. 16C shows the percentage of participants who showed a reduction of more than 5 points in CAPS scores following intervention. This shows that the majority of patients in the exposure group (75%) had a meaningful reduction of CAPS scores following intervention.
  • Fig. 17 describes changes in CAPS 5 subscales between the different groups. These subscales separately assess for PTSD symptom clusters: avoidance, Intrusion, Arousal and Cognitive and emotional alterations. In some embodiments, changes in CAPS 5 subscales are used to evaluate a condition or status of a subject following the EFP-NF.
  • Fig. 18 describes changes in PCL score (self-report) between the different groups.
  • PCL is an established and commonly used self-report measure that assesses PTSD symptoms.
  • EFP groups Neuronal group and Exposure group
  • TAU group Treatment group
  • This reduction in PTSD scores was preserved 3 and 6 months following the intervention.
  • Fig. 19 describes changes in fMRI measures between the different groups before (left column -annotated as “pre”) and after (right column- annotated as“post”) the intervention.
  • On the left is the first fMRI measure of the patients.
  • On the right is their learning in real time fMRI on the post intervention session (i.e. the delta of the second and first cycles of that session.
  • This figure demonstrates that patients who trained using the amygdala EFP were also successful at down regulating their BOLD amygdala activity following EEG training sessions, compared to participants who did not train using the EFP (Treatment as usual (TAU) group that did not receive NF training).
  • TAU Treatment as usual
  • Fig. 20 demonstrates a correlation between EFP training and subsequent BOLD activation during real-time fMRI neurofeedback. This positive correlation demonstrates that participants who were very successful at down regulating their EFP signal during training sessions (i.e. overall best performance session) were also better at down regulating their amygdala BOLD signal during real time neurofeedback following intervention. Fig. 20 shows that a change in EFP-NF is correlated with best change in EFP-NF (disregarding number of EFP-NF sessions).
  • the validation experiment was directed to study modulation of processes underlying mental disorders via Neurofeedback Technologies fMRI Informed EEG as a Reliable neurofeedback probe for Limbic Modulation in PTSD.
  • At least one of the clinical outcome measures, the scales and the questionnaires described above are also used for assessment of a PTSD patient prior to training, for example as described at block 204 in fig. 2A, and at blocks 250, 252 and 254 in fig. 2G.
  • the intervention phase included 15 training sessions, starting twice weekly for two weeks and then once a week (total of 13 weeks). Each session lasted approximately 40 minutes including preparation time. Patients were seated in a quiet room in front of a computer screen wearing headphones. The first 5 sessions were identical for both groups and employed two types of feedback interfaces in an interleaved manner: a neutral auditory interface and a multimodal scenario interface on the following session.
  • the auditory interface was a jazz music piece with no lyrics while the multimodal animated scenario interface depicted a virtual hospital waiting room including characters sitting down or walking around and approaching a receptionist (see Supplementary material for detailed interface description).
  • the auditory sessions included five consecutive training blocks each for three-minutes.
  • the volume of sound could increase or decrease as a function of AmygEFP signal power (in units of lOdB each).
  • the multimodal scenario session type also included five consecutive blocks, each consisting of one- minute active baseline (unrest level of the room was set to 75% and not affected by participant modulation), three-minute NF during which patients trained to modulate their brain signal and received feedback by means of the room's scenario (for further details see Multimodal animated scenario online calculation in Supplementary material). Patients were guided to reduce the auditory tone or relax the animated scenario by using a variety of self-generated mental strategies.
  • each NF session began with a three-minute rest recording of baseline AmygEFP signal, followed by five three-minute training blocks with either auditory or multimodal feedback interface (fig. 21B).
  • Each training block concluded with patient debriefing on the techniques they employed and a graphic display depicting their AmygEFP activity throughout the block (i.e. NF success).
  • the procedure for Trauma-NF group was identical to that of the Neutral-NF group in the first sessions until they reached the criteria to begin trauma-narrative NF (around session 7-8, see Trauma-NF criteria in Supplementary).
  • the feedback indicating AmygEFP signal was the volume of the trauma-narrative recording.
  • AmygEFP signal reduced the volume of the trauma-narrative.
  • Each session began with a three-minute rest recording of baseline AmygEFP signal, followed by one block of neutral auditory NF and then three blocks of NF with the recorded trauma-narrative. Debriefing and a graphical display of individual performance also followed each block.
  • AmygEFP amplitude was calculated on-line based on data recorder from the Pz channel using an in-house algorithm (22, 23). AmygEFP signal down-regulation was assessed by calculating a personal NF success index for each subject in each session (i.e. average of 5 NF blocks minus average of baseline blocks, divided by average baseline standard deviation) using the following formula:
  • a desired result would be lower AmygEFP values during regulation, than during baseline, resulting in a more negative NF success index (See supplementary for EEG data recording details).
  • R version 1.70, SPSS version 20 and STATISTICA version 10 were used for statistical analysis. Multiple comparisons correction was performed using FDR (£.05) for each hypothesis.
  • NNT Number Needed to Treat
  • Fig. 23A Total CAPS-5 (Clinician Administered PTSD Scale) score reflecting the severity of PTSD symptoms at TP1 and TP2 assessments for Trauma-NF, Neutral-NF and No-NF groups. Box represents first and third quartiles; the line represents the median while "x" represents the mean; whiskers depict minimum and maximum outside the first and third quartiles.
  • CAPS-5 Chronic Administered PTSD Scale
  • Amygdala activity was compared between patients in AmygEFP treatment arm and No-NF arm via a random-effects general linear model for amygdala signal change (regulate vs. watch, see fig. 24A and Supplementary 1.4 for details of model).
  • a 2- way repeated measures ANOVA was conducted with right amygdala beta values as a dependent variable, and Group (AmygEFP-NF, No-NF) and Time (TP1, TP2) as independent variables.
  • the current study presents a randomized controlled trial of a process-based NF intervention, aimed at amygdala down-regulation in a scalable manner in PTSD patients.
  • patients in the treatment arm demonstrated neuromodulation learning throughout NF sessions, with Trauma-NF showing a steeper improvement compared to Neutral-NF.
  • patients in treatment arm showed clinical improvements, compared to No-NF arm, as indicated by decreased CAPS-5 and PCL measures following the intervention; Trauma-NF group showed the largest decrease. Intriguingly, follow up at 3 and 6 months of PCL point to further decrease in symptoms only in the treatment arm.
  • Results showed a large clinical effect for chronic PTSD; total CAPS-5 score change showed a large effect size in the Trauma-NF group (Cohen's D 1.229; Hedges's g 0.828), a medium effect size in the Neutral-NF group (Cohen's D 0.636; Hedges's g 0.4306) and a large effect size when considering the treatment arm together (Cohen's D 0.853; Hedges's g 0.591).
  • Clinical efficacy was driven by a large symptom reduction following treatment (Trauma-NF -35.13%, Neutral-NF -19.48%), compared to No-NF (-0.23%; Figure 3b).
  • the AmygEFP intervention showed similar clinical benefits to commonly used cognitive-behabioral therapies.
  • Traum-NF is due to combined treatments of NF and repeated expsoure to traumatic ccontent, in line with the known effect of exposure-based psychotherapies (21).
  • Trauma-NF did not follow common practice of prolonged expsoure therapy; it was a relatively low-dose (7 sessions), short duration (3-minute segments vs. 40-60min), and limited content (only a gist of the traumatic memory and not an extended narrative), and was also not self-generated.
  • PTSD has a high rate of comorbidity mainly with major depression, anxiety disorders and substance use disorders (40, 41).
  • AmygEFP-NF probes an underlying mechanism of the disorder; emotion regulation, which is relevant transdiagnostically.
  • Future studies could delineate clinical effects with regard to other processes underlying PTSD and comorbid pathologies; e.g. reward processing (through upregulation of mesolimbic circuit) or cognitive control (through upregulation of attention circuit), all associated with depression, substance abuse and/or PTSD.
  • PTSD patients successfully down-regulated their AmygEFP signal while exposed to individually tailored traumatic content.
  • a medium size effect for clinical improvement following AmygEFP-NF treatment in PTSD patients compared to No-NF controls.
  • the effect of clinical improvement was larger for patients trained with trauma-narrative as the feedback interface, supporting process-based NF approach.
  • target-engagement and generalizability were further demonstrated by showing that patients in treatments groups exhibited greater down-regulation of amygdala BOLD signal during rtfMRI, with a different interface, compared to No-NF.
  • Hayes JP, Hayes SM, Mikedis AM Quantitative meta-analysis of neural activity in posttraumatic stress disorder. Biol Mood Anxiety Disord 2012; 2:9
  • Admon R, Milad MR, Hendler T A causal model of post-traumatic stress disorder: disentangling predisposed from acquired neural abnormalities. Trends Cogn Sci 2013; 17:337-
  • fig. 24B depicting a CONSORT flow chart.
  • Drop-out rates by group were: 26.3% in the Neutral-NF, 25% in the Trauma-NF and 10% in the no-NF group.
  • One additional participant who was randomized to the Trauma-NF group did not meet the criteria described in 'Trauma-related NF interface and procedure' and was thus excluded from Trauma-NF group analyses.
  • the exclusion criteria included current pregnancy, major medical or neurological disorders, psychosis, major depression disorder, schizophrenia and serious suicidal ideations.
  • Patients who were currently in psychotherapy and/or were receiving pharmacological treatments were included in the study, on the condition that no change was made to their treatment plan in the last three months and in the time remaining to the completion of the study.
  • Table 1 depicts results of each of the clinical measures that were used to evaluate clinical change, by group, at four time points (TP1, TP2, 3 Months and 6 Months follow up). To examine differences in TP1 between groups one-way ANOVA was conducted with Group (Trauma-NF, Neutral-NF, No-NF) as independent variables.
  • the scenario features sounds of chatter and commotion of a busy emergency room.
  • the scenario can gradually change from a resting state (all the people are seated and the sound volume is low) to an agitated state (people coming up to the receptionist and loudly protesting) and back again.
  • the overall unrest level of the room is determined by the EFP signal power.
  • the ratio between characters sitting down and protesting at the counter is considered to be a two-state Boltzmann distribution, whose evolution is driven by a‘virtual temperature’ whose value is derived from the momentary value of the targeted signal power (AmygEFP).
  • the scenario uses the probability (P value) of a momentary signal value during regulate to be sampled under the previous attend distribution.
  • P value is used to determine the probability of virtual characters to be moving in the virtual room, with the character distribution updated accordingly.
  • a matching soundtrack recorded inside a real hospital complements the system output. Three alternative soundtracks with different agitation levels were produced and switched according to the signal value.
  • 75% of the characters congregate at the front desk while expressing their frustration through body and verbal language.
  • the system is implemented using the Unreal Development Kit game engine, which controls relevant animations (walking, sitting, standing and protesting), as well as their transitions for individual characters.
  • Exemplary Trauma-NF criteria in the experiment and in some embodiments of the invention Patients who succeed in lowering AmygEFP signal during training in three out of the last five sessions, or in four out of six total sessions, continued. Patients who were not successful continued to train in the neutral context for the remaining sessions.
  • patients in the trauma-NF group trained while receiving feedback with the context of their traumatic story.
  • the interview was edited and then recorded as a three-minute audio segment (second- person male voice in present tense). Following the interview patients trained again with a neutral NF interface. Patients who were successful at down regulation of their AmygEFP signal during this session continued on to train with the trauma- narrative feedback in the following sessions.
  • EEG data was acquired using the V-AmpTM EEG amplifier (Brain ProductsTM, Kunststoff
  • BrainCapTM electrode cap with sintered Ag/AgCI ring electrodes Fet- Minow ServicesTM, Herrsching-Breitburnn, Germany. Electrodes were positioned according to the standard 10/20 system. The reference electrode was between Fz and Cz. Raw EEG signal was sampled at 250Hz and recorded using Brain Vision RecorderTM software (Brain Products). The baseline on auditory sessions was the initial rest period and in the multimodal animation scenario the baseline was the active baseline blocks in each training cycle.
  • Slice scan time correction was performed using cubic-spline interpolation. Head motions were corrected by rigid body transformations, using three translations and three rotation parameters, and the middle image served as a reference volume. Trilinear interpolation was applied to detect head motions, and sine interpolation was used to correct them.
  • the temporal smoothing process included linear trend removal and usage of a high-pass filter of 1/128 Hz. Functional maps were manually co-registered to corresponding structural maps and, together, they were incorporated into 3D data sets through trilinear interpolation. The complete data set was transformed into Talairach space and spatially smoothed with an isotropic 6-mm full width at half-maximum Gaussian kernel.
  • the visual feedback interface consisted of a 2D unimodal flash-based graphic, with an animated figure skating on a road.
  • the NF paradigm included 5 conditions.
  • 'Global baseline' 54 sec.
  • 'Active baseline' condition 60 sec.
  • the skateboard rider was riding at an average fixed speed and the speedometer was not presented.
  • Patients were instructed to passively view the skateboard rider and to try not to engage in any mental activity other than watching.
  • B(t) is the right amygdala BOLD activity value at time point t
  • m(B_BL ) is the mean BOLD value during the previous 'Active baseline'. Values varied from -4 std. below baseline average to 4 std. above average. Next, each value was transferred into a speed scale using the following formula:
  • the interval in the NF screen is set to -2 to 2.
  • This process is aimed at enabling significant regulation in one run to result in further regulation in the following run. This makes the NF paradigm more challenging and dynamic and pushes towards maximizing regulation.
  • Figs. 2H-2K depict CAPS-5 subscales, in the experiment and in some embodiments.
  • Intrusion (fig. 2H), Avoidance (fig. 2J), Alterations in Cognition and Mood (fig. 21), and Arousal (fig. 2K).
  • Scores reflect change in severity of PTSD symptom subscales between TP1 and TP2 for Trauma- NF and Neutral-NF groups. Box represents first and third quartiles; the line represents the median while "x" represents the mean; whiskers depict minimum and maximum outside the first and third quartiles.
  • Figs. 26A and 26B describe secondary clinical outcomes. Scores reflect change in depression (fig. 26A) and anxiety (fig. 26B) symptom between TP1 and TP2 for Trauma-NF, Neutral-NF and No-NF groups. Box represents first and third quartiles; the line represents the median while "x" represents the mean; whiskers depict minimum and maximum outside the first and third quartiles
  • EEG electrodes It is expected that during the life of a patent maturing from this application many relevant EEG electrodes will be developed; the scope of the term EEG electrodes is intended to include all such new technologies a priori.
  • the term“about” means“within ⁇ 10 % of’.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • singular forms“a”,“an” and“the” include plural references unless the context clearly dictates otherwise.
  • the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as“from 1 to 6” should be considered to have specifically disclosed subranges such as“from 1 to 3”,“from 1 to 4”,“from 1 to 5”,“from 2 to 4”,“from 2 to 6”,“from 3 to 6”, etc.; as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • a numerical range is indicated herein (for example“10-15”,“10 to 15”, or any pair of numbers linked by these another such range indication), it is meant to include any number (fractional or integral) within the indicated range limits, including the range limits, unless the context clearly dictates otherwise.
  • the phrases“range/ranging/ranges between” a first indicate number and a second indicate number and“range/ranging/ranges from” a first indicate number “to”,“up to”,“until” or“through” (or another such range-indicating term) a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numbers therebetween.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • the term“treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

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Abstract

L'invention concerne un procédé d'entraînement d'un sujet diagnostiqué avec un trouble de stress provoqué par un traumatisme, comprenant : la sélection d'un défi supposé déclencher un symptôme du trouble de stress chez le sujet ; l'exposition du sujet au défi ; l'enregistrement des signaux électriques générés par le cerveau du sujet par au moins une électrode, conjointement avec l'exposition ; le traitement des signaux électriques enregistrés pour estimer un niveau d'activation d'au moins une région cérébrale spécifique ; la présentation d'au moins une indication du niveau d'activation estimé au sujet ; la répétition de l'enregistrement, du traitement et de la présentation.
EP19896188.0A 2018-12-09 2019-12-09 Entraînement contre des troubles de stress Pending EP3890603A4 (fr)

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