Depression treatment

Abstract

1. A method for training a predetermined subject population that is expected to experience or is experiencing at least one depressive symptom, comprising: selecting a subject population that is expected to experience or is experiencing at least one depressive symptom in the future; and training the selected subject population with a neurofeedback (NF) training protocol for increasing activity of a brain's positive emotional valence system, the training comprising: presenting sensory indicators to each subject of the selected subject population; instructing the subject to modify the presented sensory indicators by performing at least one specific activity; detecting an increase in the brain pleasure response in the subject; and providing the subject with a feedback signal indicative of the increase in the brain pleasure response during the presentation.

Description

[Technical field]

[0001] Some embodiments of the present invention relate to modulating activity in mesolimbic brain regions associated with the reward system, and more particularly, to modulating activity in mesolimbic brain regions associated with the brain's reward system.

[0002] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 63 / 319,349, filed March 13, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] Depression is one of the most common mental health problems worldwide (Kessler et al., 2009), causing significant functional impairment and resulting in huge economic costs (Baxter, Vos, Scott, Ferrari, & Whiteford, 2014; Ferrari et al., 2013). Moreover, depression is the second leading cause of disability, accounting for approximately 8% of the global disease burden (Ferrari et al., 2013). Therefore, there is a demand for the development of more efficient treatments. Summary of the Invention

[0004] The following describes some example embodiments of the invention (several examples of the invention are described herein, and an embodiment may include one or more of the example features or may include less than all of the example features):

[0005] Example 1 delivering a stimulus to the subject, the stimulus being selected to increase a pleasure response in the subject; detecting an increase in a pleasure response in the subject; modifying the stimulus in a manner selected to increase a pleasant feeling response in the subject; A neurofeedback method comprising:

[0006] Example 2 The method of Example 1, comprising repeating the delivery with a modified stimulus.

[0007] Example 3 The method of Example 1 or 2, wherein detecting comprises detecting an increase in activity of at least one mesolimbic brain region.

[0008] Example 4 The method of Example 3, wherein the at least one mesolimbic brain region comprises a brain region associated with a reward response in the subject.

[0009] Example 5 The method of Example 3 or 4, wherein the at least one mesolimbic brain region includes at least one of the ventral striatum (VS), the nucleus accumbens, the ventral tegmental area, the orbitofrontal cortex, and the insular cortex.

[0010] Example 6 The method of any one of Examples 1-5, further comprising recording electrical signals with at least one electrode positioned on the subject's head during detection and modification of the stimulation.

[0011] Example 7 The method of Example 6, wherein at least one electrode is placed at at least one of the following locations: C3, C4, Cz, FCZ, P3, Pz, and P4 locations of an extended 10-20 electroencephalogram (EEG) coordinate system.

[0012] Example 8 delivering a stimulus to the subject, the stimulus being selected to increase a pleasure response in the subject; Detecting a reduced pleasure response or an absence of a pleasure response in a subject; and modifying the delivery in response to the detection.

[0013] Example 9 The method of Example 8, wherein modifying the delivery comprises replacing the stimulus with a different stimulus.

[0014] Example 10 The method of Example 8, wherein modifying the delivery includes modifying at least one parameter of the stimulation.

[0015] Example 11 The method of example 10, wherein the at least one parameter includes at least one of an intensity of the stimulus, a duration of the stimulus, and a type of the stimulus.

[0016] Example 12 The method of any one of Examples 8-11, comprising delivering, based on the detection, an indication related to the subject's capacity to increase a pleasure response in response to the delivered stimulus.

[0017] Example 13 The method of any one of Examples 8-12, wherein the subject has been diagnosed with anhedonia.

[0018] Example 14 determining an activity level of at least one brain region; delivering a feedback signal to the subject indicating to the subject that the determined activity level has reached a target activation level; and providing the subject with an indication that a target activation level of at least one brain region is maintained for a predetermined period of time.

[0019] Example 15 instructing the subject to reach a target activation level of at least one brain region. The method of Example 14.

[0020] Example 16 instructing the subject to maintain a target activation level of at least one brain region for a predetermined period of time. The method according to example 14 or 15.

[0021] Example 17 delivering a stimulus to the subject, the stimulus being selected to increase a pleasure response in the subject; determining an activity level of at least one brain region during the delivery; and Detecting that the subject does not perceive an increased pleasure response; and and generating an indication in response to the detection. Neurofeedback methods.

[0022] Example 18 The neurofeedback method of Example 17, wherein the detection includes detecting using a p300 algorithm and / or EFP that the subject does not perceive an increased pleasure response.

[0023] Example 19 a patient interface configured to deliver at least one human-detectable indicator to a subject; A control unit, The control unit Memory, an EEG recording unit configured to receive electrical signals from one or more electrodes placed on the subject's head; and a control circuit; The control circuit includes: signaling a patient interface to deliver to the subject a stimulus stored in the memory selected to increase a pleasure response in the subject; Measure the EEG signal according to the electrical signal received by the EEG recording unit; detecting increased activity in at least one mesolimbic brain region indicative of an increased pleasure response in the subject using at least one algorithm and / or electrical fingerprint (EFP) stored in memory; modifying the memorized stimuli in a manner selected to increase the pleasant feeling response in the subject; configured to signal a patient interface to provide the modified stimulation to the subject; A system for providing neurofeedback therapy. Below are further examples of embodiments of the present invention (several examples of the present invention are described herein, and an embodiment may include one or more of the example features and / or less than all of the example features).

[0024] Example 1 selecting a subject population that is expected to experience or is experiencing at least one depressive symptom in the future; training the selected subject population with a neurofeedback (NF) training protocol to increase activity in the brain's positive emotional valence system; Training is presenting a sensory indicator to each subject of a selected subject population; instructing the subject to modify the presented sensory indicator by performing at least one specific activity; Detecting an increase in a brain pleasure response in the subject; providing the subject with a feedback signal indicative of an increase in brain pleasure response during the presentation; A method of training a given subject population who is expected to experience or is experiencing at least one depressive symptom.

[0025] Example 2 At least one depressive symptom includes depressed mood and / or anhedonia; The method described in Example 1.

[0026] Example 3 the at least one depressive symptom includes at least one of weight loss, weight gain, insomnia, hypersomnia, psychomotor agitation, psychomotor retardation, decreased energy, feelings of worthlessness, guilt, difficulty concentrating, suicidal thoughts and / or suicidal behaviors; The method according to example 1 or 2.

[0027] Example 4 Selection may include selecting a subject population that has a first degree relative previously diagnosed with major depression or selecting a subject population that is a first responder. The method according to any one of Examples 1 to 3.

[0028] Example 5 The selection includes selecting a subject population diagnosed with at least one of the following: post-traumatic stress disorder (PTSD), attention-deficit hyperactivity disorder (ADHD), substance-induced psychiatric disorder, chronic kidney disease (CKD), and / or premenstrual dysphoric disorder (PMDD); The method according to any one of Examples 1 to 3.

[0029] Example 6 Selection includes selecting a subject population at risk of developing peripartum depression or who has already been diagnosed with peripartum and / or postpartum depression; The method according to any one of Examples 1 to 3.

[0030] Example 7 The selection may include selecting a subject population at risk for developing seasonal affective disorder (SAD) or previously diagnosed with SAD. The method according to any one of Examples 1 to 3.

[0031] Example 8 Selecting includes selecting a subject population diagnosed with cancer; The method according to any one of Examples 1 to 3.

[0032] Example 9 The cancer includes pancreatic cancer and / or lung cancer. The method described in Example 8.

[0033] Example 10 the sensory indicator comprises a visual indicator and / or an audio indicator, and providing comprises providing a feedback signal by modifying the visual indicator and / or the audio indicator; The method according to any one of Examples 1 to 9.

[0034] Example 11 Providing includes providing a feedback signal by modifying a visual indicator and / or an auditory indicator in a manner selected to increase a brain pleasure response in the subject. The method of Example 10.

[0035] Example 12 repeating the presentation of the modified visual and / or auditory indicators; The method of Example 11.

[0036] Example 13 The sensory cue presented is selected to increase a pleasant response in the subject. The method according to any one of Examples 1 to 12.

[0037] Example 14 The detecting includes measuring EEG signals from one or more electrodes positioned on the subject's head during the presenting and during the detecting, and the detecting includes detecting an increase in a brain pleasure response based on the measured EEG signals. The method according to any one of Examples 1 to 13.

[0038] Example 15 The detecting includes detecting an increase in activity of at least one mesolimbic brain region. The method according to any one of Examples 1 to 14.

[0039] Example 16 At least one mesolimbic brain region includes a brain region associated with a reward response in the subject; The method of Example 15.

[0040] Example 17 the at least one mesolimbic brain region includes at least one of the subject's ventral striatum (VS), nucleus accumbens, ventral tegmental area, orbitofrontal cortex, and insular cortex; The method according to example 15 or 16.

[0041] Example 18 providing instructions to the subject to perform at least one specific activity if the subject experiences at least one depressive symptom in the future; The method according to any one of Examples 1 to 17.

[0042] Example 19 At least one specific activity includes a cognitive or mental activity selected to increase a brain pleasure response in the subject; The method according to any one of Examples 1 to 18.

[0043] Example 20 The training includes training the subject in two or more training sessions separated by at least 12 hours using the NF training protocol; The method according to any one of Examples 1 to 19.

[0044] Example 21 and further comprising modifying the presented sensory indicator or selecting the presented sensory indicator prior to presentation in response to the selected object. The method according to any one of Examples 1 to 20.

[0045] Example 22 delivering a stimulus to the subject, the stimulus being selected to elicit and / or increase a pleasure response in the subject's brain; detecting an increase in a pleasure response in the subject's brain; and modifying the stimulus in a manner selected to increase a hedonic response in the subject. Neurofeedback methods.

[0046] Example 23 repeating the delivery with a modified stimulus. The method of Example 22.

[0047] Example 24 The detecting includes detecting an increase in activity of at least one mesolimbic brain region. The method according to example 22 or 23.

[0048] Example 25 At least one mesolimbic brain region includes a brain region associated with a reward response in the subject; The method of Example 24.

[0049] Example 26 the at least one mesolimbic brain region includes at least one of the ventral striatum (VS), the nucleus accumbens, the ventral tegmental area, the orbitofrontal cortex, and the insular cortex; The method according to example 24 or 25.

[0050] Example 27 and recording electrical signals with at least one electrode positioned on the subject's head during delivery, detection, and modification of the stimulation. The method according to any one of Examples 22 to 26.

[0051] Example 28 At least one electrode is placed at at least one of the following locations on an extended 10-20 electroencephalogram (EEG) coordinate system: C3, C4, Cz, FCZ, P3, Pz, and P4; The method of Example 27.

[0052] Example 29 delivering a stimulus to the subject, the stimulus being selected to elicit and / or increase a pleasure response in the subject; Detecting a reduced pleasure response or an absence of a pleasure response in a subject; modifying the delivery in response to the detection; A neurofeedback method comprising:

[0053] Example 30 Modifying the delivery may include replacing the stimulus with a different stimulus. The method of Example 29.

[0054] Example 31 Modifying the delivery includes modifying at least one parameter of the stimulation. The method of Example 29.

[0055] Example 32 The at least one parameter includes at least one of an intensity of the stimulation, a duration of the stimulation, and a type of the stimulation. The method according to Example 31.

[0056] Example 33 and based on the detection, delivering an indication related to the subject's capacity to increase a pleasure response in response to the delivered stimulus. The method according to any one of Examples 29 to 32.

[0057] Example 34 The subject has been diagnosed with anhedonia, The method according to any one of Examples 29 to 33.

[0058] Example 35 determining an activity level of at least one brain region; delivering a feedback signal to the subject indicating to the subject that the determined activity level has reached a target activation level; providing a subject with an indication that a target activation level of at least one brain region is maintained for a predetermined period of time; A neurofeedback method comprising:

[0059] Example 36 instructing the subject to reach a target activation level of at least one brain region. The method of Example 35.

[0060] Example 37 instructing the subject to maintain a target activation level of at least one brain region for a predetermined period of time. The method according to example 35 or 36.

[0061] Example 38 delivering a stimulus to the subject, the stimulus being selected to elicit and / or increase a pleasure response in the subject; determining an activity level of at least one brain region during the delivery; and Detecting that the subject does not perceive an increased pleasure response; and generating an indicator in response to the detection; A neurofeedback method comprising:

[0062] Example 39 The detecting includes detecting, using a p300 algorithm, that the subject does not recognize an increased pleasure response. The neurofeedback method of Example 38.

[0063] Example 40 Selecting a population of patients diagnosed with severe depression; administering NF treatment to the population; Achieving a mean reduction of at least 3 points on the Snaith-Hamilton Pleasure Scale (SHAPS-C) in a selected population at least 5 weeks after administration; and 23. A method for treating a given patient population for severe depression comprising:

[0064] Example 41 administering includes training the selected population with NF treatment to increase a pleasure response in the brain and / or to increase activity of a positive emotional valence system in the brain upon exposure to at least one sensory indicator. The method of treatment described in Example 40.

[0065] Example 42 administering includes training the selected population with NF treatment to modulate activity of at least one mesolimbic brain region or at least one biomarker of the mesolimbic brain region upon exposure to at least one sensory indicator. The method of treatment according to Example 40 or 41.

[0066] Example 43 administering the NF treatment includes recording EEG signals from the selected population in response to at least one sensory indicator, extracting from the recorded EEG signals one or more signals selectively indicative of an activity level of at least one mesolimbic brain region or a biomarker of the mesolimbic brain region, and providing feedback to the population regarding the activity of the at least one mesolimbic brain region or the at least one biomarker based on the extracted signal or signals. The method of treatment described in Example 42.

[0067] Example 44 The NF treatment offered was functional magnetic resonance imaging (fMRI) neurofeedback therapy. The treatment method according to any one of Examples 40 to 42.

[0068] Example 45 Selecting a population of patients diagnosed with severe depression; administering NF treatment to the population; achieving a mean reduction of at least 7 points on the Hamilton Depression Rating Scale (HDRS) in a selected population at least 5 weeks after administration; 23. A method for treating a given patient population for severe depression comprising:

[0069] Example 46 administering includes training the selected population with NF treatment to increase a pleasure response in the brain and / or to increase activity of a positive emotional valence system in the brain upon exposure to at least one sensory indicator. The method of treatment described in Example 45.

[0070] Example 47 administering includes training the selected population with NF treatment to modulate activity of at least one mesolimbic brain region or at least one biomarker of the mesolimbic brain region upon exposure to at least one sensory indicator. The method of treatment according to Example 45 or 46.

[0071] Example 48 administering the NF treatment includes recording EEG signals from the selected population in response to at least one sensory indicator, extracting from the recorded EEG signals one or more signals selectively indicative of an activity level of at least one mesolimbic brain region or a biomarker of the mesolimbic brain region, and providing feedback to the population regarding the activity of the at least one mesolimbic brain region or the at least one biomarker based on the extracted signal or signals. The method of treatment described in Example 47.

[0072] Example 49 The NF treatment offered was functional magnetic resonance imaging (fMRI) neurofeedback therapy. The method of treatment according to any one of Examples 45 to 47.

[0073] Example 50 selecting a subject population that is currently experiencing or is expected to experience in the future at least one depressive symptom; presenting, to each subject of the selected subject population, a sensory indicator configured to indicate or elicit a pleasant sensation response in the subject's brain, using a user interface of the system; instructing the subject using a user interface to modify the presented sensory indication by performing at least one particular activity; measuring electrical signals from the subject's brain with a control circuit; detecting, by a control circuit, an increase in a brain pleasure response in the subject based on the measured electrical signal; During the presentation, providing the subject with a feedback signal by the user interface indicative of an increase in the brain pleasure response; A neurofeedback evaluation method comprising:

[0074] Example 51 Administered before and / or after neurofeedback training, A drug used to treat depression.

[0075] Example 52 The drug may belong to the family of selective serotonin reuptake inhibitors (SSRIs), or the family of serotonin-norepinephrine reuptake inhibitors (SNRIs), or the family of tricyclic and tetracyclic antidepressants, or the family of atypical antidepressants, or the family of N-methyl-D-aspartate (NMDA) antagonists, The agent described in Example 51.

[0076] Example 53 The drug is administered before and / or after the neurofeedback training; Neurofeedback training is presenting a sensory indicator configured to produce a pleasurable response in the subject's brain; Delivering instructions to modify the presented sensory indicator by performing at least one specified activity; Measuring electrical signals from the brain; Detecting an increase in the brain pleasure response based on the measured electrical signal; providing a feedback signal indicative of an increase in the brain pleasure response; The agent according to Example 51 or 52, comprising:

[0077] Example 54 a trainee interface configured to deliver at least one human-detectable indicator to a subject; A control unit, The control unit Memory, an EEG recording unit configured to receive electrical signals from one or more electrodes positioned on the subject's head; and a control circuit; The control circuit includes: signaling the trainee interface to deliver to the subject a sensory cue stored in the memory selected to increase a pleasant feeling response in the subject's brain; Measure the EEG signal according to the electrical signal received by the EEG recording unit; Detecting an increase in activity of at least one mesolimbic brain region indicative of an increased pleasure response in the subject using at least one algorithm stored in memory based on the measured EEG signal; modifying the sensory indicators in a manner selected to increase a pleasant feeling response in the subject; signaling a trainee interface to deliver the modified sensory cue to the subject; A system for providing neurofeedback (NF) training.

[0078] Example 55 the control circuitry is configured to deliver the human detectable indication along with instructions to modify the sensory indication to the subject using the trainee interface; The system of Example 54.

[0079] Example 56 The sensory indicators include visual and / or auditory interfaces; The system of example 54 or 55.

[0080] Example 57 the detected increase in activity in at least one mesolimbic brain region is a relative increase in activity as compared to one or more other brain regions; The system described in any one of Examples 54 to 56.

[0081] Example 58 the at least one mesolimbic brain region includes at least one of the subject's ventral striatum (VS), nucleus accumbens, ventral tegmental area, orbitofrontal cortex, and insular cortex; The system described in any one of Examples 54 to 57.

[0082] Example 59 The control circuit includes: determining an activity level of at least one mesolimbic brain region based on the measured EEG signal; configured to signal the trainee interface to deliver at least one feedback signal to the subject to indicate to the subject that the determined activity level has reached the target activation level and that the target activation level has been maintained for a predetermined period of time. The system described in any one of Examples 54 to 58.

[0083] Example 60 the control circuitry is configured to deliver to the subject, using the trainee interface, a human-detectable indication along with instructions to the subject to modify the sensory indication or to reach a target activation level of at least one mesolimbic brain region; The system of Example 59.

[0084] Example 61 the control circuitry is configured to deliver to the subject, using the trainee interface, a human-detectable indication along with instructions to the subject to modify the sensory indication or to reach a target activation level of at least one mesolimbic brain region; The system of example 59 or 60.

[0085] Example 62 a supervisor interface configured to deliver a human-detectable indicator to a supervisor of the NF training, the control circuitry being configured to deliver the human-detectable indicator to the supervisor using the supervisor interface along with information regarding a change in activity of at least one mesolimbic brain region relative to a threshold or target activity level during measurement of the EEG signals and / or following the NF training; The system described in any one of Examples 54 to 61.

[0086] Example 63 At least one algorithm includes a model that correlates EEG signals recorded from a particular set of electrodes having a particular frequency range or a plurality of particular frequency ranges recorded during a particular time window with fMRI-BOLD activity of at least one mesolimbic brain region, and the control circuitry is configured to use the model to identify a subset of EEG signals indicative of activity of the at least one mesolimbic brain region in the measured EEG signals and to detect increased activity based on the identified subset of EEG signals. The system of any one of Examples 54 to 62.

[0087] Example 64 a trainee interface configured to deliver at least one human-detectable indicator to a subject; A control unit, The control unit Memory, an EEG recording unit configured to receive electrical signals from one or more electrodes positioned on the subject's head; and a control circuit; The control circuit includes: signaling the trainee interface to deliver to the subject a sensory cue stored in the memory selected to increase a pleasant feeling response in the subject's brain; Measure the EEG signal according to the electrical signal received by the EEG recording unit; detecting an activity level of at least one mesolimbic brain region indicative of a level of a pleasure response in the subject to a target activity level using at least one algorithm stored in memory based on the measured EEG signal; If the detected activity level is lower than the target activity level, decreasing the target activity level; and repeating the signaling, measuring, and detecting using the reduced target activity level. A system for providing neurofeedback (NF) training.

[0088] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this invention belongs.Although methods and materials similar or equivalent to those described herein can be used to practice or test embodiments of this invention, exemplary methods and / or materials are described below.In case of conflict, the patent specification, including definitions, shall prevail.In addition, the materials, methods, and examples are merely illustrative and are not necessarily intended to be limiting.

[0089] As will be appreciated by those skilled in the art, some embodiments of the present invention may be embodied as a system, a method, or a computer program product. Thus, some embodiments of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, microcode, etc.), or an embodiment combining software and hardware aspects, generally referred to herein as a "circuit," "module," or "system." Furthermore, some embodiments of the present invention may take the form of a computer program product embodied in one or more computer readable mediums having computer readable program code embodied on the medium. Implementation of the method and / or system of some embodiments of the present invention may involve performing and / or completing selected tasks manually, automatically, or a combination thereof. Furthermore, some selected tasks may be performed by hardware, by software, or by firmware, and / or by a combination thereof (e.g., using an operating system), depending on the actual facility and equipment of some embodiments of the method and / or system of the present invention.

[0090] For example, hardware for performing selected tasks according to some embodiments of the present invention can be implemented as a chip or circuit. As software, selected tasks according to some embodiments of the present invention can be implemented as software instructions executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to some exemplary embodiments of the methods and / or systems described herein are performed by a data processor (e.g., a computing platform for executing instructions). Optionally, the data processor includes a volatile memory for storing instructions and / or data, and / or a non-volatile storage device, such as a magnetic hard disk and / or peripheral bubble media for storing instructions and / or data. Optionally, a network connection is also provided. A display and / or a user input device such as a keyboard or mouse are also optionally provided.

[0091] In some embodiments of the present invention, any combination of one or more computer readable media may be utilized. The computer readable medium may be a computer readable signal medium or a computer readable storage medium. The computer readable storage medium may be, for example, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination thereof. More specific examples (non-exhaustive list) of computer readable storage media may include an electrical connection having one or more conductors, a portable floppy disk, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable ROM (EPROM, i.e., flash memory), an optical fiber, a portable compact disk ROM (CD-ROM), an optical storage device, an electromagnetic storage device, or any suitable combination thereof. In this specification, a computer readable storage medium may be any tangible medium that can contain or store a program that can be used by or combined with an instruction execution system, an instruction execution device, or an instruction execution device.

[0092] A computer-readable signal medium may include a propagated data signal in which computer-readable program code is embodied, either in baseband or as part of a carrier wave. Such a propagated signal may take a variety of forms, including, but not limited to, electromagnetic or optical forms, or any suitable combination thereof. A computer-readable signal medium may be any computer-readable medium that is not a computer-readable storage medium, but is capable of transmitting, propagating, or carrying a program for use by or in combination with an instruction execution system, instruction execution device, or instruction execution apparatus.

[0093] The program code embodied in the computer readable medium and / or data used by the computer readable medium may be transmitted using any suitable medium, including but not limited to wireless, wired, fiber optic cable, RF, etc., or any suitable combination thereof.

[0094] Computer programs for carrying out the operations of some embodiments of the present invention may be written in any combination of one or more programming languages, including object-oriented programming languages ​​such as Java, Smalltalk, C++, and conventional procedural languages ​​such as the "C" programming language or similar programming languages. The program code may run entirely on the user's computer, partially on the user's computer, as a standalone software package, partially on the user's computer and partially on a remote computer, or entirely on a remote computer or server. In scenarios running on a remote computer, the remote computer may be connected to the user's computer by any type of network, including a local area network (LAN) or a wide area network (WAN), or may be connected to an external computer (e.g., via the Internet using an Internet Service Provider).

[0095] Some embodiments of the present invention are described below with reference to flowcharts and / or block diagrams of methods, apparatus (systems) and computer program products according to the embodiments. It will be understood that each block of the flowcharts and / or each block of the block diagrams, and combinations of blocks in the flowcharts and / or block diagrams, can be implemented by computer program instructions. These computer program instructions can be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus, and executed by the processor of the computer or other programmable data processing apparatus to generate means for performing the functions / operations illustrated in the flowcharts and / or block diagrams.

[0096] Computer program instructions may also be stored on a computer-readable medium that may direct a computer, other programmable data processing apparatus, or other specific functional device to produce an article of manufacture that includes instructions that implement the functions / acts identified in one or more blocks of the flowchart illustrations and / or block diagrams.

[0097] Also, the computer program instructions can be loaded into a computer, other programmable data processing apparatus, or other device, and executed on the computer or other programmable apparatus to generate a computer-implemented process by causing the computer, other programmable apparatus, or other device to perform a series of operational steps to provide a process for performing the functions / operations specified in the flowchart and / or block diagram blocks.

[0098] Some of the methods described herein are generally designed for computational use only and may not be feasible or practical for purely manual performance by a human expert. A human expert wishing to manually perform a similar task, such as determining activity levels of brain regions, might be expected to use an entirely different method, such as utilizing specialized knowledge and / or the pattern recognition capabilities of the human brain, that is much more efficient than manually performing the steps of the methods described herein.

[0099] Some embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings and images. It is emphasized that the details shown below, with particular reference to the drawings, are for the purposes of illustration and for the purpose of detailed description of embodiments of the present invention. Similarly, from viewing the description together with the drawings, it will become apparent to those skilled in the art how embodiments of the present invention may be practiced. [Brief description of the drawings]

[0100] [Figure 1A] FIG. 1 is a schematic diagram of the different components of the positive emotional valence system. [Figure 1B] 1 is a flowchart of a general process for training a selected subject or a selected subject population, according to some exemplary embodiments of the present invention. [Figure 1C] 1 is a flowchart of a general process for treating a subject diagnosed with anhedonia, according to some exemplary embodiments of the present invention. [Figure 1D] 13 is a graph illustrating change in a subject's hedonic response over time, according to some exemplary embodiments of the present invention. [Figure 1E] 13 is a graph illustrating change in a subject's hedonic response over time, according to some exemplary embodiments of the present invention. [Figure 1F] 13 is a graph illustrating change in a subject's hedonic response over time, according to some exemplary embodiments of the present invention. [Figure 1G]11 is a graph illustrating changes in feedback over time, according to some exemplary embodiments of the present invention. [Figure 2A] 1 is a flow chart of a treatment program according to some exemplary embodiments of the present invention. [Figure 2B] 1 is a flowchart of a treatment session, according to some exemplary embodiments of the present invention. [Figure 2C] 1 is a flow chart of an NF cycle, according to some exemplary embodiments of the invention. [Diagram 3] FIG. 1 is a block diagram of a system for delivery of therapy, according to some exemplary embodiments of the present invention. [Figure 4] 4 is a flow chart illustrating system activity according to some exemplary embodiments of the present invention. [Figure 5A] 1 is a flowchart illustrating system activity divided into NF session blocks in accordance with some exemplary embodiments of the invention. [Figure 5B] 1 is a flowchart illustrating system activity divided into NF session blocks in accordance with some exemplary embodiments of the invention. [Figure 6A] 13A-13C are images of a patient visual interface presenting a schematic diagram of the brain, according to some exemplary embodiments of the present invention. [Figure 6B] 13A-13C are images of a patient visual interface presenting a schematic diagram of the brain, according to some exemplary embodiments of the present invention. [Figure 6C] 13A-13C are images of a patient visual interface presenting a schematic diagram of the brain, according to some exemplary embodiments of the present invention. [Figure 6D] 13A-13C are images of a patient visual interface presenting a schematic diagram of the brain, according to some exemplary embodiments of the present invention. [Figure 6E] 13A-13C are images of a patient visual interface presenting a schematic diagram of the brain, according to some exemplary embodiments of the present invention. [Figure 6F]13A-13C are images of a patient visual interface presenting a schematic diagram of the brain, according to some exemplary embodiments of the present invention. [Figure 7A] 11A-11C are images of different patient visual interfaces, according to some exemplary embodiments of the present invention. [Figure 7B] 11A-11C are images of different patient visual interfaces, according to some exemplary embodiments of the present invention. [Figure 7C] 11A-11C are images of different patient visual interfaces, according to some exemplary embodiments of the present invention. [Figure 7D] 11A-11C are images of different patient visual interfaces, according to some exemplary embodiments of the present invention. [Figure 8A] 11 is a graph presented on a supervisor interface of a system according to some exemplary embodiments of the present invention. [Figure 8B] 11 is a graph presented on a supervisor interface of a system according to some exemplary embodiments of the present invention. [Figure 9A] 1 is a graph showing the change in scores on the SHAPS-C rating scale measured during the study in a group of MDD patients receiving NF treatment. [Figure 9B] 1 is a graph showing the change in scores on the HDRS rating scale measured during the study in a group of MDD patients receiving NF treatment. [Figure 9C] 1 is a graph showing the change in scores on the CGI-I rating scale measured during the study in a group of MDD patients receiving NF treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0101] Some embodiments of the present invention relate to modulating activity of at least one mesolimbic brain region, and more particularly, to modulating activity of at least one mesolimbic brain region associated with the brain's reward system.

[0102] overview A broad aspect of some embodiments relates to providing neurofeedback (NF) training (also referred to herein as NF treatment) to treat dysfunction of the positive valence system and / or to enhance activity of the positive valence system. In some embodiments, the NF training is provided to a subject diagnosed with, for example, depression, e.g., major depressive disorder (MDD) and / or anhedonia. Alternatively or additionally, the NF training, or a portion thereof, is used to treat a subject diagnosed with a substance use disorder (SUD).

[0103] Research in mental health disorders has identified two systems underlying anxiety and depression disorders: the positive valence system and the negative valence system. The negative valence system is related to threat sensitivity, e.g., how responsive one is to immediate, remote, or persistent threats, losses, and the removal of rewards (Kozak & Cuthbert, 2016). As shown in Figure 1A, the positive valence system 104 is related to responsiveness to rewards (Kozak & Cuthbert, 2016). More specifically, the positive valence system 104 can be decomposed into reward prediction 106, consumption 108, and learning 110. That is, deficits and gains can be experienced in predicting or expecting future positive outcomes (reward prediction 106), in recognizing or appreciating positive experiences (reward consumption 108), and in learning how to obtain future rewards from previous reward acquisition (reward learning 110). Reward is defined as a positive, pleasurable, or desirable experience, outcome, or object.

[0104] Another component of the positive emotional valence system that is altered in MDD patients is the persistent response to reward.112 Abnormal persistent responses to reward have been proposed to be a major contributing factor to depressive symptoms, particularly anhedonia (Tomarken & Keener, 1998).

[0105] In clinical research, anhedonia is a term used to describe a deficiency or dysfunction in any part of the positive emotional valence system (Thomsen, Whybrow, & Kringelbach, 2015). However, clinicians have traditionally used the term to mean a loss of interest or pleasure that is a core symptom of depression (Thomsen et al., 2015). It continues to be used as a primary diagnostic criterion in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (American Psychiatric Association, 2013), the clinical handbook used by clinicians in the United States. The DSM-5 (American Psychiatric Association, 2013) defines major depressive disorder by (a) a 2-week period of low mood or loss of interest or pleasure in daily activities (i.e., anhedonia) that represents a change from baseline and results in significant functional impairment, and (b) the presence of three or four additional symptoms (i.e., appetite changes, sleep problems, psychomotor agitation / inhibition, loss of energy, poor concentration, feelings of worthlessness, or suicidal thoughts) (Dour et al., 2019, "Psychological Treatments for Anhedonia: Reward Anticipation, Consumption, and Learning").

[0106] According to some exemplary embodiments, NF therapy, also referred to herein as neurofeedback training, is neurofeedback with functional magnetic resonance imaging (fMRI). Alternatively, NF therapy is provided by recording EEG signals from the subject's brain, for example, without functional magnetic resonance imaging, during the provision of NF therapy.

[0107] One aspect of some embodiments relates to training at least one selected subject or a group of subjects to increase the activity of the positive valence system of the brain.In some embodiments, at least one selected subject or a group of subjects is expected to experience at least one depressive symptom in the future, for example, at least one day, at least one week, at least one month, at least one year, or any intermediate, shorter or longer period from the end of training.In some embodiments, at least one selected subject or a group of subjects is trained to increase the activity of the positive valence system of the brain by increasing the pleasant response in the brain.

[0108] According to some embodiments, the training is a neurofeedback (NF) training, which includes presenting a sensory cue to the trainee and instructing the trainee to modify the presented sensory cue by, optionally, performing at least one specific activity. In some embodiments, the sensory cue is selected to increase an hedonic response in the trainee's brain and / or is an indicator of a brain hedonic response in the trainee. In some embodiments, the sensory cue includes a visual cue and / or an auditory cue provided to the trainee. Optionally, the sensory cue is a stimulus.

[0109] According to some embodiments, the NF training further includes, after any instruction, detecting an increase in the brain pleasure response and providing the trainee with a feedback signal, e.g., a human detectable indicator, indicative of the increase in the brain pleasure response. In some embodiments, the feedback signal is provided to the trainee during the presentation. In some embodiments, the feedback signal is provided by modifying the sensory indicator presented to the trainee. In some embodiments, the feedback signal is provided to the trainee by modifying the sensory indicator in a manner selected to increase the subject's brain pleasure response (e.g., by modifying the sensory indicator to include additional pleasant visual and / or auditory indicators or cues).

[0110] According to some embodiments, NF training is a tool to teach subjects how to increase the pleasure response in their brain by performing specific, optionally personalized activities (e.g., specific mental or cognitive tasks). The subject will be able to apply these specific mental or cognitive tasks in the future when they experience or encounter at least one depressive symptom.

[0111] According to some embodiments, the NF training described herein is provided to a predefined selected population of subjects who are expected to experience at least one depressive symptom in the future. In some embodiments, the NF training is provided using the systems and / or devices described herein. In some embodiments, the at least one symptom is a depressive symptom according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; American Psychiatric Association, 2013).

[0112] According to some embodiments, the at least one symptom comprises depressed mood and / or anhedonia. Alternatively or additionally, the at least one depressive symptom comprises at least one of weight loss, weight gain, insomnia, hypersomnia, psychomotor agitation, psychomotor retardation, reduced energy, feelings of worthlessness, guilt, difficulty concentrating, suicidal thoughts and / or suicidal behaviors.

[0113] According to some embodiments, the predetermined selected population includes subjects who have a relative, e.g., a first degree relative, who has previously been diagnosed with depression or severe depression. In some embodiments, the predetermined selected population includes subjects who are first responders, e.g., those who arrive first to the scene of an emergency, such as an accident, disaster, medical emergency, fire, crime, or terrorist attack, to provide assistance or problem solving.

[0114] According to some embodiments, the predetermined selected population includes subjects diagnosed with at least one of post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), substance-induced psychiatric disorder, chronic kidney disease (CKD), and / or premenstrual dysphoric disorder (PMDD). In some embodiments, the predetermined selected population includes subjects at risk of developing peripartum depression, or subjects who have already been diagnosed with peripartum depression, or subjects who have previously been diagnosed with peripartum depression, for example male or female subjects who have been diagnosed with peripartum depression in a previous pregnancy.

[0115] According to some embodiments, the predetermined selected population includes subjects at risk of developing seasonal affective disorder (SAD) or subjects who have previously been diagnosed with or experienced SAD.

[0116] According to some embodiments, the predetermined selected population includes, for example, subjects diagnosed with pancreatic or lung cancer.

[0117] According to some embodiments, the predetermined selected population includes subjects diagnosed with chronic kidney disease (CKD).

[0118] An aspect of some embodiments relates to delivering a stimulus to a subject that is selected to increase a reward response in the subject's brain. In some embodiments, the stimulus is modified in a manner selected to further increase the reward response in the subject. In some embodiments, the delivered stimulus increases the reward response by increasing the pleasant response in the subject's brain. For example, it increases the release of dopamine in one or more brain regions of the reward system. In some embodiments, the stimulus is delivered via a patient interface, for example, an interface that includes different scenarios, auditory, visual, tactile, or any human-detectable sensory indicator.

[0119] According to some embodiments, after and / or during delivery of the response, an increase in the pleasant response is detected in the subject. In some embodiments, the increase in pleasant response is detected by detecting the modulation of the activity of at least one brain region, for example, the mesolimbic brain region.

[0120] According to some embodiments, detecting the modulation of activity and / or determining the activity of at least one brain region is performed based on recording of electrical signals, for example from at least one electrode of an electrode array positioned on the subject's head. In some embodiments, the at least one electrode or electrode array is configured to measure EEG signals. Alternatively, electrical signals are recorded directly from at least one brain region using implanted electrodes. In some embodiments, electrodes implanted in at least one mesolimbic region, for example the VS, allow recording of electrical signals, for example as described in Delaloye S. et. al., 2014 "Deep Brain Stimulation in the Treatment of Depression".

[0121] Alternatively or additionally, the increase in the pleasure response is detected by detecting a physiological response of the subject indicative of the pleasure response, for example, by detecting a smile or facial change of the subject, optionally using an optical sensor or a camera.Alternatively or additionally, the pleasure response is detected using at least one sensor that detects a change in at least one of skin conductance, heart rate, and muscle function.

[0122] According to some embodiments, modulating the activity and / or determining the activity of at least one brain region is performed based on EEG signals, for example using at least one Electrical Fingerprint (EFP) of at least one mesolimbic brain region. In some embodiments, the EFP is based on EEG signals that correlate with FMRI-BOLD activity of at least one mesolimbic brain region (e.g., VS).

[0123] According to some embodiments, EFP is a model that links EEG measurement to, for example, FMRI-BOLD signal that shows selective activation of VS.In some embodiments, the model has a coefficient matrix of at least 10 coefficients that correspond to frequency bands, electrodes, and one or more time windows.In some embodiments, the activity of at least one brain region or the modulation of the activity of at least one brain region is performed, for example, as described in WO2021260697A1 or WO2012104853A2, which are incorporated herein by reference in their entirety.

[0124] According to some embodiments, the EFP model is applied to EEG signals recorded from at least one electrode or from an electrode array, in some embodiments, changes in the EFP indicate changes in activity of at least one brain region.

[0125] According to some embodiments, the method for neurofeedback evaluation includes selecting a subject population currently experiencing at least one depressive symptom or expected to experience at least one depressive symptom in the future, for example as described above. In some embodiments, the method further includes presenting each subject of the selected subject population with a sensory indication configured to indicate or induce a pleasant feeling response in the subject's brain, optionally using a user interface of the system, and instructing the subject to modify the presented sensory indication by performing at least one specific activity, such as, for example, a cognitive or mental activity, optionally using the user interface. In some embodiments, the method further includes measuring, optionally by the control circuitry, an electrical signal from the subject's brain, and detecting, optionally by the control circuitry, an increase in the brain pleasant feeling response in the subject based on the measured electrical signal. In some embodiments, while presenting the sensory indication as described above, a feedback signal indicating an increase in the brain pleasant feeling response is generated and optionally delivered to the subject by the user interface, for example as described above.

[0126] An aspect of some embodiments relates to providing an inhibitory signal to a subject, e.g., reducing the activity level of at least one brain region. In some embodiments, the inhibitory signal is delivered upon detection of increased activity of at least one mesolimbic brain region in a subject diagnosed with mania.

[0127] According to some embodiments, the treatments and methods described herein are used to condition a patient to enable the patient to implement one or more of the strategies, which may include one or more of the patient interfaces, for example, while the patient is at home or outside of a clinic.

[0128] According to some embodiments, the systems described herein may be part of an overall treatment to modulate the activity of the VS striatum while modulating at least one different brain region, either by using a different or similar NF treatment or by using at least one drug.

[0129] An aspect of some embodiments relates to performing NF training before and / or after administering at least one drug, e.g., a drug or drug compound for treating depression. In some embodiments, the drug is administered according to a known dosing regimen before and / or after performing NF training, e.g., before and / or after performing at least one training session (treatment session), when treating depression. Alternatively, the dosing regimen, e.g., the dosage of the drug, is reduced, e.g., when administering the drug as part of a treatment protocol that includes administering the drug and performing NF training. In some embodiments, the dosing regimen of the drug, e.g., the dosage of the drug, is modified based on the subject's progress in modulating the activity level of at least one brain region or brain network during NF training, as described herein. Also, optionally, the subject's dosing regime is modified based on the results of an evaluation of the subject's mental and / or cognitive state during, at the end of, an NF training session, between training sessions, or after the end of NF treatment. In some embodiments, the timing of performing NF training is adjusted depending on the particular drug, e.g., depending on at least one of the pharmacokinetics and pharmacodynamics of the drug. Alternatively or additionally, the timing of NF training is adjusted depending on the effect of the drug on the trainee, for example to ensure that the trainee's mental and / or cognitive state is suitable for performing NF training.

[0130] According to some embodiments, the drug belongs to a family of drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants, atypical antidepressants, and monoamine oxidase inhibitors (MAOIs). Alternatively, the drug is an N-methyl D-aspartate (NMDA) antagonist, such as esketamine, or a neuroactive steroid gamma-aminobutyric acid (GABA)-A receptor positive modulator, such as brexanolone.

[0131] According to some embodiments, NF training includes presenting a sensory cue to a trainee (e.g., a subject taking a drug) and, optionally, instructing the trainee to modify the presented sensory cue by performing at least one specific activity. In some embodiments, the sensory cue is selected to increase a pleasant feeling response in the trainee's brain. In some embodiments, the sensory cue includes a visual cue and / or an auditory cue provided to the trainee. Optionally, the sensory cue is a stimulus.

[0132] According to some embodiments, the NF training further includes detecting, after the instruction, an increase in the brain pleasure response and providing the trainee with a feedback signal, e.g., a human detectable indicator, indicative of the increase in the brain pleasure response. In some embodiments, the feedback signal is provided to the trainee during the presentation. In some embodiments, the feedback signal is provided by modifying the sensory indicator presented to the trainee. In some embodiments, the feedback signal is provided to the trainee by modifying the sensory indicator in a manner selected to increase the subject's brain pleasure response (e.g., by modifying the sensory indicator to include additional pleasant visual and / or auditory indicators or cues).

[0133] Before describing at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of elements and / or methods set forth in the following description and / or illustrated in the drawings and / or examples. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0134] Exemplary General Training According to some exemplary embodiments, the NF protocol is provided as a NF treatment for subjects currently suffering from one or more symptoms of depression or diagnosed with MDD, to train them how to increase the activity of their positive emotional valence system, for example, how to increase the pleasant sensation response in their own brain by performing at least one activity. Alternatively or additionally, the NF protocol is provided as NF training, for example, for subjects who are not currently experiencing depressive symptoms, but are expected to experience depressive symptoms in the future. In some embodiments, the NF training teaches trainees how to deal with future depressive symptoms, for example, by performing at least one activity to increase the pleasant sensation response in the brain.

[0135] Reference is made to FIG. 1B, which illustrates a typical NF training in accordance with some exemplary embodiments of the present invention.

[0136] According to some exemplary embodiments, in block 103, a subject is optionally selected for NF training. In some embodiments, the subject is part of a predetermined subject population selected for NF training. In some embodiments, the selected subject is a subject expected to experience at least one depressive symptom in the future. In some embodiments, the at least one symptom comprises a depressive symptom according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; American Psychiatric Association, 2013). In some embodiments, the at least one symptom comprises a depressed mood and / or anhedonia. Alternatively or additionally, the at least one depressive symptom comprises at least one of weight loss, weight gain, insomnia, hypersomnia, psychomotor agitation, psychomotor retardation, reduced energy, feelings of worthlessness, feelings of guilt, difficulty concentrating, suicidal ideation and / or suicidal behavior.

[0137] According to some exemplary embodiments, the selected subject is a subject diagnosed with at least one of post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), substance-induced psychiatric disorder, chronic kidney disease (CKD), and / or premenstrual dysphoric disorder (PMDD). In some embodiments, the selected subject is a subject at risk of developing peripartum depression, or a subject who has already been diagnosed with peripartum depression or has previously been diagnosed with peripartum depression, for example a male or female subject who has been diagnosed with peripartum depression in a previous pregnancy.

[0138] In some embodiments, the selected subject is a subject at risk of developing seasonal affective disorder (SAD), or a subject who has previously been diagnosed with or experienced SAD. In some embodiments, the selected subject is, for example, a subject who has been diagnosed with pancreatic cancer or lung cancer.

[0139] According to some exemplary embodiments, the selected subject is a subject who has a relative, for example a first degree relative, who has been previously diagnosed with depression or severe depression.In some embodiments, the selected subject is a subject who is a first responder, for example, a person with specialized training who is one of the first personnel to arrive at the scene of an emergency, such as an accident, disaster, medical emergency, fire, crime, or terrorist attack, and provide assistance or problem solving.

[0140] According to some exemplary embodiments, in block 105, the NF training is optionally adjusted in response to the selected target characteristics. In some embodiments, the overall length of the NF training is shortened or lengthened. In some embodiments, at least one sensory indicator included in the NF training is adjusted or replaced in response to the selected target characteristics. In some embodiments, the number of training sessions and / or the length of each training session or at least one training session is adjusted in response to the selected target characteristics. In some embodiments, the NF training is provided to the trainee using the system 302 shown in FIG. 3.

[0141] According to some exemplary embodiments, during NF training, a sensory indication is delivered to the selected subject, for example, by being presented in block 107. In some embodiments, the sensory indication includes a visual indication and / or an auditory indication. In some embodiments, the sensory indication is optionally a stimulus, configured to evoke or elicit a pleasant sensation response in the subject's brain. In some embodiments, the sensory indication is transmitted using a trainee interface, also referred to herein as a trainee interface, such as, for example, interface 306 shown in FIG. 3.

[0142] According to some exemplary embodiments, an increase in the brain pleasure response in the subject's brain is detected in block 109. In some embodiments, the increase in the brain pleasure response is detected using electrical signals recorded from the subject's brain, for example, using electrodes 316 and 318 shown in Figure 3. In some embodiments, the recorded electrical signals are processed and used to measure electroencephalogram (EEG) signals indicative of an increase in activity of at least one mesolimbic brain region in response to the transmitted sensory indication.

[0143] According to some exemplary embodiments, in block 111, the sensory indicators presented to the subject are modified. In some embodiments, the sensory indicators are modified based on the detected increase in brain pleasure response. In some embodiments, the sensory indicators are configured or designed to increase the brain pleasure response in the subject, for example, by adding a pleasant visual and / or auditory indicator to the sensory indicator or by delivering a pleasant visual and / or auditory indicator to the subject in addition to the sensory indicator.

[0144] According to some exemplary embodiments, the delivery of the sensory indication, the detection of an increase in the brain pleasure response, and the modification of the sensory indication in response to the detected increase are repeated continuously for at least 1 minute, at least 3 minutes, at least 5 minutes, or any intermediate time therebetween, or for a shorter or longer time during a session of NF training.

[0145] Exemplary General Process for Treating Anhedonia As mentioned above, anhedonia is a term used to describe the absence or dysfunction of any part of the positive emotional valence system. Clinicians also use the term to mean the loss of interest or pleasure, which is a core depressive symptom. Refer to FIG. 1C, which shows the general process for treating a subject diagnosed with anhedonia according to some embodiments of the present invention.

[0146] According to some exemplary embodiments, in block 130, the subject is diagnosed with anhedonia. In some embodiments, the subject is diagnosed in block 130 with at least one of a dysfunction of the positive emotional valence system, such as a dysfunction in reward prediction, a dysfunction in reward consumption, and / or a dysfunction in persistent responsiveness to reward. In some embodiments, the subject is diagnosed with anhedonia using at least one of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and a score of 25 or more on the Snaith-Hamilton Pleasure Scale for Clinicians (SHAPS-C), and optionally diagnosed with Major Depressive Disorder (MDD) with Anhedonia. The diagnosis of MDD is made by the Neuropsychiatric Interview (MINI for DSM-5).

[0147] Also, optionally, information collected while a subject is using the system and / or performing a treatment protocol is used to improve an initial diagnosis of the patient and / or is used as an independent diagnostic tool.

[0148] According to some exemplary embodiments, in block 132, a signal is recorded from at least one mesolimbic region of the brain. In some embodiments, the signal is recorded from at least one brain region associated with the reward system, such as the ventral striatum (VS), the nucleus accumbens, the ventral tegmental area, the orbitofrontal cortex, and the insular cortex. In some embodiments, the signal is recorded by one or more electrodes positioned on the subject's head, optionally used to measure electroencephalography (EEG) signals. In some embodiments, the one or more electrodes are placed on the subject's head at at least one of positions C3, C4, Cz, FCZ, P3, Pz, and P4 of an extended 10-20 coordinate system. In some embodiments, five electrodes are used, each placed at one of positions C3, C4, Cz, FCZ, P3, Pz, and P4.

[0149] According to some exemplary embodiments, activity of at least one mesolimbic brain region is determined in block 134. In some embodiments, activity of the at least one mesolimbic brain region is determined based on the recordings made in block 132. In some embodiments, activity of the at least one mesolimbic brain region is determined using at least one electrical fingerprint (EFP) of the at least one mesolimbic brain region (e.g., an EFP of the ventral striatum (VS)). In some embodiments, the EFP is based on EEG signals that correlate with FMRI-BOLD activity of at least one mesolimbic brain region, for example, the VS.

[0150] According to some embodiments, EFP is a model that links EEG measurements to FMRI-BOLD signals that indicate selective activation of at least one specific brain region (e.g., VS). In some embodiments, selective activation of a brain region refers to activation of at least one specific brain region that is higher than the activation level of other brain regions, for example, 30% or more higher, 50% or more higher, 60% or more higher, 80% or more higher, 90% or more higher than the activity of other brain regions, or any percentage higher or lower than the activity of other brain regions. Alternatively or additionally, selective activation of at least one specific brain region refers to activation of at least one specific brain region that is higher than a reference value, optionally used as a baseline, or a value or indicator previously measured from at least one specific brain region. In some other embodiments, EFP is used to measure activity at any moment in time and evaluate the cumulative activity of a region over time.

[0151] According to some exemplary embodiments, the model has a coefficient matrix of at least 10 coefficients corresponding to frequency bands, electrodes, and one or more time windows. In some embodiments, the EFP includes EEG electrical signals recorded from EEG electrodes located at one or more locations on the subject's head, e.g., locations C3, C4, Cz, FCz, P3, Pz, and P4. Alternatively, the EFP includes EEG electrical signals recorded from EEG electrodes located at one or more of locations C4, F7, F8, T7, T8, P8, TP9, and TP10. In some embodiments, the EFP includes EEG electrical signals in a frequency range of 0-1 GHz and in a time delay window of 0-30 seconds, e.g., a time delay window of 0-10 seconds, a time delay window of 0-15 seconds, a time delay window of 0-20 seconds, or any intermediate, smaller, or larger time delay window.

[0152] According to some embodiments, activity of at least one mesolimbic brain region is determined in block 134 using EFP of the VS, for example as described in WO2021260697A1, the entirety of which is incorporated herein by reference.

[0153] According to some exemplary embodiments, the activity of at least one mesolimbic brain region is determined against a reference value in block 134. In some embodiments, the reference value indicates a target activation level, e.g., a threshold value of a desired activation level, of at least one mesolimbic brain region, e.g., VS. In some embodiments, the reference value is determined based on a clinical evaluation of the subject, e.g., a clinical evaluation performed at the time of diagnosis in block 130. Alternatively or additionally, the reference value is determined based on the subject's behavior during NF treatment and / or information collected from the subject. Alternatively or additionally, the reference value is determined based on clinical evaluation and / or behavior of one or more different subjects during NF treatment and / or information collected from one or more different subjects before, during, and / or after NF treatment.

[0154] According to some exemplary embodiments, activity of at least one mesolimbic brain region is determined while the subject is performing a cognitive task. In some embodiments, performing the cognitive task modulates the activation level of at least one mesolimbic brain region.

[0155] According to some exemplary embodiments, in block 136, the baseline value is adjusted to promote successful reward response in the subject. In some embodiments, the reward response is any reward system response related to reward prediction, reward consumption, and / or reward retention, such as reward-persistent response. In some embodiments, if the activity of at least one mesolimbic brain region is lower than the target baseline value, in block 136, the baseline value is lowered. In some embodiments, the degree of reduction of the baseline value varies between subjects and / or varies depending on the subject's performance during NF treatment. Alternatively, the degree of reduction of the baseline value is fixed or predetermined.

[0156] According to some exemplary embodiments, a feedback signal is provided to the subject at block 138. In some embodiments, the feedback signal is selected to enhance a reward response, such as a reward anticipation response, in the subject. In some embodiments, the feedback signal is provided when the determined activity of at least one mesolimbic brain region is higher than a baseline value.

[0157] Optionally, the system also rewards the patient even if the determined activity is below a threshold, for example to create the illusion of success.

[0158] According to some exemplary embodiments, the feedback signal includes a visual signal and / or an audio signal and / or a tactile signal and / or an olfactory signal. In some embodiments, the feedback signal is provided by modifying a visual interface presented to the subject. In some embodiments, the visual interface provides visual feedback, optionally continuous visual feedback, indicative of an activity level of at least one mesolimbic brain region. In some embodiments, the visual interface is adjusted with a delay window of 5 seconds to 20 seconds, e.g., 5 seconds to 15 seconds, 10 seconds to 20 seconds, 10 seconds to 15 seconds, or any intermediate therebetween, relative to the signal recorded in block 132 to indicate an activity level of at least one mesolimbic brain region.

[0159] Exemplary changes in pleasure responses According to some exemplary embodiments, the NF methods and systems described herein, e.g., as an interface or patient interface, deliver to a subject a stimulus selected to increase a reward response in the subject, e.g., by increasing the subject's hedonic response to the provided stimulus.

[0160] Please refer to Figures 1D-1F, which show the change in a subject's pleasure response in response to a stimulus, according to some exemplary embodiments of the present invention.

[0161] According to some exemplary embodiments, the change in the pleasure response after exposure to a stimulus is linear, for example as shown in FIG. 1D. In some embodiments, the linear phase of the change in the pleasure response is limited over a certain time period.

[0162] According to some exemplary embodiments, the subject's pleasure response reaches a plateau following the stimulation, for example, as shown in FIGS. 1E and 1F. In some embodiments, the plateau indicates the subject's limited capacity to increase the pleasure response in response to the stimulation. In some embodiments, the NF system, for example, the system shown in FIG. 3, modifies the stimulation to increase the subject's capacity to respond to the stimulation to increase the pleasure response. In some embodiments, for example, as shown in FIG. 1E, the system further modifies the stimulation to increase the subject's capacity to increase the pleasure response. In some embodiments, the system modifies the stimulation to reach a predetermined and / or desired, e.g., a target, pleasure response level.

[0163] According to some exemplary embodiments, the system is adjusted to deliver feedback (e.g., stimulation) in a specific pattern that changes over time, for example, as shown in FIG. 1G. In some embodiments, the system is configured to deliver planned feedback that increases linearly over time, for example, as shown in FIG. 1G. In some embodiments, during treatment, the system modifies the feedback or applies feedback with a different arbitrary pattern, such as when the change in the subject's pleasure response is not linear and / or when the change in the pleasure response reaches a plateau. In some embodiments, the different feedback patterns are stored in the system's memory. In some embodiments, the system determines which pattern to use using at least one algorithm or lookup table stored in the system's memory.

[0164] Exemplary Treatment Protocols According to some exemplary embodiments, NF treatment is used to treat subjects diagnosed with at least one of MDD, MDD with anhedonia, anhedonia, and reward system dysfunction or positive affective valence system dysfunction, such as reward prediction dysfunction, reward consumption dysfunction, persistent responsiveness to reward dysfunction, and reward learning dysfunction. In some embodiments, the treatment is performed in a supervisor's clinic, such as a doctor's, therapist's, or social worker's clinic or office. Alternatively or additionally, at least some of the treatment is performed in the subject's home or household. In some embodiments, at least some of the treatment is performed without the supervisor present during training, for example, when performing at least one transition cycle in which no feedback is provided to the trainee.

[0165] FIG. 2A illustrates a treatment program, e.g., a NF treatment program, according to some exemplary embodiments.

[0166] According to some exemplary embodiments, a subject, e.g., a male or female subject, is diagnosed in block 202. In some embodiments, the subject is diagnosed with at least one of MDD, MDD with anhedonia, anhedonia, a dysfunction of the reward system, and / or a dysfunction of the positive emotional valence system. In some embodiments, the subject is diagnosed as described above in block 130. Alternatively or additionally, the subject is diagnosed according to the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM), e.g., the fifth edition of the DSM (DSM-5).

[0167] According to some exemplary embodiments, the subject is diagnosed using one or more questionnaires, interviews, observation sessions, imaging techniques such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or one or more biomarkers. In some embodiments, the subject is diagnosed by a mental health professional, a physician or psychologist. In some embodiments, the mental health professional determines whether the subject may benefit from NF treatment, or from a different treatment, such as pharmacotherapy with drugs, or from a combination of both NF treatment and pharmacotherapy. In some embodiments, if the mental health professional determines that the diagnosed subject is a good candidate for NF treatment, the mental health professional refers the subject to a professional who performs NF treatment, such as, for example, a therapist.

[0168] According to some exemplary embodiments, a pre-treatment clinical evaluation is performed at block 204. In some embodiments, the clinical evaluation is optionally performed by a professional overseeing the NF treatment. In some embodiments, the pre-treatment clinical evaluation is performed to ensure that the diagnosed subject is suitable for NF treatment.

[0169] In some embodiments, the pre-treatment clinical evaluation uses one or more of the diagnostic tools described in block 202. Alternatively or additionally, in the clinical evaluation, a professional determines whether a diagnosed subject, e.g., a patient, is capable of performing NF treatment with the treatment system and / or examines the subject's response to the patient interface of the system. In some embodiments, the clinical evaluation is performed in a clinic and / or at home.

[0170] According to some exemplary embodiments, one or more parameters of the NF therapy are selected or adjusted for a particular patient in the clinical evaluation performed in block 204. In some embodiments, the one or more parameters include at least one of the number of therapy sessions, the duration of each therapy session, the interval between two consecutive therapy sessions, the number of NF cycles in each therapy session, and the type of patient interface.

[0171] Optionally, a baseline assessment is performed in block 206, for example to determine the initial clinical state of the subject before starting treatment. Also, optionally, during the baseline assessment, an initial threshold for an initial target activation level of at least one mesolimbic brain region is determined. In some embodiments, the baseline assessment is performed using a calibration system that examines the interaction between the subject and the patient interface, optionally while monitoring the activity of at least one mesolimbic brain region. Alternatively or additionally, the baseline assessment is performed during a pre-treatment clinical evaluation in block 204.

[0172] Optionally, a pre-training session is performed at block 208. In some embodiments, the pre-training session is performed by explaining the flow of the treatment program to the patient and / or practicing one or more exemplary treatment sessions or one or more NF cycles. In some embodiments, during pre-treatment, the patient receives instructions or guidelines regarding the application of one or more strategies, such as cognitive tasks, that allow for regulating the activation level of at least one mesolimbic brain region. Alternatively or additionally, the patient receives instructions or guidelines for identifying a preferred strategy and / or a method for identifying a preferred strategy.

[0173] In some embodiments, instructions during the treatment process may be provided by at least one of audio, video, text, or verbally by the therapist, or the subject does not receive instructions.

[0174] According to some exemplary embodiments, the treatment protocol includes one or more treatment sessions 210, e.g., training sessions, conducted under the supervision of a supervisor, e.g., a therapist, nurse, social worker, or psychologist. In some embodiments, the treatment sessions are conducted at the supervisor's clinic or office. In some embodiments, the treatment protocol includes up to 30 treatment sessions, e.g., up to 20 treatment sessions, up to 15 treatment sessions, up to 13 treatment sessions, up to 10 treatment sessions, or any intermediate, fewer, or more treatment sessions. In some embodiments, the treatment sessions are consecutive treatment sessions. In some embodiments, some of the sessions are provided at home or outside of a clinic.

[0175] According to some exemplary embodiments, each treatment session lasts for 5 minutes to 60 minutes, e.g., 5 minutes to 30 minutes, 10 minutes to 30 minutes, 15 minutes to 40 minutes, 20 minutes to 50 minutes, or any time in between, shorter or longer. In some embodiments, the time interval between two consecutive treatment sessions is at least 1 hour, e.g., at least 6 hours, at least 12 hours, at least 1 day, at least 3 days, or any time interval in between. In some embodiments, the time interval between consecutive treatment sessions 210 is in the range of 1 day to 14 days, e.g., 1 to 3 days, 1 to 5 days, 1 to 7 days, 3 to 7 days, 3 to 10 days, or any time interval in between, shorter or longer. In some embodiments, the treatment protocol includes up to 4 treatment sessions per week, e.g., up to 3 treatment sessions, up to 2 treatment sessions, or 1 treatment session.

[0176] According to some exemplary embodiments, the patient undergoes a post-treatment clinical evaluation in block 216. In some embodiments, a post-treatment clinical evaluation is performed to determine the subject's clinical status after the treatment session 210. Optionally, a post-treatment clinical evaluation is performed as described in blocks 204 and / or 206. In some embodiments, if the post-treatment clinical evaluation finds that the predetermined goal of the treatment has been achieved, the treatment protocol is terminated. Alternatively or additionally, if the post-treatment clinical evaluation finds that the predetermined goal of the treatment has been achieved, the patient is instructed to perform one or more transition sessions 218, e.g., transition sessions without feedback. Optionally, the patient performs one or more transition sessions at home or in a clinic, applying at least one strategy, such as at least one cognitive task that allows modulation of at least one mesolimbic brain region, as found in the treatment session 210. In some embodiments, the patient performs one or more transition sessions using application software installed on a mobile device, such as a mobile phone or a computer. Additionally, the patient optionally conducts one or more treatment sessions by accessing application software installed on a remote device, such as a server or cloud storage located outside the patient's home.

[0177] According to some exemplary embodiments, if the post-treatment clinical evaluation reveals that the predetermined goal of the treatment has not been achieved, the treatment protocol is optionally modified in block 220. In some embodiments, the change in the treatment protocol includes modifying the number and / or duration of the treatment sessions and / or the interval between successive treatment sessions. Alternatively or additionally, the modification of the treatment protocol includes modifying at least one parameter of the NF session performed during each session, such as the type of patient interface presented to the patient, the reference value used as a threshold for determining the goal, such as the desired activation level of at least one mesolimbic brain region, and / or any parameter related to the algorithm used to determine the activity of at least one mesolimbic brain region, and / or the relationship between the determined activity and the reference value.

[0178] Also, after modifying the treatment protocol, the patient may repeat one or more treatment sessions 210 according to the parameters of the modified treatment protocol.

[0179] Exemplary Treatment Session Reference is now made to FIG. 2B, which illustrates a treatment session of one or more of the treatment sessions 210 shown in FIG. 2A, according to some exemplary embodiments of the present invention.

[0180] According to some exemplary embodiments, one or more electrodes are placed on the patient's head at block 230. In some embodiments, the one or more electrodes include multiple electrodes placed at different locations on the subject's head, e.g., at C3, C4, Cz, FCZ, P3, Pz, and P4 locations of a 10-20 coordinate system. In some embodiments, the electrodes are attached to the patient's head, e.g., skull, using, for example, a gel.

[0181] According to some exemplary embodiments, recording from the electrodes is started in block 232. In some embodiments, the electrodes are used to record EEG signals. In some embodiments, recording is started in block 232 before or after positioning of the electrodes in block 230.

[0182] According to some exemplary embodiments, contact of the electrodes with the subject's head is determined in block 234. In some embodiments, contact is determined based on the recording started in block 232. In some embodiments, contact of the electrodes with the patient's head is presented to a supervisor, for example, using an interface indicating electrodes that indicate proper contact and electrodes that are not properly contacting the patient's head. In some embodiments, the system alerts the supervisor and / or user which electrodes are not properly contacted during treatment and, optionally, what action should be taken to resolve the issue. In some embodiments, after determining electrode contact in block 234, recording is started in block 232.

[0183] According to some exemplary embodiments, the treatment session optionally includes an eyes-closed session at block 236. In some embodiments, during the eyes-closed session, signals are recorded from the patient while the patient is in a resting mode, e.g., to calibrate a recording and / or EEG measurement system.

[0184] According to some exemplary embodiments, the treatment session optionally includes a global baseline session at block 238. In some embodiments, during the global baseline session, EEG signals are measured and collected for a predetermined period of time necessary to determine activity of at least one mesolimbic brain region, such as using EFPs of the mesolimbic brain region. In some embodiments, the predetermined period of time is in the range of 5 seconds to 30 seconds, such as 5 seconds to 20 seconds, 5 seconds to 15 seconds, 5 seconds to 13 seconds, 5 seconds to 10 seconds, or intermediate, smaller, or larger ranges of these ranges.

[0185] Optionally, a local baseline is calculated before each treatment session and / or before each NF cycle. In some embodiments, during the local baseline session, EEG signals are measured and collected for a predetermined period of time necessary to determine activity of at least one mesolimbic brain region, e.g., using EFP of the mesolimbic brain region. In some embodiments, the predetermined period of time is in the range of 5 seconds to 30 seconds, e.g., 5 seconds to 20 seconds, 5 seconds to 15 seconds, 5 seconds to 13 seconds, 5 seconds to 10 seconds, or intermediate, smaller, or larger ranges of these ranges.

[0186] According to some exemplary embodiments, the treatment session includes one or more training cycles in block 240. In some embodiments, the one or more training cycles include 1, 2, 3, 4, 5, 6, 7, or more NF training cycles. In some embodiments, the training cycles, e.g., NF training cycles, are consecutive training cycles. Optionally, in block 240, the NF training cycles are performed consecutively. Also, optionally, the delay between two consecutive NF training cycles is less than 30 seconds, e.g., less than 10 seconds, less than 5 seconds, less than 1 second, or any time in between, shorter, or longer. Optionally, the training cycle includes at least one transition cycle 242 in which feedback regarding the activation level of at least one mesolimbic brain region is not sent to the patient.

[0187] According to some exemplary embodiments, during an NF cycle, the patient views a patient interface while performing a task, such as a cognitive task, a visual, auditory, tactile and / or olfactory interface that presents a scenario that varies depending on the activity level of at least one mesolimbic brain region. In some embodiments, the cognitive task is selected to increase the activity level of at least one mesolimbic brain region. In some embodiments, an increase in activity of at least one mesolimbic brain region increases or decreases the amount of stimulation cues delivered to the patient as part of the interface. Additionally, a human-detectable indicator, such as a visual, auditory, tactile and / or olfactory indicator, is provided to the subject while viewing the interface to indicate whether the activity level of the target mesolimbic brain region has been exceeded or whether the determined activity is near the target activity level or in a desired direction toward the target activity level.

[0188] An exemplary NF cycle Reference is made to FIG. 2C, which illustrates an NF cycle process, according to some exemplary embodiments of the present invention.

[0189] According to some exemplary embodiments, instructions are optionally delivered to the patient at block 244. In some embodiments, the instructions are sent prior to the first NF cycle of a series of NF cycles performed during a single treatment session. In some embodiments, the instructions include a description of the following steps and / or a request for the patient to perform at least one task, e.g., a cognitive task to increase the amount of stimulation cues provided to the patient as part of the visual interface. In some embodiments, the instructions include a description of one or more specific tasks. Alternatively, the instructions include a request for the patient to try or find a task that can increase the amount of stimulation cues in the visual interface. In some embodiments, no instructions are provided.

[0190] According to some exemplary embodiments, the NF cycle includes a reward prediction block 246. In some embodiments, in the reward prediction block, a patient interface is presented to the patient and the patient is encouraged to adjust, for example, to increase or decrease the amount of stimulation cues in a visual interface. In some embodiments, adjusting the amount of stimulation cues in the patient interface indicates increased activity of at least one mesolimbic region.

[0191] According to some exemplary embodiments, if the determined activity of at least one mesolimbic brain region is close to a target activity level, e.g., a desired activity level, but less than the target activity level, a boost signal is optionally sent to the patient at block 248. In some embodiments, the boost signal indicates that the activity level of the mesolimbic brain region is in a desired direction, prompting the patient to exert additional effort to reach the target activity level, and indicates a reward cue indicative of reaching the target activity level.

[0192] According to some exemplary embodiments, when the determined activity of at least one mesolimbic brain region reaches a target activity level, a success reward cue is sent to the patient in WIN block 250. In some embodiments, the training phase including reward prediction block 246 trains the patient to increase activity in the mesolimbic brain region until they receive a success reward cue in WIN block 250 and to expect a reward cue in block 250 when the target activity level is reached. In some embodiments, during the reward prediction phase, the patient receives continuous feedback, for example visual feedback with an increasing amount of stimulation cues indicating increased activity in the mesolimbic brain region.

[0193] According to some exemplary embodiments, upon receiving a successful reward cue in block 250, the system determines in block 252 a correlation between reward consumption and activity levels in the mesolimbic brain region. In some embodiments, in block 252, the system determines whether the activity level in the mesolimbic brain region indicates that the patient recognized or valued a positive experience in receiving the successful reward cue in block 250. In some embodiments, if the determined activity level correlates with reward consumption, a positive indicator (e.g., a visual positive indicator) is delivered to the patient while presenting a visual interface. In some embodiments, this reward consumption block 252 trains the patient, for example, to find and apply a cognitive task in a manner that enhances the reward consumption response after the patient receives a reward.

[0194] According to some exemplary embodiments, following WIN block 250, the patient is instructed to maintain a desired level of activity in the mesolimbic brain region as part of a "retention" block 254. In some embodiments, if the patient maintains the desired level of activity for a predetermined time, a positive indicator (e.g., a visual positive indicator) is delivered to the patient while presenting a visual interface. Optionally, the "retention" block 254 is repeated at least twice in each NF session. In some embodiments, the "retention" block 254 trains the patient, for example, to find and apply a cognitive challenge, enhancing sustained reward responses after receiving a prize.

[0195] According to some demonstrative embodiments, each of the blocks or any combination and / or order of the blocks may be repeated at least twice, or any number of times. Note that the holding block 254 may occur before the reward prediction block 246.

[0196] Exemplary Systems for Delivery of Therapy Referring to FIG. 3, a system for delivery of NF therapy is shown, according to some exemplary embodiments.

[0197] According to some exemplary embodiments, the system 302 comprises a controller 304, a patient interface 306, and a supervisor interface 308. In some embodiments, the patient interface 306 and the supervisor interface are operatively coupled to a control circuit 310 of the controller 304. In some embodiments, the controller 304 further comprises a memory 312 that stores at least one algorithm and / or look-up table used in determining the activity level of at least one mesolimbic brain region. Alternatively or additionally, the memory 618 has at least one EFP, for example, an EFP model of at least one mesolimbic brain region, for example, the EFP model described in WO2021260697A1, which is incorporated by reference in its entirety herein. In other embodiments, the EFP model is stored in an EEG or computer.

[0198] According to some exemplary embodiments, the control unit 304 comprises an EEG recording unit 314 operatively coupled to the control circuitry 310. In some embodiments, the EEG recording unit 314 transmits signals from one or more electrodes located on the subject's head to the control circuitry 310, processes the received signals, and analyzes the processed signals to determine an activity level of at least one mesolimbic brain region and / or a relationship between the determined activity and at least one reference value or indicator thereof stored in the memory 312. In some embodiments, the control circuitry 310 determines the activity level or the relationship between the activity level and at least one reference value or indicator thereof using at least one of an algorithm, a look-up table, and an EFP stored in the memory 312, for example, as described in WO2021260697A1 or WO2012104853A2.

[0199] According to some exemplary embodiments, the EEG recording unit is operatively coupled to at least one electrode, e.g., a plurality of electrodes 316 and 318 located on the head 612 of the patient 322. In some embodiments, the plurality of electrodes includes two, three, four, five, six, seven, eight, nine, ten or more electrodes positioned and optionally attached to the head 320 of the patient 322. Optionally, the plurality of electrodes is arranged in an array. In some embodiments, the electrodes are positioned at specific locations on the subject's head, e.g., at locations C3, C4, Cz, FCZ, P3, Pz, and P4 of the extended 10-20 coordinate system. Alternatively, the electrodes are positioned at any location or combination of locations of the extended 10-20 coordinate system. In some embodiments, the controller 304 is connectable to at least one speaker or earphone 324 configured to deliver audio signals to the patient 322.

[0200] According to some exemplary embodiments, the controller comprises a communication circuit 326 configured to receive and / or transmit, for example, wireless signals to a remote device located outside the supervisor's clinic, for example, a remote computer, a remote server, or a remote cloud. In some embodiments, the remote device stores at least one algorithm, look-up table, and / or EFP. In some embodiments, the controller 304 transmits the electrical signal or the processed electrical signal to the remote device via the communication circuit 326 and receives, via the communication circuit 326, a signal indicative of an activity level of the mesolimbic brain region and / or a relationship between the activity level of the mesolimbic brain region and a reference value indicative of a target activation level of the mesolimbic brain region.

[0201] According to some exemplary embodiments, the control circuitry 310 signals the patient interface 306 to display at least one of a visual interface and / or an auditory interface and / or a tactile and / or olfactory interface on a screen, which interfaces change continuously in response to the activation level of the mesolimbic brain region or the change in activation level relative to a baseline. In some embodiments, the interfaces are updated, for example, every 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, or any value in between, lesser, or greater, based on the signals from the electrodes 316 and 318. In some embodiments, the patient interface 306 changes the visual interface presented to the patient with a delay of about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, or any value in between, lesser, or greater, relative to when the electrical signals are received from the electrodes 316 and 318. In some embodiments, the patient interface includes a display and / or a speaker.

[0202] According to some exemplary embodiments, the patient interface is provided in two dimensions (2D) or in three dimensions (3D). In some embodiments, the patient interface is provided using virtual reality, augmented reality, with or without at least one of auditory, olfactory, and tactile feedback.

[0203] According to some exemplary embodiments, the control circuitry 310 signals the supervisor interface to deliver visual and / or audio indicators to the supervisor of the treatment. In some embodiments, the visual and / or audio indicators indicate at least one of the patient's progress during the treatment, e.g., during the NF cycle 240, the activity level of the mesolimbic brain region, the change in the activity level of the mesolimbic brain region, the difference between the baseline and the activity level of the mesolimbic brain region, the stage of the NF session, the operation of the system, and an indicator or cue provided to the patient. Note that the supervisor interface 308 is optionally a supervisor's remote device coupled to the controller 304 via the communication circuitry 326. In some embodiments, the controller 304 transmits at least one of the data collected from the patient, the data transmitted or displayed to the supervisor to the remote device, e.g., to generate a database. In some embodiments, the dataset includes information collected from multiple systems and / or multiple patients.

[0204] Example System Activities Reference is now made to FIG. 4, which illustrates activity of system 302 during a treatment session, e.g., during a NF session, in accordance with some exemplary embodiments of the present invention.

[0205] According to some exemplary embodiments, recording begins at block 402. In some embodiments, recording of signals by electrodes, such as electrodes 316 and 318, begins at block 402. In some embodiments, the signals include EEG signals. In some embodiments, signals received by EEG recording unit 314 are transmitted to control circuitry 310. In some embodiments, recording of signals occurs during an NF session.

[0206] According to some exemplary embodiments, instructions are delivered to the patient at block 404, or before or after block 402. In some embodiments, the instructions are delivered to the patient via the patient interface 306. In some embodiments, the instructions are provided, for example, as described in block 244 of FIG. 2C. In some embodiments, the instructions may be provided in text format, audio format, video format, a combination thereof, or not provided at all.

[0207] According to some exemplary embodiments, if a patient interface is displayed or audio / olfactory / tactile sensations are delivered to the patient, the patient interface is displayed at block 405. In some embodiments, the patient interface includes dynamic scenarios configured to change depending on the activity level of at least one brain region, for example, the mesolimbic brain region.

[0208] According to some exemplary embodiments, the order of blocks 402 , 404 , 405 may be changed, for example, instructions may be delivered at block 404 before recording begins at block 402 .

[0209] According to some exemplary embodiments, brain activity is determined at block 406. In some embodiments, determining the brain activity includes determining an absolute brain activity level or a relative brain activity level to a reference value, e.g., a baseline. Alternatively or additionally, determining the brain activity includes determining a change in brain activity relative to the baseline. In some embodiments, the brain activity is determined by a control circuit or a remote device, as illustrated in FIG. 3. In some embodiments, the baseline is used to calculate brain activity, and a threshold, for example, is used to determine whether the brain activity exceeds a certain level.

[0210] According to some exemplary embodiments, the dynamic scenarios presented to the patient are enriched with pleasant visual indicators when brain activity in the mesolimbic brain regions increases, as described in reward prediction block 246. In other embodiments, the interface may become more degraded or change in response to changes in measured brain activity.

[0211] According to some embodiments, in block 408, if the determined brain activity is higher, or in other embodiments, lower, than a predetermined reference value indicating a threshold of a target activation level of the mesolimbic brain region, a positive indicator, for example a first positive indicator, is delivered to the patient. In some embodiments, the first positive indicator is an enhancement of the visual interface. Alternatively, the first positive indicator is a cue, such as a visual and / or auditory signal, delivered to the patient during presentation of the visual interface. In some embodiments, the first positive indicator provides the patient with an indication of success in reaching the target activation level of the mesolimbic brain region.

[0212] According to some example embodiments, if after a period of time the determined brain activity is lower than the pre-defined threshold, the pre-defined threshold is optionally lowered at block 410. In some embodiments, the lower threshold is used in subsequent NF sessions.

[0213] According to some exemplary embodiments, if brain activity is higher than a predetermined threshold, the predetermined threshold is raised, hi some embodiments, the higher threshold is used in subsequent NF sessions.

[0214] Optionally, the system also instructs, for example, the patient to apply different tasks, for example to modulate (e.g., increase or decrease) activation levels in mesolimbic brain regions.

[0215] Also, optionally, if the determined brain activity is below a predetermined threshold but within a predetermined activation level window of a boost response, a prompt is sent to the patient to, for example, provide a stimulus to prompt the patient to continue performing the currently applied task.

[0216] According to some example embodiments, if the determined brain activity is higher than a predefined threshold, the threshold is increased in block 414. In some embodiments, the threshold is used in the next NF session.

[0217] According to some exemplary embodiments, the system identifies whether the determined activation level of the mesolimbic brain region indicates reward consumption in block 416. In some embodiments, the system uses an EFP and / or an algorithm to identify whether the determined activation level indicates reward consumption, for example, the P300 algorithm described in Giroldini W. et al. (2016) and Stern Y. et al. (2016) stored in memory 312. In some embodiments, if the system identifies that the activation level of the mesolimbic brain region indicates reward consumption, a second positive indication is transmitted to the patient in block 420. In some embodiments, the second positive indication is transmitted to the subject in addition to the patient interface presented to the patient.

[0218] According to some exemplary embodiments, if the system identifies an activation level in the mesolimbic brain region that is not indicative of reward consumption, instructions are optionally given to the patient to apply a different challenge or change the way the challenge is applied in order to achieve an activation level indicative of reward consumption.

[0219] According to some exemplary embodiments, the system optionally delivers an indicator to the patient along with instructions to maintain (e.g., "hold") the current mesolimbic brain region activation level at block 422. In some embodiments, the instructions are provided using a visual reference and include a time indicator that counts the time that has elapsed since providing the instructions or the time remaining until the end of a predetermined time window.

[0220] According to some exemplary embodiments, the system determines whether the determined brain activity level is indicative of a positive sustained reward response (retention) in block 423. In some embodiments, if the determined brain activity is indicative of a positive sustained reward response, a third positive indication is transmitted to the patient in block 424.

[0221] Reference is made to Figures 5A and 5B, which illustrate system activity divided into different blocks of the NF cycle, according to some exemplary embodiments of the present invention.

[0222] According to some exemplary embodiments, instructions are provided to the patient as depicted in block 244 of FIG. 2C or as depicted in block 404 of FIG.

[0223] According to some exemplary embodiments, in prediction block 246, a visual interface is presented to the patient, e.g., as described in block 405, and activity of at least one mesolimbic brain region is measured in block 406. In some embodiments, if the measured activity is within a booster range, booster feedback is sent to the patient in block 502. In some embodiments, the booster activity range is a window located, e.g., between 40% and 98% of a threshold, of activity levels below a baseline value that indicates a target activation level of a mesolimbic brain region.

[0224] According to some exemplary embodiments, if the activity level of the mesolimbic brain region is higher than a predetermined threshold, a WIN feedback indicator is delivered to the patient in WIN block 250. Alternatively, if the activity level of the mesolimbic brain region is lower than a predetermined threshold, a threshold, e.g., a threshold for receiving WIN feedback, is lowered in block 410.

[0225] According to some exemplary embodiments, in reward consumption block 252, the system determines whether the measured mesolimbic activity is indicative of a reward consumption pattern, for example, using EFP and / or P300 algorithms. In some embodiments, if the activity is indicative of reward consumption, a positive indication is delivered to the user. In some embodiments, if the activity is not indicative of reward consumption, an instruction is optionally delivered to the patient in block 418.

[0226] According to some exemplary embodiments, during retention block 254, as illustrated in FIG. 2C and FIG. 4, the patient is instructed to maintain a desired activity level in the mesolimbic brain region for a predetermined period of time. In some embodiments, if the measured activity level in the mesolimbic brain region indicates a sustained reward response, a positive indication is sent to the patient in block 424. In some embodiments, if the measured activity level in the mesolimbic brain region does not indicate a sustained reward response (retention), instructions are optionally given to the patient to change or modify a strategy, e.g., a task, to reach a desired activity level indicative of a sustained reward response. In some embodiments, the feedback provided in block 424 is provided continuously or intermittently.

[0227] Exemplary Patient Interface Reference is made to FIG. 6A, which illustrates exemplary instructions provided to a patient, and FIGS. 6B-6F, which illustrate changes in the brain interface during an NF session, according to some exemplary embodiments of the present invention.

[0228] In some embodiments, FIG. 6A is an image of a visual interface that includes instructions for the patient.

[0229] In some embodiments, FIG. 6B, for example, is an image of the brain visual interface during the reward prediction block, with the magenta color restricted and concentrated in a central region 602 of the brain interface, indicating a relatively low activation level of the brain, e.g., a relatively low activation level of at least one mesolimbic brain region, as determined in block 406.

[0230] In some embodiments, FIG. 6C is an image of a visual interface of the brain, where the magenta color has expanded and is now distributed in different brain regions 604 throughout the brain, indicating increased activity in the mesolimbic brain region. Also, for example, when booster feedback is delivered to the patient, a series of colored regions 606 are presented and / or more regions of the brain are highlighted. In some embodiments, the booster feedback is configured to encourage the patient to move toward the reward signal. In some embodiments, when a reward signal, e.g., WIN feedback, is delivered, e.g., as shown in FIG. 2C, the magenta color is widely distributed in the brain image.

[0231] In some embodiments, as shown in Figure 6D, in the reward consumption block, if the activity level of the mesolimbic brain region indicates reward consumption, a visual indication is presented in the brain scheme. The same applies to audio feedback.

[0232] In some embodiments, as shown in FIG. 6E, during the hold block 254, a time or progress indicator 610 is presented to the patient and magenta spots and colored areas are distributed over brain regions to indicate high activation levels in the mesolimbic brain regions.

[0233] In some embodiments, if the patient is successful in maintaining a high activation level, a visual indicator is presented in the brain scheme, and optionally auditory, tactile, and / or olfactory feedback is delivered, to indicate a sustained reward response, as shown in FIG. 6F.

[0234] 7A-7D show different interfaces and how they change between different blocks of the NF session shown in FIG. 2C.

[0235] Exemplary Supervisor Interface According to some exemplary embodiments, the supervisor interface is a visual interface presented to a supervisor of a treatment session, for example, to review a patient's progress during an NF session and / or various activities performed by the system and / or past performance. Reference is now made to FIG. 8A, which illustrates a visual interface of an NF session, according to some embodiments of the invention.

[0236] According to some exemplary embodiments, the visual interface 800 is displayed as a graph including an EFP line 802 that indicates the change in EFP of the mesolimbic brain region over time. In some embodiments, the EFP line 802 represents an accumulation of measurements over a time period of, for example, up to 30 seconds. In some embodiments, the change in EFP is correlated with a determined activity or change in the mesolimbic brain region, and is shown, for example, as described in block 406 of FIG. 4. In some embodiments, the graph further has a threshold line 804 that indicates a predetermined value that is a threshold for receiving positive feedback of a WIN following a prediction block. In some embodiments, the threshold line 804 indicates a target activation level of the mesolimbic brain region.

[0237] According to some embodiments, as shown in the figure, the system delivers a booster indication to the patient at 808 when the EFP line is below the threshold line 804. In some embodiments, despite receiving a booster indication, e.g., booster visual indication 606 in FIG. 6C, the EFP level remained below the threshold at point 810 indicating the absence of a WIN signal. In some embodiments, as shown in the graph, once the "no WIN" point is reached, the threshold 804 is lowered for the subsequent NF session 2. In session 2, the EFP 802 level is above the threshold 804 and the system delivers WIN feedback at 806. In some embodiments, once the WIN feedback is delivered, the threshold 804 is raised for the subsequent NF session. As shown in the graph, once the activity level EFP 802 indicates reward consumption, a positive indication of reward consumption 812 is delivered to the patient. In some embodiments, as shown in diagram 800, if the activity level indicated by the EFP line 802 during the hold block remains high for a predetermined period of time, an indicator indicating successful hold 814, such as indicator 612, as shown in FIG. 6F, is delivered to the patient.

[0238] According to some exemplary embodiments, the visual interface presented to the supervisor includes information regarding the patient's progress. In some embodiments, as shown for example in FIG. 8B, a graph 830 illustrates the change in score received by the patient between NF sessions via line 832. In some embodiments, the score is calculated based on the number of positive indicators collected by the patient in each NF cycle, e.g., positive indicators related to successful reward consumption and / or successful retention blocks.

[0239] Illustrative Experiment A study was conducted on a group of subjects diagnosed with MDD. In the study, subjects were administered the NF treatment described in the present application according to a treatment plan that included a total of 10 training sessions twice a week during a period of 5 weeks. Subjects were assessed before starting the NF treatment, referred to here as NF training, before starting training, after 5 training sessions, and at the end of NF training, i.e., after completing 10 sessions of NF training. The assessment included the use of self-administered questionnaires such as the SNAITH-HAMILTON Pleasure Scale (SHAPS-C), the HAMILTON Depression Rating Scale (HDRS), and the Clinical Global Impression-Improvement (CGI-I) scale, as well as the SHAPS-SR.

[0240] In some embodiments of the present invention and in some experiments, subjects diagnosed with MDD receive one or more medications for depression, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic and tetracyclic antidepressants, atypical antidepressants, monoamine oxidase inhibitors (MAOIs), and N-methyl-D-aspartate (NMDA) antagonists. In some embodiments of the present invention and in some experiments, subjects receive one or more medications before and / or after NF training (NF treatment).

[0241] Selective serotonin reuptake inhibitors (SSRIs) include one or more of citalopram, escitalopram, paroxetine, fluoxetine, vortioxetine, vilazodone, and sertraline.

[0242] Serotonin-norepinephrine reuptake inhibitors (SNRIs) include one or more of the following: duloxetine, venlafaxine, levomilnacipran, and desvenlafaxine.

[0243] Tricyclic and tetracyclic antidepressants include one or more of amoxapine, amitriptyline, maprotiline, desipramine, nortriptyline, doxepin, trimipramine, imipramine, protriptyline.

[0244] Atypical antidepressants include one or more of trazodone, bupropion, mirtazapine, and nefazodone.

[0245] Monoamine oxidase inhibitors (MAOIs) include one or more of the following: selegiline, isocarboxazid, phenelzine, and tranylcypromine.

[0246] N-methyl-D-aspartate (NMDA) antagonists include esketamine.

[0247] 9A is a graph showing the change in scores on the SHAPS-C scale measured in 13 subjects before training (902), after 5 sessions (904), and after 10 sessions (906). As shown in FIG. 9A, the trainee group achieved an average reduction of 1.93 points after 5 training sessions and an average reduction of 3.46 points after 10 training sessions.

[0248] Figure 9B is a graph showing the change in scores on the HDRS scale measured in 13 subjects before training (908), after 5 sessions (910), and after 10 sessions (912). As shown in Figure 9B, the trainee group achieved an average reduction of 5.13 points after 5 training sessions and an average reduction of 7.15 points after 10 training sessions.

[0249] Figure 9C is a graph showing the change in scores on the CGI-I scale measured in 13 subjects before training (914), after 5 sessions (916), and after 10 sessions (918). As shown in Figure 9C, the trainee group achieved a mean reduction of 1.27 points after 5 training sessions and a mean reduction of 1.77 points after 10 training sessions.

[0250] According to experiments and in accordance with some exemplary embodiments of the present invention, a group of subjects diagnosed with MDD who underwent the NF training described in the present application achieved an average reduction of at least 3 points on the SHAPS-C scale 5 weeks after the provision of the NF training. Alternatively or additionally, the group of subjects achieved a reduction of at least 7 points on the HDRS scale 5 weeks after the provision of the NF training. Alternatively or additionally, the group of subjects achieved a reduction of at least 1.7 points on the CGI-I scale 5 weeks after the provision of the NF training.

[0251] As used herein, "about" refers to ±10% or ±5%.

[0252] The terms "comprises," "comprising," "includes," "including," "having" and conjugations thereof mean "including but not limited to."

[0253] The term "consisting of" means "including and limited to."

[0254] The term "consisting essentially of" means that a composition, method, or structure may include additional ingredients, steps, and / or moieties, provided that the additional ingredients, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0255] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" or "at least one compound" includes a plurality of compounds, and may also include mixtures thereof.

[0256] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity, and is not an inflexible limitation of the scope of the invention. Thus, the description of a range should be considered to specifically disclose all of the possible subranges, as well as each individual numerical value within that range. For example, the description of a range such as 1 to 6 is intended to specifically disclose not only the subranges 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., but also each individual numerical value within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the magnitude of the range.

[0257] When numerical ranges are given herein (e.g., any set of numbers joined by "10-15," "10 to 15," or other range designations), they are intended to include any number (fractional or integer) within the limits of the range given, unless the context clearly dictates otherwise. The phrases "range between" a first recited number and a second recited number and "range from" a first recited number to a second recited number (or other range terms) are used interchangeably herein, and these phrases are intended to include the first recited number and the second recited number, and all fractional and integer numbers therebetween.

[0258] Unless otherwise indicated, numbers used herein, and any numerical ranges based thereon, are approximations within the accuracy of reasonable measurement and rounding errors, as will be understood by one of ordinary skill in the art.

[0259] The term "method" as used herein refers to methods, means, techniques, and procedures for accomplishing a particular task, and includes, but is not limited to, methods, means, techniques, and procedures that are known or that can be readily developed from known methods, means, techniques, and procedures by practitioners of the chemical, pharmacological, biological, biochemical, and medical arts.

[0260] The term "treating" as used herein includes arresting, substantially inhibiting, slowing, or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the worsening of the clinical or cosmetic symptoms of a condition.

[0261] It will be understood that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in a single embodiment in any combination of those features. Conversely, several features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or with respect to other described embodiments as appropriate. Certain features described in the context of various embodiments should not be construed as essential to that embodiment, unless the particular embodiment is inoperable without that element.

[0262] While the present invention has been described in conjunction with specific embodiments thereof, many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0263] It is the intention of the applicant that all publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, and patent application was specifically and individually incorporated herein by reference.In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention.Also, to the extent that section headings are used, they should not necessarily be construed as limiting.In addition, the priority documents of this application, if any, are incorporated herein by reference in their entirety.

Claims

1. A system for providing neurofeedback (NF) training, A trained user interface configured to deliver a presentation to a subject that is perceptible to at least one person, It comprises a control unit and, The control unit, A memory for storing at least one NF training protocol for training the subject to increase the activity of the brain's positive valence system in the subject, A signal recording unit configured to receive electrical signals recorded from the subject's brain using one or more electrodes, Equipped with a control circuit, The aforementioned control circuit is (a) Signaling the trainee user interface to deliver a sensory presentation stored in the memory to the subject, wherein the sensory presentation is selected to increase the pleasure response in the subject's brain, and the sensory presentation includes a dynamic visual scenario. (b) Measuring a signal indicating activity in at least one mesolimbic brain region according to the received electrical signal, (c) Based on the measured signals, detecting an increase in activity in the at least one mesolimbic brain region using at least one algorithm stored in the memory, wherein the detected increase in activity in the at least one mesolimbic brain region indicates an increase in the pleasure response in the subject. (d) Modifying the dynamic visual scenario in a manner selected to further increase the pleasure response in the subject, (e) Signaling the trainee user interface to deliver the modified dynamic visual scenario to the subject, It is configured to do, system.

2. The memory stores information relating to the subject's clinical diagnosis, the information including information indicating that the subject has been diagnosed with anhedonia, and the NF training protocol is suitable for training a subject diagnosed with anhedonia to increase activity in at least one mesolimbic brain region of the brain's positive valence system. The system according to claim 1.

3. The memory stores information relating to the subject's clinical diagnosis, the information including indicators indicating that the subject has been diagnosed with major depressive disorder (MDD) or MDD and anhedonia, and the NF training protocol is suitable for training subjects diagnosed with MDD or MDD and anhedonia to increase activity in at least one mesolimbic brain region of the brain's positive valence system. The system according to claim 1.

4. The aforementioned at least one mesolimbic brain region includes at least one of the subject's ventral striatum (VS), nucleus accumbens, ventral tegmental area, orbitofrontal cortex, and insular cortex. The system according to claim 1.

5. The control circuit continuously repeats (b) to (e) for at least one session or part thereof of the NF training. The system according to claim 1.

6. The detected increase in activity in the at least one mesolimbic brain region indicates an increase in the brain's positive valence system activity in the subject. The system according to claim 1.

7. The at least one NF training protocol comprises at least one NF training protocol of an NF training program which includes administering at least one NF training session to the subject, wherein in the at least one NF training session, the at least one NF training protocol includes a reward prediction training phase and a reward consumption training phase. The system according to claim 1.

8. The control circuit is configured to signal the trainee user interface to generate and deliver a positive reward cue to the subject while delivering the modified sensory presentation when the activity of at least one mesolimbic brain region is above a predetermined threshold. The system according to claim 1.

9. The sensory presentation includes a dynamic visual scenario, and the positive reward cue is delivered to the subject while the modified dynamic visual scenario is being delivered to the subject. The system according to claim 8.

10. The control circuit is configured to determine, after the presentation of the positive reward cue, that the activity in at least one mesolimbic brain region indicates a brain process related to reward consumption, and to transmit a signal to the trainee user interface to generate a display in accordance with the determination. The system according to claim 8.

11. The control circuit is configured to signal the trainee user interface to generate and deliver instructions to the subject to continue performing the current cognitive task for a predetermined period of time after the presentation of the positive reward cue. The system according to claim 9.

12. The control circuit is configured to signal the trainee user interface to generate and present a time display related to the predetermined time period during or after the delivery of the instruction. The system according to claim 11.

13. The control circuit is configured to transmit signals to the trainee user interface to deliver instructions to the subject to perform cognitive activities that are expected to increase the subject's brain's pleasure response. The system according to claim 1.

14. The control circuit is configured to signal the trainee user interface to deliver instructions to the subject to apply a different cognitive activity if the detected increase in activity in the at least one mesolimbic brain region is lower than the target activity in the at least one mesolimbic brain region. The system according to claim 13.

15. The memory stores the results or scores of the Hamilton Depression Rating Scale (HDRS) and / or the results or scores of the Clinical Snaith-Hamilton Pleasure Scale (SHAPS-C). The system according to claim 1.

16. The one or more electrodes are positioned on the subject's head or implanted in the subject's brain. The system according to any one of claims 1 to 15.

17. The one or more electrodes include a plurality of electrodes, The system according to claim 16.

18. The supervisor interface is configured to generate at least one visual display as part of a visual interface showing the subject's performance during at least one session of the NF training, the at least one visual display including information about changes in detected activity in the at least one mesolimbic brain region relative to a criterion during the at least one session, and information about whether the detected activity indicates the subject's reward consumption process. The system according to claim 17.

19. The signal recording unit is configured to receive signals recorded by one or more electrodes positioned at at least one of the positions C3, C4, Cz, FCZ, P3, Pz, and P4 in the extended 10-20 electroencephalogram (EEG) coordinate system. The system according to claim 16.

20. The control circuit is configured to measure an EEG signal indicating the activity of the at least one mesolimbic brain region using at least one model that correlates a subset of the EEG signal with functional magnetic resonance imaging (fMRI) blood oxygen concentration-dependent (BOLD) activity of the at least one mesolimbic brain region, according to the received electrical signal. The system according to claim 16.

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