Neurofeedback learning

Abstract

A method for delivery of neurofeedback (NF) training to a subject, including: stimulating at least one stimulation brain target in a brain of the subject; delivering the NF training to the subject following the stimulating, wherein the delivering includes teaching the subject by the NF training to self-modulate activity of at least one NF brain target, wherein the stimulating is performed with parameter values and / or timing suitable to increase efficacy of the teaching.

Description

[0001] NEUROFEEDBACK LEARNING

[0002] RELATED APPLICATION / S

[0003] This application claims the benefit of priority under 35 USC § 119(e) of U.S. Provisional Patent Application No. 63 / 679,128 filed August 4, 2024, the contents of which are incorporated herein by reference in their entirety.

[0004] FIELD AND BACKGROUND OF THE INVENTION

[0005] The present invention, in some embodiments thereof, relates to learning enhancement and, more particularly, but not exclusively, to enhancement of neurofeedback learning.

[0006] The fronto- striatal circuit has been identified as a neural mechanism involved in reinforcement learning and cognitive control (Schonberg, T. et al. Front. Neurosci. 6, (2012), Jiang, J., Beck, J., Heller, K. & Egner, T. Nat. Commun. 6, 8165 (2015), Averbeck, B. & O’Doherty, J. P. Neuropsychopharmacology 47, 147-162 (2022)). Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that has been used to modulate neural activity in the fronto-striatal network, for example through direct excitation of the dorsolateral prefrontal cortex (DLPFC) (Strafella, A. P., Paus, T., Barrett, J. & Dagher, J. Neurosci. 21, RC157 (2001), Pogarell, O. et al. J. Psychiatr. Res. 40, 307-314 (2006), Mas- Herrero, E., Dagher, A., Farres-Franch, M. & Zatorre, R. J. J. Neurosci. 41, 3889-3899 (2021)).

[0007] Additional background art includes U.S. Patent No. US10893822B2, International Patent Application No. WO2021260697A1, and Keynan, J. N. et al. Limbic Activity Modulation Guided by Functional Magnetic Resonance Imaging-Inspired Electroencephalography Improves Implicit Emotion Regulation. Biol. Psychiatry 80, 490-496 (2016).

[0008] SUMMARY OF THE INVENTION

[0009] Following is a non-exclusive list including some examples of embodiments of the invention. The invention also includes embodiments which include fewer than all the features in an example and embodiments using features from multiple examples, also if not expressly listed below.

[0010] Example 1. A method for delivery of neurofeedback (NF) training to a subject, comprising: stimulating at least one stimulation brain target in a brain of said subject, to modulate an activity and / or connectivity and / or reactivity thereat; delivering said NF training to said subject following said stimulating, wherein said delivering comprises teaching said subject by said NF training to self-modulate activity and / or connectivity of at least one NF brain target, wherein said stimulating is performed with parameter values and / or timing suitable to increase efficacy of said teaching to provide learning by said subject.

[0011] Example 2. A method according to example 1, comprising: selecting said at least one stimulation brain target prior to said stimulating, wherein said selected at least one stimulation brain target comprises a brain region of a network or a circuit activated during said teaching, associated with the success of the said teaching, associated with learning and / or memory processes that underlie capacity of neuromodulation and / or is a brain target affecting an activation and / or connectivity of said network or circuit.

[0012] Example 3. A method according to example 2, wherein said selected at least one stimulation target comprises at least one brain region of a brain / NF learning circuit.

[0013] Example 4. A method according to any one of the previous examples, wherein said at least one stimulation brain target comprises a dorsolateral prefrontal cortex (DLPFC).

[0014] Example 5. A method according to any one of the previous examples, wherein said at least one stimulation brain target comprises at least one brain region which is part of a procedural learning process (e.g. fronto striatal circuit) or an episodic learning process (e.g. parietal hippocampus circuit).

[0015] Example 6. A method according to any one of the previous examples, wherein said delivering comprises delivering said NF training up to 40 minutes from completion of said stimulating.

[0016] Example 7. A method according to any one of the previous examples, wherein said stimulating comprises applying stimulation to said at least one stimulation brain target with parameter values suitable to provide said modulating by increasing plasticity of neurons in said at least one stimulation brain target in at least 5% relative to baseline activity during an effective time window, and wherein said delivering comprises delivering said NF training during said effective time window.

[0017] Example 8. A method according to any one of the previous examples, wherein said delivering comprises delivering said NF training after receiving an indication that said stimulation is completed.

[0018] Example 9. A method according to any one of the previous examples, wherein said stimulation comprises stimulating said at least one stimulation brain target using stimulation parameters stored in a memory of a system used for said delivering.

[0019] Example 10. A method according to any one of the previous examples, comprising: determining that said subject did not reach a target activity of said at least one NF brain target following said delivering; and repeating said stimulating and said delivering following said determining. Example 11. A method according to example 10, wherein said determining is in a next session.

[0020] Example 12. A method according to example 10 or example 11, comprising modifying at least one parameter of said stimulating and / or said delivering in response to said determining, and whereon said repeating comprises repeating said stimulating and said delivering using said at least one modified parameter.

[0021] Example 13. A method according to example 12, wherein said at least one parameter of said stimulating comprises at least one of, a stimulation brain target, stimulation duration, stimulation duty cycle, stimulation envelope, waveform, frequency within a pulse, inter-train interval, stimulation pulses frequency, stimulation bursts frequency, total number of pulses, stimulation intensity, interval between stimulation bursts, and / or duration of stimulation bursts.

[0022] Example 14. A method according to any one of examples 12 or 13, wherein said at least one NF parameter comprises, a NF brain target, duration of said NF training, duration of at least one session of said NF training, duration of active NF blocks in which the subject actively regulates the activity of the at least one NF brain target, feedback signal presented to the subject, and / or sensory interface presented as a feedback signal to the subject.

[0023] Example 15. A method according to any one of examples 1 to 9, comprising: determining that said subject did not reach a target activity of said at least one NF brain target following said delivering; and providing at least one different treatment to said subject in response to said determining.

[0024] Example 16. A method according to example 15, wherein said at least one different treatment comprises at least one of, a drug treatment, a psychotherapy treatment, and / or a cognitive behavior treatment (CBT).

[0025] Example 17. A method according to any one of examples 1 to 9, comprising: determining that said subject has reached a target activity of said at least one NF brain target following said delivering; and repeating said delivering of said NF training in response to said determining.

[0026] Example 18. A method according to any one of the previous examples, wherein said stimulating comprises applying noninvasive brain stimulation (NIBS) to said at least one stimulation brain target.

[0027] Example 19. A method according to example 18, wherein said applying comprises applying said NIBS with parameter values suitable to transiently modulate activity or connectivity of said at least one stimulation brain target during and / or following said stimulating. Example 20. A method according to example 19, wherein said NIBS comprises transcranial magnetic stimulation (TMS), and wherein said applying comprises applying said TMS by applying Intermittent theta burst stimulation (iTBS) to said at least one stimulation brain target.

[0028] Example 21. A method according to example 20, wherein said iTBS is delivered as bursts of a series of magnetic pulses having a frequency of about 50Hz, wherein the bursts are applied intermittently with a frequency of about 5Hz for about 2 seconds with intervals between 5 seconds and 12 seconds.

[0029] Example 22. A method according to any of the preceding examples, wherein said stimulating modulates by having an inhibitory effect.

[0030] Example 23. A method according to any of the preceding examples, wherein said stimulating modulates by having an excitatory effect.

[0031] Example 24. A method according to any of the preceding examples, wherein said stimulating modulates by modifying connectivity within and / or between brain areas.

[0032] Example 25. A method according to any of the preceding examples, comprising delivering NF to said patient also before said stimulating.

[0033] Example 26. A method according to any one of the previous examples, comprising diagnosing said subject with at least one mental disorder and wherein said NF training is a training used to treat said mental disorder or at least one symptom thereof.

[0034] Example 27. A method according to example 26, wherein said at least one mental disorder comprises at least one of, Neurodevelopmental Disorder, Schizophrenia Spectrum and Other Psychotic Disorders, Bipolar and Related Disorders, Depressive Disorders, Anxiety Disorders, Obsessive-Compulsive and Related Disorders, Trauma- and Stressor-Related Disorders, Dissociative Disorders, Somatic Symptom and Related Disorders, Feeding and Eating Disorders, Elimination Disorders, Sleep-Wake Disorders, Sexual Dysfunctions, Gender Dysphoria, Disruptive, Impulse-Control, and Conduct Disorders, Substance-Related and Addictive Disorders, Neurocognitive Disorders, and Personality Disorders.

[0035] Example 28. A method according to example 26, wherein said at least one mental disorder comprises post-traumatic stress disorder (PTSD) or depression, and wherein said at least one NF brain target comprises at least one of, at least one brain region of a limbic system, at least one brain region of a salience network or default mode network, at least one brain region of a reward system, and / or an amygdala.

[0036] Example 29. A method according to any one of the previous examples, wherein said at least one brain stimulation target and said at least one NF brain target are the same brain target. Example 30. A method according to any one of the previous examples, comprising displaying to said subject during said stimulating at least one interface of said NF training, and wherein said delivering comprises presenting a feedback signal to said subject which includes said at least one interface, said interface being visual and / or audible.

[0037] Example 31. A method for selecting a subject for neurofeedback (NF) training, comprising: stimulating at least one stimulation (NIBS) brain target in a brain of a subject; delivering at least one NF screening session to said subject following said stimulating, wherein said delivering comprises requesting said subject to modify at least one feedback signal presented to the subject, wherein said at least one feedback signal indicates activity of at least one target of said NF training; determining performance of said subject in said at least one NF screening session and / or at a later NF session; selecting said subject for said NF training based on the results of said determining.

[0038] Example 32. A method according to example 31, wherein said determining comprises determining an ability of said subject to modify said at least one feedback signal to reach a target modification of said at least one feedback signal, and wherein said selecting comprises selecting said subject for said NF training if said subject succeeded in reaching said target modification.

[0039] Example 33. A method according to any one of examples 31 or 32, wherein said at least one stimulation brain target comprises a brain region of a network or a circuit activated during said delivering, or is a brain target affecting an ability of said subject to modify said at least one feedback signal.

[0040] Example 34. A method according to any one of examples 31 to 33, example 33, wherein said at least one stimulation target comprises at least one brain region of a brain learning circuit.

[0041] Example 35. A method according to any one of examples 31 to 34, wherein said at least one stimulation brain target comprises (a) a dorsolateral prefrontal cortex (DEPFC), and / or (b) a brain region which is part of a fronto striatal circuit and / or a parietal-hippocampus circuit.

[0042] Example 36. A method according to any one of examples 31 to 35, wherein said delivering comprises delivering said NF training up to 40 minutes from completion of said stimulating.

[0043] Example 37. A method according to any one of examples 31 to 36, wherein said stimulating comprises applying stimulation to said at least one stimulation brain target with parameter values suitable to increase plasticity of neurons in said at least one stimulation brain target in at least 10% relative to baseline activity, during an effective time window, and wherein said delivering comprises delivering said NF training during said effective time window. Example 38. A method according to any one of examples 31 to 37, comprising diagnosing said subject with at least one mental disorder and wherein said NF training and NIBS include or are included in a training used to treat said mental disorder or at least one symptom thereof.

[0044] Example 39. A method according to any one of examples 31 to 37, comprising diagnosing said subject with at least one mental disorder and wherein said NF training includes or is included in a training used to treat said mental disorder or at least one symptom thereof.

[0045] Example 40. A method according to example 38 or example 39, wherein said at least one mental disorder comprises at least one of, Neurodevelopmental Disorder, Schizophrenia Spectrum and Other Psychotic Disorders, Bipolar and Related Disorders, Depressive Disorders, Anxiety Disorders, Obsessive-Compulsive and Related Disorders, Trauma- and Stressor-Related Disorders, Dissociative Disorders, Somatic Symptom and Related Disorders, Feeding and Eating Disorders, Elimination Disorders, Sleep-Wake Disorders, Sexual Dysfunctions, Gender Dysphoria, Disruptive, Impulse-Control, and Conduct Disorders, Substance-Related and Addictive Disorders, Neurocognitive Disorders, and Personality Disorders.

[0046] Example 41. A method according to example 38 or example 39, wherein said at least one mental disorder comprises post-traumatic stress disorder (PTSD) or depression, and wherein said at least one NF brain target comprises at least one of, at least one brain region of a limbic or mesolimbic system, at least one brain region of a salience network at least one brain region of a default mode network, at least one brain region of a reward system, and / or threat system.

[0047] Example 42. A method according to any one of examples 31 to 41, comprises determining that said subject is not a suitable candidate for said NF training prior to said stimulating.

[0048] Example 43. A method for increasing efficacy of a neurofeedback (NF) training, comprising: delivering at least one session of a NF training program to a subject, wherein said delivering comprises requesting said subject to modify at least one feedback signal presented to the subject, wherein said at least one feedback signal indicates activity of at least one NF brain target; determining during and / or following said delivering if said subject was able to modify said at least one feedback signal towards a target modified feedback signal; stimulating at least one stimulation brain target in a brain of said subject following said delivering of said at least one session if said subject was not able to modify said at least one feedback signal towards said target modified feedback signal; delivering at least one additional session of said NF training after said stimulating.

[0049] Example 44. A method according to example 43, wherein said delivering comprises delivering said at least one additional session of said NF training up to 40 minutes after said stimulating. Example 45. A method according to any one of examples 43 or 44, wherein said at least one stimulation brain target comprises a brain region of a network or a circuit activated during said delivering, or is a brain target affecting an ability of said subject to modify said at least one feedback signal towards said target modified feedback signal.

[0050] Example 46. A method according to any one of examples 43 to 45, wherein said at least one stimulation target comprises at least one brain region of a brain learning circuit, a brain reward circuit or of a brain memory circuit.

[0051] Example 47. A method according to any one of examples 43 to 46, wherein said at least one stimulation brain target comprises a dorsolateral prefrontal cortex (DLPFC), or a brain region which is part of a fronto striatal circuit and parietal-hippocampus circuit.

[0052] Example 48. A method according to any one of examples 43 to 47, comprising: measuring during said delivering of said at least one session, EEG signals indicating activity of said at least one NF brain target; calculating a score indicating changes in said activity during said delivering of said at least one session; wherein said determining comprises determining if said subject is able to modify said at least one feedback signal towards a target modified feedback signal, based on said calculated score.

[0053] Example 49. A method according to example 48, wherein said EEG signals comprise neuroanatomically informed EEG signals.

[0054] Example 50. A method according to any one of examples 43 to 49, comprising diagnosing said subject with a mental disorder and wherein said NF training is a training used to treat said mental disorder or at least one symptom thereof.

[0055] Example 51. A system for delivery of neurofeedback (NF) training to a subject, comprising: a memory which stores at least one NF protocol or indication thereof, wherein said at least one NF protocol includes providing stimulation to at least one stimulation brain target and delivery of at least one NF session; a user interface configured to generate and deliver at least one human detectable indication and / or to receive at least one input signal; a control circuitry, wherein said control circuitry is configured to signal said user interface to generate a human detectable indication with information about said at least one NF protocol.

[0056] Example 52. A system according to example 51, wherein said control circuitry is configured to signal said user interface to generate and deliver a reminder indication for delivery of said at least one NF session following said providing of said stimulation. Example 53. A system according to any one of examples 51 or 52, wherein said control circuitry is configured to signal said user interface to generate a human detectable indication with information about parameter values of said stimulation.

[0057] Example 54. A system according to example 53, wherein said information comprises information about a location on a subject head for applying said stimulation and / or information about a brain target of said stimulation.

[0058] Example 55. A system according to any one of examples 51 to 54, wherein said control circuitry is configured to receive an input signal via said user interface that application of stimulation to said subject was completed, and to signal said user interface to generate and deliver a human detectable indication with information about said at least one NF session in response to said receive of said input signal.

[0059] Example 56. A system according to example 55, wherein said information about said at least one NF session comprises information about an effective time window following said stimulation application for initiating said at least one NF session.

[0060] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0061] As will be appreciated by one skilled in the art, some embodiments of the present invention may be embodied as a system, method or computer program product. Accordingly, some embodiments of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, microcode, etc.) or an embodiment combining software and hardware aspects that may all generally be referred to herein as a “circuit,” “module” or “system.” Furthermore, some embodiments of the present invention may take the form of a computer program product embodied in one or more computer readable medium(s) having computer readable program code embodied thereon. Implementation of the method and / or system of some embodiments of the invention can involve performing and / or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of some embodiments of the method and / or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware and / or by a combination thereof, e.g., using an operating system.

[0062] For example, hardware for performing selected tasks according to some embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to some embodiments of the invention could be implemented as a plurality of software instructions being 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 method and / or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and / or data and / or a non-volatile storage, for example, a magnetic hard-disk and / or removable media, for storing instructions and / or data. Optionally, a network connection is provided as well. A display and / or a user input device such as a keyboard or mouse are optionally provided as well.

[0063] Any combination of one or more computer readable medium(s) may be utilized for some embodiments of the invention. The computer readable medium may be a computer readable signal medium or a computer readable storage medium. A computer readable storage medium may be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination of the foregoing. More specific examples (a non-exhaustive list) of the computer readable storage medium would include the following: an electrical connection having one or more wires, a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), an optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing. In the context of this document, a computer readable storage medium may be any tangible medium that can contain, or store a program for use by or in connection with an instruction execution system, apparatus, or device.

[0064] A computer readable signal medium may include a propagated data signal with computer readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electro-magnetic, optical, or any suitable combination thereof. A computer readable signal medium may be any computer readable medium that is not a computer readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device. Program code embodied on a computer readable medium and / or data used thereby may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, RF, etc., or any suitable combination of the foregoing.

[0065] Computer program code for carrying out operations for some embodiments of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages. The program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider).

[0066] Some embodiments of the present invention may be described below with reference to flowchart illustrations and / or block diagrams of methods, apparatus (systems) and computer program products according to embodiments of the invention. It will be understood that each block of the flowchart illustrations and / or block diagrams, and combinations of blocks in the flowchart illustrations and / or block diagrams, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions / acts specified in the flowchart and / or block diagram block or blocks.

[0067] These computer program instructions may also be stored in a computer readable medium that can direct a computer, other programmable data processing apparatus, or other devices to function in a particular manner, such that the instructions stored in the computer readable medium produce an article of manufacture including instructions which implement the function / act specified in the flowchart and / or block diagram block or blocks.

[0068] The computer program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other devices to cause a series of operational steps to be performed on the computer, other programmable apparatus or other devices to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions / acts specified in the flowchart and / or block diagram block or blocks.

[0069] Some of the methods described herein are generally designed only for use by a computer, and may not be feasible or practical for performing purely manually, by a human expert. A human expert who wanted to manually perform similar tasks, such as monitor brain activity, determine if a subject was able to reach a target modulation of a brain target and determine TMS and / or NF treatment parameters, might be expected to use completely different methods, e.g., making use of expert knowledge and / or the pattern recognition capabilities of the human brain, which would be vastly more efficient than manually going through the steps of the methods described herein.

[0070] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0071] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0072] In the drawings:

[0073] Fig. 1 is a flow chart of a general process for delivery of neurofeedback (NF) following non-invasive brain stimulation (NIBS), according to some exemplary embodiments of the invention;

[0074] Figs. 2A-2C are schematic illustrations showing an effect of stimulation and NF on one or more brain targets, according to some exemplary embodiments of the invention;

[0075] Fig. 2D is a schematic illustration showing flow of a NF training session which includes brain stimulation, according to some exemplary embodiments of the invention;

[0076] Fig. 3 is a block diagram of a system for delivery of NF training, according to some exemplary embodiments of the invention;

[0077] Fig. 4 is a flow chart of a process for delivering stimulation, such as TMS, during a NF training program, according to some exemplary embodiments of the invention;

[0078] Fig. 5 is a flow chart of a process for selecting a subject for a NF training program, according to some exemplary embodiments of the invention;

[0079] FIG. 6 is a flow chart of a process performed by a system for delivery of NF training, according to some exemplary embodiments of the invention; FIG. 7A is a schematic illustration showing a design of a first validation study;

[0080] FIG. 7B is a graph showing an effect of excitatory stimulation relative to an effect of sham stimulation on self-regulation of a NF target during NF training in the first validation study;

[0081] FIGs. 8A-8C are graphs showing an effect of excitatory stimulation relative to an effect of sham stimulation on activity of a NF target during NF training in the first validation study;

[0082] FIG. 9A is a is a schematic illustration showing a design of a second validation study; and

[0083] FIGs. 9B and 9C showing an effect of excitatory stimulation relative to an effect of sham stimulation on changes in modulation of activity of a NF target during NF training when a training feedback signal is presented to the subject (9A), and during a transfer stage when a different feedback signal is used (9B).

[0084] DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0085] The present invention, in some embodiments thereof, relates to learning enhancement and, more particularly, but not exclusively, to enhancement of neurofeedback learning.

[0086] An aspect of some embodiments of the invention relates to delivering brain stimulation, for example noninvasive brain stimulation (NIBS), to a subject, before providing neurofeedback (NF) training to the subject. In some embodiments, the NF training is delivered within an effective time window following the NIBS, and / or with parameter values expected to increase efficacy of NF relative. In some embodiments, the NIBS is delivered with parameter values expected to increase efficacy of NF relative to delivery of NF without prior NIBS.

[0087] According to some embodiments, the brain stimulation is performed with parameter values and / or with timing suitable to increase efficacy of the NF training, optionally suitable to increase efficacy of a teaching process performed during the NF training. The term “teaching” is used, inter alia, to describe the actions taken by a system and / or operator to guide a subject to learn or otherwise figure out how to self-neuromodulate. In some embodiments, the parameter values and / or timing of said brain stimulation is suitable to increase efficacy of the NF training in at least 10%, in at least 25%, in at least 50%, or any intermediate, smaller or larger percentage value, relative to efficacy of the NF training when provided without brain stimulation, for example without pre-brain stimulation. In some embodiments, and without being bound by any theory, the brain stimulation is delivered, for example applied to a stimulation brain target with parameter values suitable to increase plasticity of neurons in the stimulation brain target in at least 10%, in at least 25%, in at least 50%, in at least 100%, or any intermediate, smaller or larger percentage value, relative to baseline activity of the neurons, optionally baseline activity of the neurons prior to applying the stimulation. According to some embodiments, the use of NIBS in conjunction with NF can allow for fewer, shorter and / or more effective NF sessions administered to the patient while still attaining the same or potentially better clinical outcomes.

[0088] According to some embodiments, the NIBS is delivered to the subject before the subject is actively engaged in active NF training in which the subject is requested to modify a feedback signal, for example a human detectable feedback signal presented to the subject. Additionally, in some embodiments, the NBS is delivered to the subject during and / or following the active NF. In some embodiments, the NIBS comprises at least one of, transcranial magnetic stimulation (TMS), deep TMS, transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), random noise stimulation (RNS), transcranial ultrasound stimulation (TUS), vagus nerve stimulation (VNS), and galvanic vestibular stimulation (GVS). In some embodiments, the NIBS is delivered before (and / or during and / or after) most, or even all, NF sessions.

[0089] According to some embodiments, the NIBS, for example TMS is provided to the subject with parameter values suitable to modify activity of neurons in at least one brain target that affects directly or indirectly an ability of the subject to reach a desired, for example a target, goal of the NF training. In some embodiments, the at least one brain target comprises at least one brain region, for example a cortical or a sub-cortical brain region, or a brain network which includes two or more brain regions. In some embodiments, the at least one brain target comprises a brain target that affects NF learning, for example a brain target that affects directly or indirectly one or more learning related brain regions comprising at least one of, an anterior insula, an anterior cingulate cortex, a striatum, and / or basal ganglia. In some embodiments, the TMS brain target comprises a dorsolateral prefrontal cortex (DLPFC), optionally a left DLPFC. In some embodiments, the NIBS is delivered with parameter values suitable to induce the DLPFC to enhance NF learning, for example to enhance reinforcement learning, by optionally inducing an increase in release of Dopamine in the Striatum.

[0090] According to some embodiments, the delivery of active NF to the subject is initiated within a predetermined time window from the completion of the TMS. In some embodiments the time window is up to 40 minutes from completion of the TMS, for example up to 5 minutes, up to 10 minutes, up to 20 minutes, up to 30 minutes, up to 40 minutes, up to 60 minutes, or any intermediate, shorter or longer time period from completion of the TMS, potentially within a time window where the TMS is still affecting the brain sufficiently to affect NF. Alternatively, the delivery of the active NF to the subject is initiated at least 1 minute from initiating the TMS, for example at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, or any intermediate, shorter or longer time period from initiating the TMS. According to some embodiments, TMS is delivered to a subject, in a form of theta burst stimulation (TBS), by delivering an intermittent theta burst stimulation (iTBS) with parameter values suitable for activating neurons. In some embodiments, the iTBS is delivered as a triplet of single pulses at a frequency of about 50Hz applied in about 200ms intervals (about 5Hz) for a total of about 600 pulses, or a total number of pulses between 300 and 1000 pulses, or any intermediate, smaller or larger number of pulses. In some embodiments, iTBS is applied intermittently for about 2 seconds with intervals between 5 seconds and 12 seconds, for a total time period of TMS delivery between 1 minute and 5 minutes, for example between 1 minute and 4 minutes, between 2 minutes and 4 minutes, a time period of about 2 minutes, a time period of about 3 minutes, or any intermediate, smaller or larger time period. In some embodiments, an intensity of the applied stimulation is set to a stimulation intensity between 70% and 100%, between 75% and 85%, between 80% and 90%, or any intermediate, smaller or larger percentage value of a resting motor threshold measured at each session in the subject.

[0091] According to some embodiments, during stimulation, for example TMS, the subject is presented with a visual interface, optionally a sensory interface of the NF training. Additionally or optionally, during the NF training a sensory interface presented to the subject, optionally as a feedback signal, includes an audio and / or a visual signal related to the stimulation process and / or stimulation device. For example, in some embodiments, the interface presented to the subject during NF training includes sounds generated during stimulation, optionally by a stimulation device. Optionally, during the NF training the subject is requested to modify a feedback signal which includes the sounds to reach a desired modified feedback signal.

[0092] An aspect of some embodiments relates to selecting a subject for a NF training based on an ability of the subject to reach a goal of a combined NIBS and NF training. In some embodiments, a subject selected for a NF training undergoes at least one screening session that includes combined NIBS and NF training. In some embodiments, if the subject was able to modify an activity of at least one brain target to reach a target activity, then the subject is selected for a NF training. In some embodiments, if the subject was unable to reach the target activity, then the subject receives an additional combined treatment, optionally with modified TMS and / or NF parameter values. Alternatively or additionally, the subject receives a different treatment from the NF treatment, for example, cognitive behavioral therapy (CBT) or EMDR. In some embodiments, the NIBS comprises at least one of, transcranial magnetic stimulation (TMS), deep TMS, transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), random noise stimulation (RNS), transcranial ultrasound stimulation (TUS), vagus nerve stimulation (VNS), and galvanic vestibular stimulation (GVS). In some embodiments of the invention, success in NF is used as an indication that a combination of NIBS and NF for ongoing therapy may be more effective than just NF, resulting, potentially in fewer NF sessions and / or a more sustained neuromodulation effect.

[0093] In some embodiments, the NIBS brain target, for example TMS brain target comprises a dorsolateral prefrontal cortex (DLPFC), optionally a left DLPFC. In some embodiments, the NIBS is delivered with parameter values suitable to induce the DLPFC to enhance NF learning, for example to enhance reinforcement learning, by optionally induce an increase in release of Dopamine within the striatum.

[0094] According to some embodiments, the delivery of active NF to the subject is initiated within a predetermined time window from the completion of the TMS. In some embodiments the time window is up to 40 minutes from completion of the TMS, for example up to 5 minutes, up to 10 minutes, up to 20 minutes, up to 30 minutes, up to 40 minutes, or any intermediate, shorter or longer time period from completion of the TMS. Alternatively the delivery of the active NF to the subject is initiated at least 1 minute from initiating the TMS, for example at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, or any intermediate, shorter or longer time period from initiating the TMS.

[0095] According to some embodiments, TMS is delivered to a subject, in a form of theta burst stimulation (TBS), by delivering an intermittent theta burst stimulation (iTBS) with parameter values suitable for activating neurons. In some embodiments, the iTBS is delivered as a triplet of single pulses at a frequency of about 50Hz applied in about 200ms intervals (about 5Hz) for a total of about 600 pulses, or a total number of pulses between 300 and 1000 pulses, or any intermediate, smaller or larger number of pulses. In some embodiments, iTBS is applied intermittently for about 2 seconds with intervals of about 8 seconds, for a total time period of TMS delivery between 1 minute and 5 minutes, for example between 1 minute and 4 minutes, between 2 minute and 4 minutes, a time period of about 2 minutes, a time period of about 3 minutes, or any intermediate, smaller or larger time period. In some embodiments, an intensity of the applied stimulation is set to a stimulation intensity between 70% and 100%, between 75% and 85%, between 80% and 90%, or any intermediate, smaller or larger percentage value of a resting motor threshold measured at each session in the subject.

[0096] An aspect of some embodiments relates to increasing an efficacy of an already initiated NF training by a subject by delivering a combined NIBS and NF training if the subject is not able to reach at least one goal of the NF training, or at least one goal of a NF session. In some embodiments, if a subject already undergoing a NF training is not able to reach a target regulation of a brain region, then a NIBS treatment is delivered to the subject before and / or during at least one additional NF session. Optionally, the NIBS is stopped, at least intermittently to allow for measurement of EEG signals. In some embodiments, the NIBS comprises at least one of, transcranial magnetic stimulation (TMS), deep TMS, transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), random noise stimulation (RNS), transcranial ultrasound stimulation (TUS), vagus nerve stimulation (VNS), and galvanic vestibular stimulation (GVS).

[0097] In some embodiments, the NIBS brain target, for example TMS brain target comprises a dorsolateral prefrontal cortex (DLPFC), optionally a left DLPFC. In some embodiments, the NIBS is delivered with parameter values suitable to induce the DLPFC to enhance NF learning, for example to enhance reinforcement learning, by optionally induce an increase in release of Dopamine within the striatum.

[0098] According to some embodiments, the delivery of active NF to the subject is initiated within a predetermined time window from the completion of the TMS. In some embodiments the time window is up to 40 minutes from completion of the TMS, for example up to 5 minutes, up to 10 minutes, up to 20 minutes, up to 30 minutes, up to 40 minutes, up to 60 minutes or any intermediate, shorter or longer time period from completion of the TMS, especially times where the effect of TMS is sustained enough to significantly affect NF results (e.g., improve a score of a session by 10% more than without TMS and / or improve the sustainability of an effect by at least 10% in time). Alternatively the delivery of the active NF to the subject is initiated at least 1 minute from initiating the TMS, for example at least 5 minutes, at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, or any intermediate, shorter or longer time period from initiating the TMS.

[0099] According to some embodiments, TMS is delivered to a subject, in a form of theta burst stimulation (TBS), by delivering an intermittent theta burst stimulation (iTBS) with parameter values suitable for activating neurons. In some embodiments, the iTBS is delivered as a triplet of single pulses at a frequency of about 50Hz applied in about 200ms intervals (about 5Hz) for a total of about 600 pulses, or a total number of pulses between 300 and 1000 pulses, or any intermediate, smaller or larger number of pulses. In some embodiments, iTBS is applied intermittently for about 2 seconds with intervals of about 8 seconds, for a total time period of TMS delivery between 1 minute and 5 minutes, for example between 1 minute and 4 minute, between 2 minute and 4 minute, a time period of about 2 minutes, a time period of about 3 minutes, or any intermediate, smaller or larger time period. In some embodiments, an intensity of the applied stimulation is set to a stimulation intensity between 70% and 100%, between 75% and 85%, between 80% and 90%, or any intermediate, smaller or larger percentage value of a resting motor threshold measured at each session in the subject.

[0100] Before explaining 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 set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

[0101] Exemplary general process for delivery of TMS prior to NF

[0102] Reference is now made to fig. 1 depicting a general process for delivery of TMS prior to delivery of NF training to a subject, according to some exemplary embodiments of the invention. It is noted that in some embodiments, TMS or other NIBS are applied after NF and / or after determining a response of a subject to NF.

[0103] According to some exemplary embodiments, deciding to deliver NF training to a subject, at block 102. In some embodiments, the subject is diagnosed with a disorder, for example a mental disorder or a cognitive disorder. In some embodiments, a goal of the NF training is to teach the subject to modulate, optionally self-modulate, an activity of at least one brain target. In some embodiments, the at least one brain target comprises at least one brain region, for example a cortical brain region or a sub-cortical brain region, or at least one network of brain regions.

[0104] According to some exemplary embodiments, brain stimulation, for example noninvasive brain stimulation (NIBS), is provided to the subject, at block 104. In some embodiments, the stimulation, for example NIBS, is applied to at least one stimulation brain target with parameter values suitable for modulating the activity of neurons in the brain target (e.g., excitatory and / or inhibitory effects) and / or suitable for modulating the activity of the brain target, such as increasing or decreasing and / or modify (e.g., increase and / or decrease) the reactivity of that brain target and / or modifying connectivity within or between brain areas.

[0105] According to some exemplary embodiments, the NIBS, for example TMS is applied to at least one brain target affecting a learning process in the subject. In some embodiments, the TMS is applied to a DEPFC brain region of the subject, for example a left DEPFC, using an iTBS protocol. In some embodiments, during the providing of the TMS to the subject, a human detectable interface, for example a visual and / or an audio interface is presented to the subject. Optionally, the human detectable interface is an interface presented to the subject during a NF training.

[0106] According to some exemplary embodiments, NF training is delivered to the subject, at block 106. In some embodiments, the NF training is delivered to the subject up to 60 minutes, up to 40 minutes, up to 30 minutes, up to 20 minutes, up to 15 minutes, up to 10 minutes, up to 5 minutes, or any intermediate, smaller or larger time period, from completion of the TMS provided to the subject. Alternatively, the NF training is delivered during the application of the TMS or partially overlaps with the application of the TMS. In some embodiments, during the NF training the subject is trained to self-modulate activity of at least one NF brain target by modulating an online feedback signal presented to the subject. Optionally, the feedback signal comprises at least part of the human detectable interface presented to the subject during the application of NF (optionally with TMS) at block 106.

[0107] According to some exemplary embodiments, during the NF training at block 106 the subject brain is measured directly or indirectly (e.g., using EEG, fMRI informed EEG, intracranial EEG, fMRI or neuroanatomically informed NF-fMRI), and the feedback signal is modified according to changes in the measurements. For clarity and without necessarily being limited to it, EEG is used as a representative signal used for feedback. In some embodiments, EEG signals with specific parameter values which indicate an activity of the at least one NF brain target are identified in the measured EEG signals, and the feedback signal is modified based on the identified EEG signals according to the activation of the at least one NF brain target, for example as described in US Patent No. 10,893,822 “method and system for use in monitoring neural activity in a subject's brain”, international patent application publication no. WO202 1260697 Al “ventral striatum activity”, international patent application publication no. W02020100144A1 “resilience training”, and international patent application publication no. WO2023175610A1 “depression treatment”, all incorporated herein in their entirety.

[0108] In some embodiments of the invention, NF is applied to modulate activity, reactivity and / or connectivity to parts of the reward system, for example, the ventral striatum and / or to parts of the threat system, e.g., the amygdala.

[0109] According to some exemplary embodiments, optionally NIBS is provided to the subject at block 108. In some embodiments, the NIBS is optionally applied to at least one brain target of the subject, after completion of the NF. In some embodiments, the NIBS is optionally applied up to 1 hour from completion of the NF, for example up to 40 minutes, up to 30 minutes, up to 20 minutes, up to 10 minutes, up to 5 minutes, or any intermediate, shorter or longer time period from completion (or start) of an NF session. In some embodiments, the NIBS is applied to at least one brain target affecting a memory process in the subject, for example to strengthen memory formation and / or memory consolidation in the subject. In one example, the hippocampus (via connectivity) is used as a target, for example, based on “Hippocampal-targeted Theta-burst Stimulation Enhances Associative Memory Formation”, J Cogn Neurosci. 2018 Oct; 30(10): 1452-1472. doi: 10.1162 / jocn_a_01300.

[0110] In another example, such connectivity can serve as an empowerment for improving targeted hippocampus-NF which is aimed to improve memory consolidation during stress to enhance resilience. See Schwabe, E., & Wolf, O. T. (2013), “Stress and multiple memory systems: from 'thinking' to 'doing'” Trends Cogn Sci, 17(2), 60-68.

[0111] It is noted that various timed relationships between NIBS and NF may be used, including, NIBS followed by NF (per session), NIBS applied during a session and / or a session and interleaving NIBS applications with NF during an NF session. For example, if an NF session includes between 3 and 5 NF units, NIBS may be applied, before, during and / or after more than one of these NF units.

[0112] It is also noted that a treatment may include multiple different NIBS applications, potentially targeting more than one brain region (e.g., different applications targeting different brain regions). Similarly, more than one type (e.g., different target scoring) of NF may be applied, with different NF types potentially targeting different brain regions of networks. Such applications and types may be mixed within a session and / or between sessions.

[0113] Exemplary stimulation effect

[0114] According to some exemplary embodiments, stimulation of at least one stimulation brain target is delivered with parameter values suitable to or predicted to increase efficacy of NF training. In some embodiments, the stimulation brain target is a region or network that is activated during NF training and is associated with training success or learning. In some embodiments, increasing activity of the stimulation brain target prior to NF training generates a time window in which the activity of the stimulation brain target is modulated, for example, enhanced or decreased and / or its responsiveness is increased or decreased and / or its connectivity is increased or decreased (in general, the term “neuromodulated” may be used) and delivery of NF training during the generated time window is expected to increase the efficacy of the NF training compared to efficacy of NF training without prior stimulation. In some embodiments, the time window, for example beneficial time window is up to 60 minutes, up to 40 minutes from completion of the stimulation, for example up to 30 minutes, up to 20 minutes, up to 10 minutes from completion of the stimulation. According to some exemplary embodiments, the stimulation parameters values (e.g., optionally including a location of the stimulation target) are selected according to a selected stimulation target brain area. For example, if an increase in activity, optionally leading to increased plasticity, of a stimulation target inhibits or interferes, directly or indirectly with NF training, then the selected stimulation parameters values include stimulation parameters values that reduce an activity of the selected stimulation target, thereby reducing, directly or indirectly, an inhibiting effect of the selected stimulation target on the NF training. Alternatively, if an increase in activity, optionally leading to increased plasticity, of a stimulation target enhances, directly or indirectly, the NF training, then the selected stimulation parameters values include stimulation parameters values that are suitable to increase an activity of the selected stimulation target, thereby enhancing directly or indirectly a beneficial effect of the selected stimulation target on the NF training.

[0115] Reference is now made to figs. 2A-2C depicting effect of brain stimulation on brain activity, according to some exemplary embodiments of the invention.

[0116] According to some exemplary embodiments, stimulation 202, for example NIBS is applied to at least one stimulation target 204 in a brain 205 of a subject. In some embodiments, the stimulation target 204 is part of a network 206 comprising the stimulation target 204 and at least one brain region 208. In some embodiments, activation of the network 206 affects an ability of a subject to self-modulate at least one NF target 210, for example during a NF treatment. In some embodiments, network 206 is involved in a learning process performed by a subject undergoing NF treatment.

[0117] According to some exemplary embodiments, the NIBS stimulation is delivered with parameter values suitable to modulate, for example, increase activity of the stimulation target 204, for example as shown in fig. 2B. In some embodiments, the effect of the stimulation 202 on the regions 204, 208 and the network 206 is transient and possibly lasts up to 40 or 60 minutes, or longer, from completion of the NIBS. It is noted that stimulation target 204 may be functionally connected to another region 208.

[0118] According to some exemplary embodiments, for example as shown in fig. 2C, delivery of NF 212, for example active NF, following the stimulation 202 increases an efficacy of the NF training. In some embodiments, delivery of NF 212 following the stimulation 202 may allow the subject, for example, to reach a better capacity for self-neuromodulation of the NF target 210 and / or in a shorter time period. Additionally, or optionally, delivery of NF 212 following the stimulation 202 may allow, for example, to enhance one or more memory processes (e.g., implicit, procedural, episodic and / or semantic) of the subject to acquire and / or remember the applied self-neuromodulation process and / or features of the NF 212, for example a mental strategy applied by the subject during the NF 212 to self-modulate activity of the NF target 210 or the interface itself.

[0119] It is noted that such effect may not be direct between the NIBS stimulation and the increase in NF efficacy - e.g., with no direct connection (so ignoring the small arrow shown) between the NF target and the learning circuit, but rather an influence domain-general aspects of the NF.

[0120] Exemplary stimulation-NF training

[0121] According to some exemplary embodiments, stimulation, for example NIBS is provided to a subject as part of a NF training program. In some embodiments, the NIBS, for example TMS, is provided prior to performing NF training in which the subject is requested to modify a feedback interface presented to the subject, by performing a mental task. In some embodiments, the NF training program comprises one or more NF training sessions. In some embodiments, at least one NF training session of the NF training program comprises providing stimulation to a subject prior to performing active NF training. Alternatively, each NF training session comprises providing stimulation prior to performing active NF. Alternatively, stimulation is provided on- demand to a subject, for example in a case where the subject was not able to reach a target goal of a previous NF training session.

[0122] Reference is now made to fig. 2D, depicting portions of a NF training session that includes stimulation, according to some exemplary embodiments of the invention.

[0123] According to some exemplary embodiments, a NF training session 230 comprises a stimulation portion 232, in which NIBS stimulation is applied to at least one stimulation brain target in a subject brain, and NF training 234 delivered to the subject after completion of the stimulation 232. In some embodiments, the NF training 234 is delivered to the subject within an effective time window 236 following stimulation 232. In some embodiments, the effective time window is a time window in which the stimulation delivery is expected to improve results of the NF training. In some embodiments, the effective time window lasts up to 40 minutes from completion of the stimulation, for example up to 30 minutes, up to 20 minutes, up to 10 minutes or any intermediate, shorter or longer time duration from completion of the stimulation 232.

[0124] According to some exemplary embodiments, optionally, a second stimulation 238 is optionally provided to the subject following the NF training 234, for example to enhance and prolong a long term effect of the NF training 234, for example by enhancing memory generation and / or consolidation processes in the brain. This is optionally provided by targeting the hippocampus. Targeting the DLPFC may augment procedural learning.

[0125] According to some exemplary embodiments, stimulation 232 is delivered as a series / trains 240 of magnetic field pulses or bursts, optionally delivered in a certain temporal configuration (e.g., at a given frequency, pattern, and interval 242 between trains). For example to increase activity of neuron cells at the stimulation brain target at one exemplary temporal configuration (e.g., intermittent theta burst stimulation). Alternatively, the temporal configuration of the pulses or bursts are delivered, for example, to reduce and / or inhibit activity of neurons cells at a stimulation brain target (e.g., continuous theta burst stimulation). Other types of TMS may be applied as well.

[0126] According to some exemplary embodiments, an overall duration of the stimulation 232 is between 30 seconds and 10 minutes, for example between 30 seconds and 5 minutes, between 1 minute and 4 minutes, between 2 minutes and 4 minutes, between 3 minutes and 10 minutes, or any intermediate, shorter or longer time period.

[0127] Typically, a theta burst TMS application is up to 5-6 minutes, but shorter or longer applications may be used. A repetitive TMS may be typically longer, for example, up to 20-40 minutes, though shorter or longer applications may be provided.

[0128] According to some exemplary embodiments, the NF training 234 is delivered as a series of NF blocks 244 and 246. In some embodiments, each or at least one NF block 244 and 246, comprises a baseline portion in which baseline activity of at least one NF brain target is measured, followed by a regulate portion in which the subject is requested to modify a feedback signal and activity of the of at least one NF brain target is measured while the subject applies the task, for example mental task in order to modify the feedback signal. In some embodiments, optional stimulation 238 is delivered, for example as described with respect to stimulation 232, optionally to the same stimulation brain target. Alternatively, stimulation 238 is delivered to at least one different stimulation brain target, different from the stimulation target in stimulation 232.

[0129] According to some exemplary embodiments, an overall duration of the NF training 234 is between 3 minutes and 60 minutes, for example between 3 minutes and 20 minutes, between 10 minutes and 30 minutes, or any intermediate, shorter or longer time period. Alternatively or optionally, the NF training duration is determined according to the effective time window generated by the stimulation 232. Optionally, the NF training duration is shorter than the expected effective time window 236. According to some exemplary embodiments, an overall duration of a NF training session which includes at least one stimulation portion, for example NF session 230, is between 3 minutes and 120 minutes, for example between 3 minutes and 30 minutes, between 10 minutes and 50 minutes, or any intermediate, shorter or longer time period. In some embodiments, stimulation 232, NF training 234 and / or optional stimulation 238 are repeated at least twice during a NF training session. In some embodiments of the invention, a delay (e.g., by the system described below and / or by guidance provided thereby) is enforced between TMS applications, for example, between 1-10 minutes, between 10-40 minutes and / or between 40-80 minutes.

[0130] Exemplary system

[0131] According to some exemplary embodiments, at least one system is used for delivery of NF and for delivery of stimulation to the same subject. In some embodiments, the system is a system that comprises at least one parameter of a combined stimulation and NF treatment, for example timing for delivery of the NF following stimulation, and / or stimulation parameters. In some embodiments, the system delivers one or more indications with instructions to activate a stimulation device according to the at least one parameter. Optionally or additionally, the system receives an input signal regarding the activation of the stimulation device, and generates one or more indications regarding the NF treatment in response to the received input signal.

[0132] Alternatively, the system is configured to actively deliver both NF training and stimulation to the subject, and comprises a stimulator, for example a pulse generator, for delivery of the stimulation.

[0133] Reference is now made to fig. 3 depicting a system to be used in delivering NF and stimulation to a subject, according to some exemplary embodiments of the invention.

[0134] According to some exemplary embodiments, a system 302 is used for delivery of a combined procedure which includes delivery of NF training and delivery of stimulation, for example TMS, to the same subject. In some embodiments, the system comprises a NF device 304 comprising a control circuitry 206 and a memory circuitry, for example memory 308 functionally coupled to the control circuitry 306. In some embodiments, the memory 308 stores at least one protocol of a combined stimulation and NF treatment, or at least one parameter thereof. In some embodiments, at least one parameter of stimulation comprises at least one of, information on at least one stimulation target, for example coordinates, name, and / or location, stimulation parameters for example stimulation intensity, stimulation frequency, stimulation duration, and / or duration of intervals between bursts of pulses, previously used stimulation parameters values and / or stimulation target, duration of a time window for delivering NF following stimulation. According to some exemplary embodiments, the control circuitry 306 is configured to determine values of the at least one stimulation parameter according to the stimulation target. In some embodiments, the control circuitry 306 is configured to determine a duration of the time window following stimulation for delivery of NF based on the stimulation target and / or the determined stimulation parameters.

[0135] According to some exemplary embodiments, the NF device 304 comprises a user interface 310 configured to generate and deliver an indication, for example a human detectable indication. In some embodiments, the control circuitry 306 is configured to signal the user interface 310 to generate and deliver an indication with information about at least one of, a stimulation target, stimulation parameter values and / or duration of the time window for delivery of NF training, optionally to a user of the NF device 304.

[0136] According to some exemplary embodiments, the control circuitry 306 signals the user interface to generate and deliver a human detectable indication with at least one of, information about the at least one stimulation target, location of the stimulation target, coordinates of the stimulation target, and / or name of the stimulation target. In some embodiments, the user interface 310 is configured to receive an input signal from the user with information that a stimulation was initiated and / or that the stimulation was completed. In some embodiments, the control circuitry 306 is configured to calculate a duration of the time window for delivering of the NF training based on the input signal received by the user interface 310.

[0137] According to some exemplary embodiments, the memory 308 stores information about at least one NF training, for example a NF training configured to teach a subject to modulate an activity of at least one NF brain target. In some embodiments, the memory 308 stores at least one model, for example a fingerprint or an electrical fingerprint (EFP) of activity of the at least one NF target, that correlates between EEG signals and activity of the at least one NF brain target. In some embodiments, the model correlates between EEG signals and activity of the at least one NF target as identified in spatial scan data, for example Blood Oxygenation Level Dependent (BOLD) activity of the at least one NF brain target, for example as described at US Patent No. US10893822B2, incorporated herein as a reference in its entirety.

[0138] According to some exemplary embodiments, during NF training, at least one electrode 312 coupled to the subject head 314 records at least one electrical signal. In some embodiments, the control circuitry 306 measures at least one EEG signal based on the recorded signals. In some embodiments, the control circuitry 306 applies the model of the NF target on the measured EEG signal to identify at least one EEG signal that indicates activity of the at least one NF target. In some embodiments, the control circuitry 306 signals the user interface 310 to modify a feedback signal presented to the subject during active NF training, according to the activity of the at least one NF brain target.

[0139] According to some exemplary embodiments, during active NF training the control circuitry 306 signals the user interface 310 to generate and deliver an indication to the subject with instructions to apply a strategy, for example a mental strategy, to try and modify the feedback signal to reach a target modified activity signal. In some embodiments, the control circuitry 306 is configured to determine an efficacy of the active NF training by calculating a score indicating an ability of the subject to modulate an activity of the at least one NF target in a desired direction, for example to downregulate or to upregulate activity, based on changes in the identified EEG signal indicating activity of the at least one NF target during the active NF training. An example of a use for determining activity of at least one brain target based on signals indicating brain activity is described at US Patent No. US10893822B2, incorporated herein as a reference in its entirety. An example of a NF training is described at international patent applications publication numbers: WO2020121299A1, WO2021260697A1, and WO2023175610A1, all incorporated herein as a reference in their entirety.

[0140] According to some exemplary embodiments, the control circuitry 306 is configured to modify or suggest a modification of at least one parameter of the stimulation, for example TMS, based on a determined efficacy of the NF training. In some embodiments, the control circuitry 306 is configured to signal the user interface 310 to generate and deliver a human detectable indication with a suggested modification of the at least one stimulation parameter to a user of the device 304. Optionally or additionally, the control circuitry modifies or suggest to modify at least one parameter of the NF training based on a determined efficacy of the NF training.

[0141] According to some exemplary embodiments, the NF device 304 comprises a communication circuitry 316 configured to communicate with at least one remote device 318, optionally using wireless signals. In some embodiments, the remote device 318 comprises at least one of, a server, a cloud storage and / or processing unit, a remote computer, for example a computer located at a distance of at least 1 meter from the device 304, and / or a handheld device. In some embodiments, at least some or all of the actions performed by the control circuitry 306 are performed by the remote device 318. In some embodiments, results of the processing performed by the remote device are transmitted to the device 304 via the communication circuitry 316, and are optionally stored in the memory 308 and / or are delivered to the user interface or to the control circuitry 306.

[0142] According to some exemplary embodiments, the system 302 comprises a stimulation device 320, optionally in communication with the remote device 318 and / or with the NF device 304. In some embodiments, the stimulation device 320, for example a TMS device, comprises a control circuitry 322 and a memory circuitry 324 functionally coupled to the control circuitry 322. In some embodiments, the memory 324 stores at least one stimulation protocol or values of at least one parameter of the stimulation. In some embodiments, the at least one parameter comprises, stimulation location, stimulation target, stimulation intensity, stimulation frequency, stimulation duration, duration of one or more stimulation bursts each includes one or more pulses, duration of an interval between stimulation bursts, overall stimulation duration, and / or maximal number of pulses delivered to the subject during stimulation.

[0143] Where stimulation device 320 is manual, the system may indicate to an operator where to place device 320 and / or what (other) parameters to use in activating and / or receive indication that it was operated.

[0144] According to some exemplary embodiments, the stimulation device 320 comprises at least one pulse generator 326 configured to generate electrical pulses according to the stimulation protocol and / or stimulation parameter values stored in the memory 324. In some embodiments, the pulse generator 326 is connectable to at least one coil 328 configured to be positioned near or in contact with the subject head 314 and above a location of a selected stimulation target. Alternatively, for example when delivering deep TMS, the device 320 and / or the pulse generator 326 is functionally coupled to helmet configured to be positioned on the subject head 314 that comprises at least one coil. In some embodiments, the pulse generator is configured to deliver to the electrical pulses to the coil 328 (or other magnetic field generator is used), for generating a magnetic field with an intensity sufficient to penetrate through a skull of the subject head 314 and affect the activity of the at least one selected stimulation target.

[0145] According to some exemplary embodiments, the stimulation device 320 comprises at least one user interface 330 configured to generate and deliver at last one human detectable indication, for example to a user of the device 320.In some embodiments, the control circuitry 322 is configured to signal said user interface 330 to generate said human detectable indication when stimulation initiates, during stimulation and / or when stimulation is completed. Optionally, the user interface 330 generates and delivers the human detectable indication when the coil 328 is positioned above a selected stimulation target.

[0146] According to some exemplary embodiments, the stimulation device 320 comprises a communication circuitry 332 configured to communicate, optionally via wireless signals, with the remote device 318. In some embodiments, the remote device 318 is used to control both the stimulation device 320 and the NF device 304, optionally when delivery a combined stimulation and NF training. Exemplary process for delivering of stimulation during NF training

[0147] According to some exemplary embodiments, during NF training, a subject, for example a trainee, is requested to modulate a feedback signal which correlates with activity of at least one brain target, optionally by requesting the subject to apply a mental strategy. In some embodiments, in case the subject is not able to modulate the feedback signal to reach a target modified signal, the subject receives a stimulation treatment, for example TMS stimulation prior to at least one additional NF training. In some embodiments, the stimulation is applied to increase a beneficial effect of at least one brain target on a learning process performed during the NF training.

[0148] Reference is now made to fig. 4, depicting a process for delivering of stimulation during a NF training program, according to some exemplary embodiments of the invention.

[0149] According to some exemplary embodiments, a NF training program comprises two or more NF training sessions, scheduled with a minimum interval of at least 1 hour between them, for example a minimum interval of at least 6 hours, of at least 12 hours, of at least 24 hours, of at least 48 hours, of at least 3 days, or any intermediate, shorter or longer interval between them.

[0150] According to some exemplary embodiments, a NF training session is delivered to a subject, at block 402, using optionally a system or a device, for example the device 304 shown in fig. 3. In some embodiments, during the NF training session, the subject is instructed to try and modulate a feedback signal presented to the subject, for example by applying at least one mental task, for example mental strategy. In some embodiments, during the NF training session, EEG signals indicating activity of at least one brain target are measured from the subject brain using at least one electrode. In some embodiments, the EEG signals indicate activity of the at least one brain target, for example BOLD activity of the brain target. In some embodiments, the feedback signal presented to the subject during the NF training session is modulated according to the activity of the brain target.

[0151] According to some exemplary embodiments, a goal of the NF training session is to teach a subject to self-regulate, for example to downregulate or upregulate activity of the brain target, to reach a desired activity of the brain target, by applying at least one mental task.

[0152] According to some exemplary embodiments, a healthcare professional (HCP), and / or a NF device determines if regulation performance of the subject is a target performance, at block 404. In some embodiments, the HCP and / or device determines if the subject participating in the NF training session was able to reach a target regulation of the brain target during the NF training. For example, if the subject was able to downregulate or upregulate the brain target according to goals of the NF training, during the NF training session. According to some exemplary embodiments, if regulation performance of the subject during the NF session is a target performance, then the subject receives at least one additional NF session, for example at block 402 or 408. In some embodiments, the subject ends the NF training program following at least one additional NF session, at block 410.

[0153] Optionally, after completion of the NF training program, the subject, receives at least one additional maintenance NF training session, for example to maintain an effect of the NF training program. In some embodiments, the NF maintenance comprises a combined treatment, in which the subject first receives NIBS, for example TMS, followed by an NF training session. In some embodiments, the NF training session is delivered during the TMS, at least partly simultaneously with the TMS, or up to 60 minutes, up to 40 minutes, up to 30 minutes, up to 20 minutes, up to 10 minutes, up to 5 minutes from completion of the TMS.

[0154] According to some exemplary embodiments, if the regulation performance is not a target performance after the NF session (optionally measured at a later session), the subject receives an additional NF session which includes applying TMS stimulation to at least one stimulation brain target, optionally delivered during the NF training or prior to NF training, at block 406. In some embodiments, the subject receives the TMS stimulation with parameter values expected to improve the performance of the subject in the NF training following the TMS. In some embodiments, NF training is delivered to the subject during the TMS, at least partly simultaneously with the TMS, or up to 60 minutes, up to 40 minutes, up to 30 minutes, up to 20 minutes, up to 10 minutes, up to 5 minutes from completion of the TMS.

[0155] According to some exemplary embodiments, regulation performance of the subject following the TMS and the NF training, is determined at block 414. In some embodiments, if the regulation performance is not a target performance, then optionally at least one parameter of the TMS and / or of the NF training is modified at block 416. In some embodiments, the at least one parameter of the TMS comprises at least one of, stimulation target, stimulation intensity, stimulation frequency, overall stimulation duration, and / or interval duration between delivery of stimulation bursts. In some embodiments, the at least one parameter of the NF training comprises at least one of, a feedback signal presented to the subject, duration of NF training, a starting level of the NF training.

[0156] According to some exemplary embodiments, an additional NF session which includes TMS is delivered to the subject, at block 406, optionally with the modify NF and / or TMS parameter.

[0157] Alternatively, a different treatment or training is provided to the subject at block 418. Other screening methods (which may lead to various treatment methods) may be used as well. In a first variant, the response of a subject to TMS (or other NIBS), without NF, is evaluated. Such patients may be subjected to fewer NF sessions. This may result in reduced costs and / or bother to the patient

[0158] In another variant, NF training is applied until the subject shows some ability to self- neuromodulate (e.g., reduction in a brain area activity by 10% from baseline, e.g., of the amygdala) and thereafter TMS or other NIBS is applied, optionally only thereafter. This is supported by observations of a small number of subjects which suggest that TMS has a more beneficial effect in subjects that show some amount of self-neuromodulation capacity beforehand.

[0159] In another variant, NF+TMS treatment is provided specifically to subjects shown to respond to TMS and / or NF+TMS, even if (or, optionally, especially) their NF response is sufficient for therapy. This may result in shorter and / or fewer NF sessions or a more sustained effect in long term (one or more days or weeks or months).

[0160] In another variant, NF is used to enhance the leaming / memory circuits before the NIBS application. An EEG-signature of the relevant learning circuit may help in detecting that the NF had such desired effect.

[0161] It is noted that therapy may include targeting multiple brain regions / circuits and this may apply both to NIBS and NF. For example, TMS may be selectively used both to improve procedural learning circuits and to improve episodic learning circuits. For example, TMS may be used to target the fronto striatal through the DLPFC and / or target using parietal stimulation for hippocampus based learning circuit.

[0162] Exemplary selection of a subject for NF training

[0163] Reference is now made to fig. 5, depicting a process for selecting a subject for a NF training procedure, according to some exemplary embodiments of the invention.

[0164] According to some exemplary embodiments, a subject is optionally diagnosed with a disorder or at least one symptom thereof, at block 502. In some embodiments, the disorder comprises a mental disorder, for example as defined in the diagnostic and statistical manual of mental disorders (DSM). In some embodiments, the subject is diagnosed with the mental disorder or at least one symptom thereof, by a HCP. In some embodiments, the mental disorder comprises a stress disorder, for example PTSD, or depression. In some embodiments, the mental disorder as defined in the DSM, for example in version 5 of the DSM comprises at least one of, a Neurodevelopmental Disorder, a Schizophrenia Spectrum and Other Psychotic Disorder, a Bipolar and Related Disorder, a Depressive Disorder, an Anxiety Disorder, an Obsessive- Compulsive and Related Disorder, a Trauma- and Stressor-Related Disorder, a Dissociative Disorder, a Somatic Symptom and Related Disorder, a Feeding and Eating Disorder, an Elimination Disorder, a Sleep-Wake Disorder, a Sexual Dysfunction disorder, a Gender Dysphoria disorder, a Disruptive, an Impulse-Control, and Conduct Disorder, a Substance- Related and Addictive Disorder, a Neurocognitive Disorder, a Personality Disorder, a Paraphilic Disorder, or any other mental disorder according to the DSM.

[0165] According to some exemplary embodiments, a HCP decides to provide NF training to the subject, at block 504. In some embodiments, the NF training is a method to treat a subject diagnosed with the mental disorder and / or to treat at least one symptom of the mental disorder. In some embodiments, the NF training is a procedure in which the subject, for example a trainee, learns how to self-modulate activity of at least one NF brain target in a way that improves the mental disorder and / or at least one symptom thereof.

[0166] According to some exemplary embodiments, a screening NF session which includes delivery of stimulation, for example TMS, is delivered to the subject. In some embodiments, during the NF screening session, the subject receives stimulation to at least one brain target followed by NF training, in which the subject tries to self-modulate activity of the at least one NF brain target, by trying to modify a feedback signal presented to the subject. In some embodiments, the feedback signal is modified according to changes in activity of the at least one NF brain target. In some embodiments, during the NF training the subject is requested to apply a mental strategy that will result with a target modification of the feedback signal. In some embodiments, the NF training is delivered up to 60 minutes, up to 40 minutes, up to 20 minutes, up to 10 minutes, or any intermediate, shorter or longer time period from completion of the TMS delivery. In some embodiments, the TMS and NF are delivered, for example as described at block 406 in fig. 4, and / or as described at blocks 104 and 106 in fig. 1.

[0167] According to some exemplary embodiments, the process includes determining if regulation of the NF brain target during the NF screening is a target regulation, for example a desired regulation, at block 508. In some embodiments, the determining comprises determining if the subject was able to self-regulate an activity of the NF brain target to reach a target activity of the NF brain target, during the NF screening session.

[0168] According to some exemplary embodiments, if the subject was able to reach a target activity of the NF target, then optionally one or more parameters of the NF training is modified, at block 510.

[0169] According to some exemplary embodiments, if the subject was able to reach a target activity of the NF target during the NF screening session, then the subject is selected to receive the NF training program, at block 512. Alternatively, the subject is selected to receive a combined treatment of both TMS and NF training, at block 514.

[0170] According to some exemplary embodiments, if the subject was not able to reach a target activity of the NF target during the NF screening at block 506, then at least one parameter of the NF training is optionally modified at block 516. Alternatively or optionally, at least one parameter of the TMS is modified at block 518. In some embodiments, the NF screening session is repeated at block 506, optionally with the modified NF parameter and / or with the modified TMS parameter.

[0171] Alternatively, if the subject was not able to reach a target activity of the NF target during the NF screening at block 506, then a different treatment or a different training is optionally provided to the subject. In some embodiments, target activity is evaluated at a later session. This has the potential benefit of capturing any delayed effect of TMS or of combined TMS+NF. In a particular example, patients with better regulation during a first session have been observed, anecdotally, to have regulation in later NF sessions enhanced by TMS+NF application as compared to just NF. Such enhancement is not always detectable in the current session.

[0172] According to some exemplary embodiments, a subject that is optionally diagnosed with a disorder at block 502, is found not suitable for undergoing the NF training, and is optionally receiving a different treatment, for example, a drug treatment. In some embodiments, the process described in fig. 5, from block 506 is used to select a subject for the NF training, even if the subject was initially found to be not suitable for the NF training. In some embodiments, if regulation performance of the subject is a target performance, then the subject is selected either to receive the NF training at block 512 or to receive a NF training that includes TMS at block 514.

[0173] Exemplary system actions

[0174] According to some exemplary embodiments, a system for delivery of NF training, for example system 302 shown in fig. 3 is used to guide a user in delivering a NF training which is combined with stimulation. In some embodiments, the system provides at least one suggestion and / or at least one indication to the user, which are related to activating a stimulation device, for example TMS device 320. Alternatively, the system, is functionally coupled and optionally directly controls the operation of the stimulation device.

[0175] Reference is now made to fig. 6, depicting actions performed by a system for delivery of a neurofeedback training, according to some exemplary embodiments of the invention.

[0176] According to some exemplary embodiments, a system, for example system 302 initiates a protocol of a combined NF and TMS procedure, at block 602. In some embodiments, a control circuitry of a NF device, for example control circuitry 306 of NF device 304 initiates the protocol in response to an input signal received by a user interface, for example user interface 310. In some embodiments, the user of the NF device selects the protocol stored in the memory of the NF device, for example memory 308, using the user interface 310.

[0177] According to some exemplary embodiments, an indication to initiate application of stimulation, for example TMS, is generated and delivered at block 604. In some embodiments, the indication, for example a human detectable indication, is generated and / or delivered by the user interface 310.

[0178] According to some exemplary embodiments, an indication with stimulation parameters is optionally provided at block 606. In some embodiments, the indication, for example a human detectable indication, is delivered with information about suggested stimulation parameter values, optionally by the user interface 310.

[0179] According to some exemplary embodiments, optionally, during the delivery of TMS, the NF device presents to the subject an interface, for example a visual and / or an audio interface, that will be used during the NF training, at block 608.

[0180] According to some exemplary embodiments, an input signal indicating that TMS is completed is received by the NF device, at block 610. In some embodiments, the input signal is received from a user of the NF device delivering the TMS, optionally using the user interface 310.

[0181] According to some exemplary embodiments, the NF device sets or calculates a time window for delivery of NF training, at block 612. In some embodiments, the time window, is the effective time window 236 shown in fig. 2D. In some embodiments, the control circuitry, for example control circuitry 306 of the NF device sets or calculates the effective time window.

[0182] According to some exemplary embodiments, optionally the NF device delivers an indication with information about the effective time window, at block 614. In some embodiments, the indication is delivered by the user interface 310.

[0183] According to some exemplary embodiments, the NF device delivers one or more active NF sessions, at block 616. In some embodiments, the one or more active NF sessions, comprise sessions 244 and 246 shown in fig. 2D. In some embodiments, during the one or more active NF sessions, the subject receives NF training 618. In some embodiments, during the NF training the subject is presented with a feedback signal comprising a visual and / or an audio interface, and is instructed to apply a strategy, for example a mental strategy, to try and modify the feedback signal into a modified target feedback signal. In some embodiments, the feedback signal and optionally the instructions to the user are delivered by the user interface 310. According to some exemplary embodiments, during the presentation of the feedback signal, at least one EEG signal is measured at block 620. In some embodiments, the EEG signal is measured by the control circuitry 306 using at least one algorithm, software program, and / or formula stored in the memory 308. In some embodiments, the control circuitry 306 is configured to identify at least one activity EEG signal in the measured EEG signal, which indicates activity, for example BOLD activity, of at least one NF brain target, and to modify the feedback signal according to the identified activity EEG signal. Optionally, prior to presentation of the feedback signal, a baseline activity EEG signal is measured while the subject is at rest and is presented with a neutral audio and / or visual interface configured not to affect the activity of the at least one NF brain target.

[0184] According to some exemplary embodiments, the NF training at block 618, the measurement of EEG signals at block 620, and / or the delivery of the one or more active NF sessions at block 616, is performed as previously described at US Patent No. 10,893,822 “method and system for use in monitoring neural activity in a subject's brain”, international patent application publication no. WO2021260697 Al “ventral striatum activity”, international patent application publication no. W02020100144A1 “resilience training”, and international patent application publication no. WO2023175610A1 “depression treatment”, all incorporated herein in their entirety.

[0185] According to some exemplary embodiments, optionally, the NF device delivers an indication to initiate at least one additional TMS, optionally after a delay, for example stimulation 238 shown in fig. 2D, at block 622. In some embodiments, the indication, for example a human detectable indication, is delivered by the user interface 310. In some embodiments, the indication comprises information and / or a suggestion for a stimulation target and / or values of at least one stimulation parameter.

[0186] According to some exemplary embodiments, the NF device calculates a regulation score, indicating a change in the activity of the at least one NF target during the NF training, at block 624. In some embodiments, the regulation score is calculated based on a change in activity of the at least one NF target during NF training, relative to baseline activity of the NF target.

[0187] According to some exemplary embodiments, the NF device determines a success of the subject in reaching a desired modulation of the NF brain target, at block 626. In some embodiments, the success is determined by determining a relation between the regulation score calculated at block 624 and reference value indicating a target, for example a desired regulation of the NF brain target. According to some exemplary embodiments, if the subject has not reached a target success in regulation of the NF target, then the NF device provides an indication with a suggestion to modify at least one parameter of the TMS and / or of the NF delivered to the subject, at block 628. In some embodiments, the indication is provided by the user interface 310. In some embodiments, NF training is provided until a patient can meet a first target, such as downregulating the amygdala a certain percentage below a baseline (and / or upregulating a hippocampus or striatum - a learning circuit - potentially improving the effect of TMS applied prior to NF, so the overall effect on target-NF is improved) and thereafter TMS may be applied as well.

[0188] According to some exemplary embodiments, the NF device optionally provides an indication with at least one modified TMS parameter, at block 630.

[0189] According to some exemplary embodiments, the NF device provides an indication to repeat the TMS, at block 632.

[0190] According to some exemplary embodiments, if the subject has reached a target success in regulation of the NF target, then the NF device delivers an indication with suggestion to continue with a protocol of NF only, at block 634. Alternatively, the NF device delivers an indication with suggestion to continue with a protocol on NF combined with TMS, at block 636.

[0191] Exemplary validation studies

[0192] Studies were conducted in order to see whether a combined TMS-NF training protocol is more effective in teaching subjects to regulate activity of at least one brain target, compared to a training protocol which includes only NF training with sham TMS stimulation.

[0193] In a first study, Healthy participants ages 18-40 were recruited through ads in social media and university forums. Participants signed informed consent according to the declaration of Helsinki and the institutional procedures. Exclusion criteria included neurologic or psychiatric diagnosis, metallic implants or non-removable metals, history of migraines, pregnancy, - history of epilepsy or seizures, also of first degree relatives and history of bad reaction to TMS. Each participant participated in 3 sessions lasting up to 2 hours, with at least 24 hours between sessions. During the first session, a general explanation of the study was given, and consent forms signed. Then, each participant underwent a short MRI scan including anatomical and resting-state sequences which were used to select the stimulation target. In the second session all participants received sham TMS stimulation before the NF training session. In the third session participants randomly assigned to excitatory TMS or sham (and in some embodiments could be assigned to inhibitory TMS) and if in a TMS group, received real stimulation before the NF training session. Fig. 7A shown the general study scheme. NF training: down regulation of amygdala finger print with a bar interface. NF transfer: down regulation with no feedback & with another feedback interface (e.g., a virtual 3D scenario, following Keynan et al, 2018). fMRI before TMS Acquisition:

[0194] Data was acquired on a Siemens Magnetom Prisma 3T scanner at the Sagol Brain Institute of the Tel Aviv Medical Center using a 64-channel head coil. A multi-echo, multi-band resting-state fMRI scan was collected using a Ti- weighted echo-planar sequence covering the full brain (TR: 1500ms; TE1: 12.40ms, TE2:28.63ms, TE3:44.86ms, TE4:61.09ms; FOV: 216mm; FA: 70° ; voxel size: 2.73x2.73x2.5mm; 60 slices) with 400 volumes for a total acquisition time of 10 minutes. A pair of spin echo EPI images with opposite phase encoding directions (AP and PA) were acquired to correct spatial distortions. Additionally, a high-resolution (MPRAGE) Tl- weighted image was acquired (TR: 2200ms; TE: 2.51ms; FOV: 256; flip angle: 8°, and 192 axial slices with a 0.9 mm thickness). Analysis: Data was preprocessed using fmriprep version 22.1.1 in each participant’s native T1 space for navigation purposes. Multi-echo data was optimally combined using an adaptive T2* map generated by the tedana package. The stimulation hotspot can be found in various manners. In this example, the location of the hotspot was preselected based on a coordinate used in a previous study (e.g., as described in www(dot)nature(dot)com / articles / s41562-017-0241-z). However, other ways can be used. For example, a seed can be placed in the left dorsal striatum region (MNI -14, 8, 8) for whole -brain functional connectivity analysis, and resulting activation clusters can be combined with an 8mm spherical ROI of the left dorsolateral prefrontal cortex (centered at MNI -41, 32, 3) for a final stimulation hotspot.

[0195] TMS session

[0196] According to some exemplary embodiments, and in the validation study, the TMS was delivered using a Magstim Rapid2 stimulator (Magstim Co. Ltd) and an air-cooled figure-8 coil in a recently developed protocol of intermittent or continuous theta-burst stimulation (iTBS / cTBS). TBS utilizes a triplet of single pulses at a frequency of 50Hz applied in 200ms intervals (5Hz) for a total of 600 pulses. In the cTBS protocol pulses are applied non-stop for 40 seconds, while in the iTBS protocol pulses were in 2-second runs with an ITI of 8 seconds. During the stimulation sessions, a frameless neuronavigation system (BrainSight) consisting of an infrared camera and positioning reflectors was used to direct the coil to the fMRI determined target (see above). Stimulation power was set to 80% of the resting motor threshold measured at each session. In this example, only iTBS was used, but cTBS may be used in some embodiments, in addition or instead. It is noted that, typically, iTBS has excitatory effects and cTBS has inhibitory effects. Depending on the brain region being targeted and the desired effect on NF, either or both may be used, in a same session or in different sessions.

[0197] The coil was placed on the participant’s hand motor cortex, which was identified per participant based on their MRI scan (and in some embodiments may be marked on the EEG cap, for example, manually or using a LED or other computer controlled visual marker), and single pulses at decreasing power were given until a reliable muscle movement (or Motor Evoked Potential by EMG) can no longer be elicited. Each participant was assigned to one of two groups - Sham or iTBS in a semi randomized manner. Optionally some participants may be assigned also to a cTBS group, e.g., in a semi-randomized manner. Optionally or alternatively, grouping assignment may also control for success in the first NF session. To control for sensory effects, sham stimulation was done using the same protocols, but the coil was placed on the participant’s head at a 90-degree angle such that the magnetic field generated is directed away from the scalp.

[0198] NF session following TMS

[0199] An EEG based protocol, aimed at Amygdala-EFP down-regulation was used. At the beginning of each session, participants were mounted with a fabric EEG cap consisting of 16 Ag / AgCl electrodes (EasyCap GmBH), along with conductive gel to reduce the impedance between the electrodes and the scalp. Raw EEG was sampled at 250Hz using a Brainamp amplifier (BrainProducts GmBH) and the OpenVibe software enabling real-time acquisition and manipulation of the data. The software enabled online calculation of the amygdala related EFP, applying a previously developed computational model on the EEG power spectrum. Following a 3-minute open-eyes rest recording, each participant performed 6 cycles of NF training. Each cycle consisted of two condition blocks. First, during the ‘Watch’ condition, the size of a displayed bar is constant, and participants were asked to clear their minds. Then, during the ‘Regulate’ condition, participants are required to decrease the size of the bar as much as possible using any mental strategy. The actual size of the bar will change every 3 seconds according to the calculated EFP during that period normalized by the mean and standard deviation of the ‘Watch’ condition samples.

[0200] Results of the study shown in fig. 7B demonstrate that participants receiving stimulatory stimulation 702 achieved better downregulation of the signal indicating activity of the amygdala brain region (the NF target) relative to the group receiving sham stimulation 704. Additionally, in meeting 3 where stimulation was applied prior to NF, a starting point for regulation was lower in the participants receiving stimulatory stimulation compared to the group receiving sham stimulation. In this study, the iTBS group had n=3 and sham has n=2. In the following study, both iTBS and sham were n=5.

[0201] Figs. 8A-8C show changes in a signal indicating average activity of the amygdala EFP during NF training, between groups of participants receiving stimulation (blue, 802, 804 and 806) compared to groups of participants receiving sham (red, 808, 810 and 812) in each of the three sessions. As shown in fig. 8C, in session 3 (meeting 3) where TMS stimulation is provided, participants receiving stimulation (802, 804, 806) exhibited a larger downregulation in amygdala EFP signal during the regulate session, compared to participants receiving sham stimulation (808, 810, 812), especially during regulation onset.

[0202] In a second validation study, a modified protocol was used, e.g., to assess the effects of learning on the regulation in the session following stimulation, for example as shown in fig. 9A, in which in meeting 2 participants were divided into a first group of participants that received stimulatory, for example excitatory, TMS, a second group of participants received sham stimulation, prior to NF training. In some embodiments, some participants would receive inhibitory TMS. In meeting 3 all groups continue to an NF session without TMS.

[0203] Results of the second validation study shown in figs. 9B and 9C, that the group receiving excitatory TMS (iTBS 902) and which were able to show NF self-neuromodulation during meeting 1 (n=5) was able to downregulate the activity of the amygdala during the third session (the session that followed TMS application prior to training) better than the group of participants receiving sham stimulation when using a training interface during NF, as shown in fig. 9B, and when using a different interface during NF, as shown in fig. 9C.

[0204] As used herein with reference to quantity or value, the term “about” means “within ± 20 % of’.

[0205] The terms “comprises”, “comprising”, “includes”, “including”, “has”, “having” and their conjugates mean “including but not limited to”.

[0206] The term “consisting of’ means “including and limited to”.

[0207] The term “consisting essentially of’ means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0208] As used herein, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof. Throughout this application, embodiments of this invention may be presented with reference to a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as “from 1 to 6” should be considered to have specifically disclosed subranges such as “from 1 to 3”, “from 1 to 4”, “from 1 to 5”, “from 2 to 4”, “from 2 to 6”, “from 3 to 6”, etc.; as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0209] Whenever a numerical range is indicated herein (for example “10-15”, “10 to 15”, or any pair of numbers linked by these another such range indication), it is meant to include any number (fractional or integral) within the indicated range limits, including the range limits, unless the context clearly dictates otherwise. The phrases “range / ranging / ranges between” a first indicate number and a second indicate number and “range / ranging / ranges from” a first indicate number “to”, “up to”, “until” or “through” (or another such range-indicating term) a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numbers therebetween.

[0210] Unless otherwise indicated, numbers used herein and any number ranges based thereon are approximations within the accuracy of reasonable measurement and rounding errors as understood by persons skilled in the art.

[0211] As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0212] As used herein, the term “treating” includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.

[0213] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0214] Although the invention has been described in conjunction with specific embodiments thereof, it is evident that 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.

[0215] It is the intent of the applicant(s) that all publications, patents and patent applications referred to in this specification are to be incorporated in their entirety by reference into the specification, as if each individual publication, patent or patent application was specifically and individually noted when referenced that it is to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is / are hereby incorporated herein by reference in its / their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method for delivery of neurofeedback (NF) training to a subject, comprising: stimulating at least one stimulation brain target in a brain of said subject, to modulate an activity and / or connectivity and / or reactivity thereat; delivering said NF training to said subject following said stimulating, wherein said delivering comprises teaching said subject by said NF training to self-modulate activity and / or connectivity of at least one NF brain target, wherein said stimulating is performed with parameter values and / or timing suitable to increase efficacy of said teaching to provide learning by said subject.

2. A method according to claim 1, comprising: selecting said at least one stimulation brain target prior to said stimulating, wherein said selected at least one stimulation brain target comprises a brain region of a network or a circuit activated during said teaching, associated with the success of the said teaching, associated with learning and / or memory processes that underlie capacity of neuromodulation and / or is a brain target affecting an activation and / or connectivity of said network or circuit.

3. A method according to claim 2, wherein said selected at least one stimulation target comprises at least one brain region of a brain and / or NF learning circuit.

4. A method according to any one of the previous claims, wherein said at least one stimulation brain target comprises a dorsolateral prefrontal cortex (DLPFC).

5. A method according to any one of the previous claims, wherein said at least one stimulation brain target comprises at least one brain region which is part of a procedural learning process or is part of an episodic learning process.

6. A method according to any one of the previous claims, wherein said delivering comprises delivering said NF training up to 40 minutes from completion of said stimulating.

7. A method according to any one of the previous claims, wherein said stimulating comprises applying stimulation to said at least one stimulation brain target with parameter values suitable to provide said modulating by increasing plasticity of neurons in said at least one stimulation brain target in at least 5% relative to baseline activity during an effective timewindow, and wherein said delivering comprises delivering said NF training during said effective time window.

8. A method according to any one of the previous claims, wherein said delivering comprises delivering said NF training after receiving an indication that said stimulation is completed.

9. A method according to any one of the previous claims, wherein said stimulation comprises stimulating said at least one stimulation brain target using stimulation parameters stored in a memory of a system used for said delivering.

10. A method according to any one of the previous claims, comprising: determining that said subject did not reach a target activity of said at least one NF brain target following said delivering; and repeating said stimulating and said delivering following said determining.

11. A method according to claim 10, wherein said determining is in a next session.

12. A method according to claim 10 or claim 11, comprising modifying at least one parameter of said stimulating and / or said delivering in response to said determining, and whereon said repeating comprises repeating said stimulating and said delivering using said at least one modified parameter.

13. A method according to claim 12, wherein said at least one parameter of said stimulating comprises at least one of, a stimulation brain target, stimulation duration, stimulation duty cycle, stimulation envelope, waveform, frequency within a pulse, inter-train interval, stimulation pulses frequency, stimulation bursts frequency, total number of pulses, stimulation intensity, interval between stimulation bursts, and / or duration of stimulation bursts.

14. A method according to any one of claims 12 or 13, wherein said at least one NF parameter comprises, a NF brain target, duration of said NF training, duration of at least one session of said NF training, duration of active NF blocks in which the subject actively regulates the activity of the at least one NF brain target, feedback signal presented to the subject, and / or sensory interface presented as a feedback signal to the subject.

15. A method according to any one of claims 1 to 9, comprising: determining that said subject did not reach a target activity of said at least one NF brain target following said delivering; and providing at least one different treatment to said subject in response to said determining.

16. A method according to claim 15, wherein said at least one different treatment comprises at least one of, a drug treatment, a psychotherapy treatment, and / or a cognitive behavior treatment (CBT).

17. A method according to any one of claims 1 to 9, comprising: determining that said subject has reached a target activity of said at least one NF brain target following said delivering; and repeating said delivering of said NF training in response to said determining.

18. A method according to any one of the previous claims, wherein said stimulating comprises applying noninvasive brain stimulation (NIBS) to said at least one stimulation brain target.

19. A method according to claim 18, wherein said applying comprises applying said NIBS with parameter values suitable to transiently modulate activity or connectivity of said at least one stimulation brain target during and / or following said stimulating.

20. A method according to claim 19, wherein said NIBS comprises transcranial magnetic stimulation (TMS), and wherein said applying comprises applying said TMS by applying Intermittent theta burst stimulation (iTBS) to said at least one stimulation brain target.

21. A method according to claim 20, wherein said iTBS is delivered as bursts of a series of magnetic pulses having a frequency of about 50Hz, wherein the bursts are applied intermittently with a frequency of about 5Hz for about 2 seconds with intervals between 5 seconds and 12 seconds.

22. A method according to any of the preceding claims, wherein said stimulating modulates by having an inhibitory effect.

23. A method according to any of the preceding claims, wherein said stimulating modulates by having an excitatory effect.

24. A method according to any of the preceding claims, wherein said stimulating modulates by modifying connectivity within and / or between brain areas.

25. A method according to any of the preceding claims, comprising delivering NF to said patient also before said stimulating.

26. A method according to any one of the previous claims, comprising diagnosing said subject with at least one mental disorder and wherein said NF training is a training used to treat said mental disorder or at least one symptom thereof.

27. A method according to claim 26, wherein said at least one mental disorder comprises at least one of, Neurodevelopmental Disorder, Schizophrenia Spectrum and Other Psychotic Disorders, Bipolar and Related Disorders, Depressive Disorders, Anxiety Disorders, Obsessive-Compulsive and Related Disorders, Trauma- and Stressor-Related Disorders, Dissociative Disorders, Somatic Symptom and Related Disorders, Feeding and Eating Disorders, Elimination Disorders, Sleep-Wake Disorders, Sexual Dysfunctions, Gender Dysphoria, Disruptive, Impulse-Control, and Conduct Disorders, Substance-Related and Addictive Disorders, Neurocognitive Disorders, and Personality Disorders.

28. A method according to claim 26, wherein said at least one mental disorder comprises post-traumatic stress disorder (PTSD) or depression, and wherein said at least one NF brain target comprises at least one of, at least one brain region of a limbic system, at least one brain region of a salience network or default mode network, at least one brain region of a reward system, and / or an amygdala.

29. A method according to any one of the previous claims, wherein said at least one brain stimulation target and said at least one NF brain target are the same brain target.

30. A method according to any one of the previous claims, comprising displaying to said subject during said stimulating at least one interface of said NF training, and wherein saiddelivering comprises presenting a feedback signal to said subject which includes said at least one interface, said interface being visual and / or audible.

31. A method for selecting a subject for neurofeedback (NF) training, comprising: stimulating at least one stimulation (NIBS) brain target in a brain of a subject; delivering at least one NF screening session to said subject following said stimulating, wherein said delivering comprises requesting said subject to modify at least one feedback signal presented to the subject, wherein said at least one feedback signal indicates activity of at least one target of said NF training; determining performance of said subject in said at least one NF screening session and / or at a later NF session; selecting said subject for said NF training based on the results of said determining.

32. A method according to claim 31, wherein said determining comprises determining an ability of said subject to modify said at least one feedback signal to reach a target modification of said at least one feedback signal, and wherein said selecting comprises selecting said subject for said NF training if said subject succeeded in reaching said target modification.

33. A method according to any one of claims 31 or 32, wherein said at least one stimulation brain target comprises a brain region of a network or a circuit activated during said delivering, or is a brain target affecting an ability of said subject to modify said at least one feedback signal.

34. A method according to any one of claims 31 to 33, wherein said at least one stimulation target comprises at least one brain region of a brain learning circuit.

35. A method according to any one of claims 31 to 34, wherein said at least one stimulation brain target comprises (a) a dorsolateral prefrontal cortex (DLPFC), and / or (b) a brain region which is part of a fronto striatal circuit and / or a parietal-hippocampus circuit.

36. A method according to any one of claims 31 to 35, wherein said delivering comprises delivering said NF training up to 40 minutes from completion of said stimulating.

37. A method according to any one of claims 31 to 36, wherein said stimulating comprises applying stimulation to said at least one stimulation brain target with parameter values suitable to increase plasticity of neurons in said at least one stimulation brain target in at least 10% relative to baseline activity, during an effective time window, and wherein said delivering comprises delivering said NF training during said effective time window.

38. A method according to any one of claims 31 to 37, comprising diagnosing said subject with at least one mental disorder and wherein said NF training and NIBS include or are included in a training used to treat said mental disorder or at least one symptom thereof.

39. A method according to any one of claims 31 to 37, comprising diagnosing said subject with at least one mental disorder and wherein said NF training includes or is included in a training used to treat said mental disorder or at least one symptom thereof.

40. A method according to claim 38 or claim 39, wherein said at least one mental disorder comprises at least one of, Neurodevelopmental Disorder, Schizophrenia Spectrum and Other Psychotic Disorders, Bipolar and Related Disorders, Depressive Disorders, Anxiety Disorders, Obsessive-Compulsive and Related Disorders, Trauma- and Stressor-Related Disorders, Dissociative Disorders, Somatic Symptom and Related Disorders, Feeding and Eating Disorders, Elimination Disorders, Sleep-Wake Disorders, Sexual Dysfunctions, Gender Dysphoria, Disruptive, Impulse-Control, and Conduct Disorders, Substance-Related and Addictive Disorders, Neurocognitive Disorders, and Personality Disorders.

41. A method according to claim 38 or claim 39, wherein said at least one mental disorder comprises post-traumatic stress disorder (PTSD) or depression, and wherein said at least one NF brain target comprises at least one of, at least one brain region of a limbic or mesolimbic system, at least one brain region of a salience network at least one brain region of a default mode network, at least one brain region of a reward system, and / or threat system.

42. A method according to any one of claims 31 to 41, comprises determining that said subject is not a suitable candidate for said NF training prior to said stimulating.

43. A method for increasing efficacy of a neurofeedback (NF) training, comprising:delivering at least one session of a NF training program to a subject, wherein said delivering comprises requesting said subject to modify at least one feedback signal presented to the subject, wherein said at least one feedback signal indicates activity of at least one NF brain target; determining during and / or following said delivering if said subject was able to modify said at least one feedback signal towards a target modified feedback signal; stimulating at least one stimulation brain target in a brain of said subject following said delivering of said at least one session if said subject was not able to modify said at least one feedback signal towards said target modified feedback signal; delivering at least one additional session of said NF training after said stimulating.

44. A method according to claim 43, wherein said delivering comprises delivering said at least one additional session of said NF training up to 40 minutes after said stimulating.

45. A method according to any one of claims 43 or 44, wherein said at least one stimulation brain target comprises a brain region of a network or a circuit activated during said delivering, or is a brain target affecting an ability of said subject to modify said at least one feedback signal towards said target modified feedback signal.

46. A method according to any one of claims 43 to 45, wherein said at least one stimulation target comprises at least one brain region of a brain learning circuit, a brain reward circuit or of a brain memory circuit.

47. A method according to any one of claims 43 to 46, wherein said at least one stimulation brain target comprises a dorsolateral prefrontal cortex (DLPFC), or a brain region which is part of a fronto striatal circuit and parietal-hippocampus circuit.

48. A method according to any one of claims 43 to 47, comprising: measuring during said delivering of said at least one session, EEG signals indicating activity of said at least one NF brain target; calculating a score indicating changes in said activity during said delivering of said at least one session; wherein said determining comprises determining if said subject is able to modify said at least one feedback signal towards a target modified feedback signal, based on said calculated score.

49. A method according to claim 48, wherein said EEG signals comprise neuroanatomically informed EEG signals.

50. A method according to any one of claims 43 to 49, comprising diagnosing said subject with a mental disorder and wherein said NF training is a training used to treat said mental disorder or at least one symptom thereof.

51. A system for delivery of neurofeedback (NF) training to a subject, comprising: a memory which stores at least one NF protocol or indication thereof, wherein said at least one NF protocol includes providing stimulation to at least one stimulation brain target and delivery of at least one NF session; a user interface configured to generate and deliver at least one human detectable indication and / or to receive at least one input signal; a control circuitry, wherein said control circuitry is configured to signal said user interface to generate a human detectable indication with information about said at least one NF protocol.

52. A system according to claim 51, wherein said control circuitry is configured to signal said user interface to generate and deliver a reminder indication for delivery of said at least one NF session following said providing of said stimulation.

53. A system according to any one of claims 51 or 52, wherein said control circuitry is configured to signal said user interface to generate a human detectable indication with information about parameter values of said stimulation.

54. A system according to claim 53, wherein said information comprises information about a location on a subject head for applying said stimulation and / or information about a brain target of said stimulation.

55. A system according to any one of claims 51 to 54, wherein said control circuitry is configured to receive an input signal via said user interface that application of stimulation to said subject was completed, and to signal said user interface to generate and deliver a humandetectable indication with information about said at least one NF session in response to said receive of said input signal.

56. A system according to claim 55, wherein said information about said at least one NF session comprises information about an effective time window following said stimulation application for initiating said at least one NF session.

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