WO2025083560A1

WO2025083560A1 - Vagus nerve stimulation

Info

Publication number: WO2025083560A1
Application number: PCT/IB2024/060115
Authority: WO
Inventors: Tamir Ben David; Adam BRONCEL
Original assignee: Cogniguard Medical Holdings Ltd
Current assignee: Cogniguard Medical Holdings Ltd
Priority date: 2023-10-16
Filing date: 2024-10-16
Publication date: 2025-04-24
Anticipated expiration: 2026-04-16

Abstract

A method to treat a predetermined subject population diagnosed with Alzheimer's disease (AD), including: selecting subjects diagnosed with early AD or having at least one symptom of early AD, with a goal to improve a score of the subjects in an assessment scale in at least one point, wherein the assessment scale comprises at least one of, an Alzheimer's Disease Assessment Scale– Cognitive Subscale (ADAS-Cog) or variations thereof, and/or a Mini-Mental State Examination (MMSE) scale or variations thereof; delivering auricular VNS treatment to the subjects for a time period of at least one month; identifying an improvement of at least one point in the scale in the subjects following the delivering.

Description

VAGUS NERVE STIMULATION

RELATED APPLICATION/S

This application claims the benefit of priority of U.S. Provisional Patent Application No. 63/544,257 filed on 16 October 2023, the contents of which are incorporated herein by reference in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to cranial nerve stimulation and, more particularly, but not exclusively, to cranial nerve stimulation in different clinical and/or physiological states.

U.S. Patent Number US 11684771B2 describes “a neuromodulation system for treatment of physiological disorders. The system includes one or more stimulators for stimulating one or more cranial nerves; one or more detectors configured for detecting a predetermined physiological state; and a control unit that controls nerve stimulation by the one or more stimulators so that it is synchronized with the at least one predetermined physiological state detected by the one or more detectors. A method of neuromodulating a patient for treatment of physiological disorder. The method includes the steps of detecting a predetermined physiological state and applying stimulation to one of the cranial nerves during the predetermined physiological state by one or more stimulators of a neuromodulation system” (Abstract).

International patent Application Publication Number WO2023119276A1 describes “disclosed herein is a device for auricular vagal nerve stimulation in a. subject, said device having an electrode configuration including at least one electrode contact operative io be adhered io a first portion of inner skin surface of an ear Concha of the subject, and at least one return electrode with an opposite polarity operative to be adhered to a second portion of the inner skin surface” (Abstract).

SUMMARY OF THE INVENTION

Some examples of some embodiments of the invention are listed below (it should be noted that one or more features of an example may be used in combination with one or more features of another example):

Example 1. A method to treat a predetermined subject population diagnosed with Alzheimer’s disease (AD), comprising: selecting subjects diagnosed with early AD or having at least one symptom of early AD, with a goal to improve a score of the subjects in an assessment scale in at least one point, wherein the assessment scale comprises at least one of, an Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or variations thereof, and a Mini-Mental State Examination (MMSE) scale or variations thereof; delivering auricular VNS treatment to the subjects for a time period of at least one month; identifying an improvement of at least one point in the scale in the subjects following the delivering.

Example 2. A method according to example 1, wherein the identifying comprises identifying a reduction of at least 4 points in the ADAS-Cog scale, after at least one month of the delivering.

Example 3. A method according to any one of examples 1 or 2, wherein the delivering comprises delivering the VNS treatment for a time period of at least 3 months, and wherein the identifying comprises identifying a reduction of at least 4 points in the ADAS-Cog in the subjects, after 3 months of the delivering.

Example 4. A method according to any one of the previous examples, wherein the identifying comprises identifying a reduction of at least 4 points in the ADAS-Cog in the subjects, up to 3 months from completing the delivering.

Example 5. A method according to any one of the previous examples, wherein the identifying comprises identifying an increase of at least 1.5 points in a score of the MMSE, after at least one month of the delivering.

Example 6. A method according to any one of the previous examples, wherein the delivering comprises delivering the VNS treatment to the subjects for a time period of at least 3 months, and wherein the identifying comprises identifying an increase of at least 1.5 points in a score of the MMSE, after 3 months of the delivering.

Example 7. A method according to any one of the previous examples, wherein the identifying comprises identifying a an increase of at least 1.5 points in a score of the MMSE, up to 3 months from completing the delivering.

Example 8. A method according to any one of the previous examples, wherein the selecting comprises selecting subjects that achieved an ADAS-COG 13 score within a range between 10 and 50 points, and/or an ADAS-COG 11 score within a range between 10 and 40 points.

Example 9. A method according to any one of the previous examples, wherein the selecting comprises selecting subjects that achieved a MMSE score within a range between 10 and 25 points.

Example 10. A method according to any one of the previous examples, comprising associating at least part of a VNS device configured to deliver the VNS treatment with an ear of a subject prior to the delivering. Example 11. A method according to example 10, wherein the associating comprising positioning at least one electrode of the VNS in contact with an ear of the subject.

Example 12. A method according to any one of the previous examples, wherein the delivering comprises delivering the VNS treatment while the subjects are asleep and/or in synchronization with at least one sleeping stage.

Example 13. A method according to any one of the previous examples, wherein the delivering comprises delivering the VNS treatment which comprises one or more VNS treatment sessions, each includes separate active stimulation blocks, and wherein the VNS is actively delivered intermittently during the active stimulation blocks.

Example 14. A method according to example 13, wherein each active stimulation block comprises two or more active stimulation sessions in which stimulation is actively delivered via a least one electrode, and wherein an interval duration between two consecutive active stimulation sessions in an active stimulation block is within a range between 0.5 second and 240 seconds.

Example 15. A method according to any one of the previous examples, wherein the delivering comprises delivering during the VNS treatment an electric field with parameter values sufficient to affect an auricular branch of the vagus nerve.

Example 16. A method according to example 15, wherein the parameter values comprise an intensity in a range between about 0.1 mA and about 4 mA.

Example 17. A method according to any one of examples 15 or 16, wherein the parameter values comprise a frequency in a range between about 1 Hertz (Hz) and about 100 Hz.

Example 18. A method according to any one of examples 15 to 17, wherein the parameter values comprise a pulse width in a range between about 0.1 millisecond (ms) and about 2 ms.

Example 19. A method according to any one of the previous claims, wherein the delivering comprises delivering the auricular VNS with VNS parameter values suitable to affect an auricular branch of a vagus network via at least one electrode positioned behind the ear, within the ear canal and/or at a concha of the ear.

Example 20. A method to treat a predetermined subject population diagnosed with MCI or early AD and other cognitive decline conditions, comprising: selecting subjects diagnosed with early AD or mild cognitive impairment (MCI); delivering VNS to at least one cranial nerve of the subjects via one or more electrodes; achieving based on parameters of the VNS a reduction of at least 4 points in an ADAS -Cog scale, at least one month from initiating the delivering. Example 21. A method according to example 20, wherein the achieving comprises achieving based on parameters of the VNS a reduction of at least 4 points in the ADAS-Cog, at least 3 months from initiating the delivering.

Example 22. A method according to any one of examples 20 or 21, wherein the achieving comprises achieving based on parameters of the VNS a reduction of at least 4 points in the ADAS-Cog, up to 3 months from completing the delivering.

Example 23. A method to treat a predetermined subject population diagnosed with MCI or early AD, comprising: selecting subjects diagnosed with early AD or mild cognitive impairment (MCI); delivering VNS to at least one cranial nerve of the subjects via one or more electrodes; achieving based on parameters of the VNS treatment an increase of at least 1.5 points in a score of a Mini-Mental State Examination (MMSE) scale or variations thereof, at least one month from initiating the delivering.

Example 24. A method according to example 23, wherein the achieving comprises achieving based on parameters of the VNS an increase of at least 1.5 points in a score of a MMSE scale or variations thereof, at least 3 months from initiating the delivering.

Example 25. A method according to any one of examples 23 or 24, wherein the achieving comprises achieving based on parameters of the VNS an increase of at least 1.5 points in a score of a MMSE scale or variations thereof, up to 3 months from completing the delivering.

Example 26. A method for delivery of vagal nerve stimulation (VNS) stimulation, comprising: providing a VNS stimulation treatment protocol comprising at least one stimulation treatment session, wherein the at least one stimulation treatment session is divided into two or more separate stimulation blocks, and wherein in each stimulation block of the two or more stimulation blocks, active VNS stimulation is delivered intermittently to the subject; delivering VNS to the subject according to the provided protocol.

Example 27. A method according to example 26, wherein a duration of each stimulation block or an interval between two consecutive stimulation blocks is in a range between 1 minute and 60 minutes.

Example 28. A method according to any one of examples 26 or 27, comprising positioning at least one electrode of a VNS stimulation device in contact with at least one part of an ear of the subject prior to aid delivering.

Example 29. A method according to example 28, wherein the positioning comprises positioning the at least one electrode in contact with a concha of the ear. Example 30. A method according to example 29, wherein the delivering comprises delivering an electric field via the at least one electrode intermittently during each stimulation block, wherein parameter values of the electric field are sufficient to affect an auricular branch of a vagus network in the subject.

Example 31. A method according to example 30, wherein the parameter values of the electric field comprise an intensity in a range between about 0.1 mA and about 4 mA.

Example 32. A method according to any one of examples 30 or 31, wherein the parameter values comprise a frequency in a range between about 1 Hertz (Hz) and about 100 Hz.

Example 33. A method according to any one of examples 30 to 32, wherein the parameter values comprise a pulse width in a range between about 0.1 millisecond (ms) and about 2 ms.

Example 34. A method according to example 30, wherein the two or more separate stimulation blocks are separated by interval blocks in which an electric field is not delivered via the at least one electrode with parameter values sufficient to affect the auricular branch, or in which no electric field is delivered to the subject via the at least one electrode.

Example 35. A method according to any one of examples 26 to 34, wherein the delivering comprises delivering the VNS when the subject is asleep.

Example 36. A method according to example 35, detecting that the subject is asleep prior to the delivering.

Example 37. A method according to any one of examples 35 or 36, wherein the delivering comprises delivering the VNS in synchronization with at least one sleeping stage of a sleep cycle. Example 38. A method according to example 37, wherein the at least one sleeping stage comprises Nl, N2, N3 and/or rapid eye movement (REM) stages.

Example 39. A device for delivery of vagal nerve stimulation (VNS), comprising:a memory, wherein the memory stores at least one VNS protocol which comprises at least one VNS treatment session divided into two or more separate stimulation blocks, and wherein in each stimulation block of the two or more stimulation blocks, active VNS stimulation is configured to be delivered intermittently to the subject; a pulse generator configured to generate an electric field and to deliver the electric field to at least one electrode connectable to the device; a control circuitry, wherein the control circuitry is configured to signal the pulse generator to generate the electric field according to the stored VNS protocol.

Example 40. A device according to example 39, wherein in the stored VNS treatment protocol a duration of each stimulation block or an interval between two consecutive stimulation blocks is in a range between 1 minute and 60 minutes. Example 41. A device according to any one of examples 39 or 40, comprising the at least one electrode, wherein the at least one electrode is shaped and sized to be placed in contact with at least part of an ear of a subject.

Example 42. A device according to example 41, wherein the at least one electrode is shaped and sized to be placed in contact with a concha region of the ear.

Example 43. A device according to any one of examples 41 or 42, comprising at least one fastener for coupling the at least one electrode to the part of the ear and/or for coupling the device or part thereof to a head of the subject.

Example 44. A device according to any one of examples 39 to 43, comprising a communication circuitry configured to transmit and/or receive one or more signals from a remote device, wherein the device is programmed with the at least one protocol by receiving the one or more signals from the remote device.

Example 45. A device according to example 44, wherein the memory stores at least two different VNS protocols of the at least one VNS protocol, and wherein the control circuitry is configured to select a VNS protocol for treating a specific subject from the at least two different VNS protocols based on the one or more signals received using the communication circuitry.

Example 46. A device according to example 45, wherein the one or more signals comprise results of an assessment scale achieved by the subject.

Example 47. A device according to example 46, wherein the assessment scale comprises at least one of, ADAS-COG or variations thereof, and a MMSE or variations thereof.

Example 48. A device according to any one of examples 45 to 47, wherein the one or more signals comprise an indication that the subject is identified with cognitive impairment.

Example 49. A device according to any one of examples 39 to 48, comprising a user interface configured to receive one or more input signals, wherein the device is programmed with the at least one protocol based on the received one or more input signals.

Example 50. A device according to example 49, wherein the memory stores at least two different VNS protocols of the at least one VNS protocol, and wherein the control circuitry is configured to select a VNS protocol for treating a specific subject from the at least two different VNS protocols based on the one or more input signals received by the user interface.

Example 51. A device according to example 50, wherein the one or more input signals comprise results of an assessment scale achieved by the subject, wherein the assessment scale comprises at least one of, ADAS-COG or variations thereof, and a MMSE or variations thereof.

Example 52. A method for delivery of vagal nerve stimulation (VNS) to a subject, comprising: functionally coupling a stimulation device configured to deliver VNS, to a subject body; detecting movement of the subject when the subject is asleep; determining a dose of VNS to be provided to the subject according to the detected movement, delivering VNS to the subject according to the determined dose..

Example 53. A method according to example 52, comprising identifying at least one period when the subject is asleep and in which the detected movement is lower than a reference value, wherein the determining comprises determining to provide an increased dose of the VNS to the subject, and wherein the delivering comprises delivering the increased dose of the VNS to the subject during and/or following the the period.

Example 54. A method according to example 52, comprising identifying at least one period when the subject is asleep and in which the detected movement is higher than a reference value, wherein the determining comprises determining to provide an increased dose of the VNS to the subject, and wherein the delivering comprises delivering the increased dose of the VNS to the subject during and/or following the the period.

Example 55. A method according to example 52, wherein the detecting comprises detecting an increase in movement of the subject, and wherein the determining comprises determining to provide an increased dose of the VNS according to the detected increase.

Example 56. A method according to example 52, wherein the detecting comprises detecting an increase in movement of the subject, and wherein the determining comprises determining to provide a decreased dose of the VNS according to the detected increase.

Example 57. A method according to any one of examples 52 to 56, wherein the determining a dose of the VNS comprising determining to modify duration in which the VNS is actively delivered to the subject body and/or determining to modify frequency of the VNS.

Example 58. A method according to any one of examples 52 to 57, wherein the subject is diagnosed with dementia and/or with at least one sleeping disorder.

Example 59. A method for calibrating a vagal nerve stimulation (VNS) treatment, comprising: delivering VNS to a subject when the subject is asleep; measuring at least one body parameter of the subject before, during and/or following the delivering, wherein the at least one body parameter comprises a body movement related parameter and/or at least one physiological parameter, wherein the measuring comprises measuring the at least one body parameter during two or more sleep stages; determining a therapeutic effect of the delivered VNS on the subject in each of the two or more sleep stages based on the measuring; calibrating the VNS treatment by scheduling a delivery of the VNS to at least one sleep stage of the two or more sleep stages in which the determined therapeutic effect was the largest therapeutic effect.

Example 60. A method according to example 59, wherein the at least one body parameter comprises at least one of, heart rate, heart rate variability (HRV), electrocardiogram (ECG), electromyography (EMG), electroencephalogram (EEG), electrooculogram (EOG), sweat level , respiration rate, oxygen saturation, and/or limb movement.

Example 61. A method for delivery of vagal nerve stimulation (VNS) for increasing probability of a subject to fall asleep, comprising: measuring EEG signals from a subject planning to fall asleep; detecting an increase in alpha waves in the measured EEG signals that is higher than a predetermined reference value; delivering VNS to the subject in response to the detecting, wherein the VNS is delivered with parameter values suitable to increase a level of theta waves in the measured EEG signals.

Example 62. A method for delivery of vagal nerve stimulation (VNS) for prolonging sleep in a subject, comprising: measuring when a subject is asleep, signals indicating activity of two brain hemispheres ; detecting a difference in activity between the two hemispheres; delivering in response to the detecting, VNS to at least one hemisphere of the two brain hemispheres, according to the detected difference.

Example 63. A method according to example 62, wherein the measuring comprises measuring the signals when the subject is in a deep sleep stage, and wherein the delivering comprises delivering the VNS with parameter values suitable to prolong the deep sleep stage.

Example 64. A method according to any one of examples 62 or 63, wherein the delivering comprises delivering VNS to a less active hemisphere of the two brain hemispheres with parameter values suitable to increase activity of the less active hemisphere.

Example 65. A method according to any one of examples 62 or 63, wherein the delivering comprises delivering VNS to the more active hemisphere with parameter values suitable to reduce activity of the more active hemisphere.

Example 66. A method for delivery of vagal nerve stimulation (VNS) to a subject diagnosed with dementia, comprising: diagnosing a subject with dementia and at least one additional clinical condition; functionally coupling a stimulation device to the subject; delivering VNS to the subject by the stimulation device with a first set of treatment parameter values suitable to treat the dementia, and with at least one second set of treatment parameter values suitable to treat the at least one clinical condition.

Example 67. A method according to example 66, wherein the at least one clinical condition comprises at least one sleep disorder or a symptom tehreof.

Example 68. A method according to any one of examples 66 or 67, wherein the dementia comprises Alzheimer’ s disease.

Example 69. A method according to any one of examples 65 to 67, wherein the delivering comprises delivering VNS with the first set of treatment parameter values in synchronization with the second set of treatment parameter values.

Below are some additional examples of some embodiments of the invention (it should be noted that one or more features of an example may be used in combination with one or more features of another example):

Example 2. A method according to any one of the previous examples, wherein the identifying comprises identifying an increase of at least 1.5 points in a score of the MMSE, after at least one month of the delivering.

Example 3. A method according to any one of the previous examples, wherein the delivering comprises delivering the VNS treatment to the subjects for a time period of at least 3 months, and wherein the identifying comprises identifying an increase of at least 1.5 points in a score of the MMSE, after 3 months of the delivering.

Example 4. A method according to any one of the previous examples, wherein the identifying comprises identifying a an increase of at least 1.5 points in a score of the MMSE, up to 3 months from completing the delivering. Example 5. A method according to any one of the previous examples, wherein the selecting comprises selecting subjects that achieved a MMSE score within a range between 10 and 25 points.

Example 6. A method according to any one of the previous examples, comprising associating at least part of a VNS device configured to deliver the VNS treatment with an ear of a subject prior to the delivering.

Example 7. A method according to example 6, wherein the associating comprising positioning at least one electrode of the VNS in contact with an ear of the subject.

Example 8. A method according to any one of the previous examples, wherein the delivering comprises delivering the VNS treatment while the subjects are asleep and/or in synchronization with at least one sleeping stage.

Example 9. A method according to any one of the previous examples, wherein the delivering comprises delivering the VNS treatment which comprises one or more VNS treatment sessions, each includes separate active stimulation blocks, and wherein the VNS is actively delivered intermittently during the active stimulation blocks.

Example 10. A method according to example 9, wherein each active stimulation block comprises two or more active stimulation sessions in which stimulation is actively delivered via a least one electrode, and wherein an interval duration between two consecutive active stimulation sessions in an active stimulation block is within a range between 0.5 second and 240 seconds.

Example 11. A method according to any one of the previous examples, wherein the delivering comprises delivering during the VNS treatment an electric field with parameter values suitable to affect an auricular branch of the vagus nerve via at least one electrode positioned behind the ear, within the ear canal and/or at a concha of the ear.

Example 12. A method according to example 11, wherein the parameter values comprise an intensity in a range between about 0.1 mA and about 4 mA, and/or wherein the parameter values comprise a frequency in a range between about 1 Hertz (Hz) and about 100 Hz, and/or wherein the parameter values comprise a pulse width in a range between about 0.1 millisecond (ms) and about 2 ms.

Example 13. A method to treat a predetermined subject population diagnosed with MCI or early AD, comprising: selecting subjects diagnosed with early AD or mild cognitive impairment (MCI); delivering VNS to at least one cranial nerve of the subjects via one or more electrodes; achieving based on parameters of the VNS a reduction of at least 4 points in an ADAS -Cog scale, at least one month from initiating the delivering. Example 14. A method according to example 13, wherein the achieving comprises achieving based on parameters of the VNS a reduction of at least 4 points in the ADAS-Cog, at least 3 months from initiating the delivering.

Example 15. A method according to any one of examples 13 or 14, wherein the achieving comprises achieving based on parameters of the VNS a reduction of at least 4 points in the ADAS-Cog, up to 3 months from completing the delivering.

Example 16. A method for delivery of vagal nerve stimulation (VNS) stimulation, comprising: providing a VNS stimulation treatment protocol comprising at least one stimulation treatment session, wherein the at least one stimulation treatment session is divided into two or more separate stimulation blocks, and wherein in each stimulation block of the two or more stimulation blocks, active VNS stimulation is delivered intermittently to the subject; delivering VNS to the subject according to the provided protocol.

Example 17. A method according to example 16, wherein a duration of each stimulation block or an interval between two consecutive stimulation blocks is in a range between 1 minute and 60 minutes.

Example 18. A method according to any one of examples 16 or 17, comprising positioning at least one electrode of a VNS stimulation device in contact with at least one part of an ear of the subject prior to aid delivering.

Example 19. A method according to example 18, wherein the positioning comprises positioning the at least one electrode in contact with a concha of the ear, and wherein the delivering comprises delivering an electric field via the at least one electrode intermittently during each stimulation block, wherein parameter values of the electric field are sufficient to affect an auricular branch of a vagus network in the subject.

Example 20. A method according to example 19, wherein the parameter values of the electric field comprise an intensity in a range between about 0.1 mA and about 4 mA, and/or wherein the parameter values comprise a frequency in a range between about 1 Hertz (Hz) and about 100 Hz, and/or wherein the parameter values comprise a pulse width in a range between about 0.1 millisecond (ms) and about 2 ms.

Example 21. A method according to example 20, wherein the two or more separate stimulation blocks are separated by interval blocks in which an electric field is not delivered via the at least one electrode with parameter values sufficient to affect the auricular branch, or in which no electric field is delivered to the subject via the at least one electrode.

Example 22. A method according to any one of examples 16 to 21, wherein the delivering comprises delivering the VNS when the subject is asleep. Example 23. A method according to example 22, detecting that the subject is asleep prior to the delivering.

Example 24. A method according to any one of examples 22 or 23, wherein the delivering comprises delivering the VNS in synchronization with at least one sleeping stage of a sleep cycle, and/or wherein the at least one sleeping stage comprises Nl, N2, N3 and/or rapid eye movement (REM) stages.

Example 25. A device for delivery of vagal nerve stimulation (VNS), comprising: a memory, wherein the memory stores at least one VNS protocol which comprises at least one VNS treatment session divided into two or more separate stimulation blocks, and wherein in each stimulation block of the two or more stimulation blocks, active VNS stimulation is configured to be delivered intermittently to the subject; a pulse generator configured to generate an electric field and to deliver the electric field to at least one electrode connectable to the device; a control circuitry, wherein the control circuitry is configured to signal the pulse generator to generate the electric field according to the at last one stored VNS protocol.

Example 26. A device according to example 25, wherein in the stored VNS treatment protocol a duration of each stimulation block or an interval between two consecutive stimulation blocks is in a range between 1 minute and 60 minutes.

Example 27. A device according to any one of examples 25 or 26, comprising the at least one electrode, wherein the at least one electrode is shaped and sized to be placed in contact with at least part of an ear of a subject.

Example 28. A device according to example 27, wherein the at least one electrode is shaped and sized to be placed in contact with a concha region of the ear.

Example 29. A device according to any one of examples 25 to 28, comprising a communication circuitry configured to transmit and/or receive one or more signals from a remote device, wherein the device is programmed with the at least one protocol by receiving the one or more signals from the remote device.

Example 30. A device according to example 29, wherein the memory stores at least two different VNS protocols of the at least one VNS protocol, and wherein the control circuitry is configured to select a VNS protocol for treating a specific subject from the at least two different VNS protocols based on the one or more signals received using the communication circuitry.

Example 31. A device according to example 30, wherein the one or more signals comprise results of an assessment scale achieved by the subject. Example 32. A device according to example 31, wherein the assessment scale comprises at least one of, ADAS-COG or variations thereof, and a MMSE or variations thereof.

Example 33. A device according to any one of examples 30 to 32, wherein the one or more signals comprise an indication that the subject is identified with cognitive impairment.

Example 34. A device according to any one of examples 25 to 33, comprising a user interface configured to receive one or more input signals, wherein the device is programmed with the at least one protocol based on the received one or more input signals.

Example 35. A device according to example 34, wherein the memory stores at least two different VNS protocols of the at least one VNS protocol, and wherein the control circuitry is configured to select a VNS protocol for treating a specific subject from the at least two different VNS protocols based on the one or more input signals received by the user interface.

Example 36. A device according to example 35, wherein the one or more input signals comprise results of an assessment scale achieved by the subject, wherein the assessment scale comprises at least one of, ADAS-COG or variations thereof, and a MMSE or variations thereof.

Example 37. A device according to any one of examples 25 to 36, comprising at least one detector configured to record at least one signal related to at least one parameter of a body of the subject, wherein the control circuitry is further configured to: measure values of the at least one body parameter; determine a subject state based on the measured values, wherein the subject state comprises at least one of, if the subject is asleep, at least one sleep stage, subject movement, activity of the subject brain and/or activity of each brain hemisphere of the subject; and deliver VNS to the subject according to the determined subject state by signaling the pulse generator to generate an electric field according to at least one set of parameter values and/or according the at least one VNS protocol stored in the memory.

Example 38. A device according to any one of examples 25 to 37, wherein the at least one VNS protocol comprises parameter values suitable to affect an auricular branch of the vagus nerve, and wherein the control circuitry is configured to signal the pulse generator to generate the electric field using the parameter values.

Example 39. A method for delivery of vagal nerve stimulation (VNS) to a subject, comprising: functionally coupling a stimulation device configured to deliver VNS, to a subject body; detecting movement of the subject when the subject is asleep; determining a dose of VNS to be provided to the subject according to the detected movement, delivering VNS to the subject according to the determined dose. Example 40. A method according to example 39, comprising identifying at least one period when the subject is asleep and in which the detected movement is lower than a reference value, wherein the determining comprises determining to provide an increased dose of the VNS to the subject, and wherein the delivering comprises delivering the increased dose of the VNS to the subject during and/or following the the period.

Example 41. A method according to example 40, comprising identifying at least one period when the subject is asleep and in which the detected movement is higher than a reference value, wherein the determining comprises determining to provide an increased dose of the VNS to the subject, and wherein the delivering comprises delivering the increased dose of the VNS to the subject during and/or following the the period.

Example 42. A method according to example 40, wherein the detecting comprises detecting an increase in movement of the subject, and wherein the determining comprises determining to provide an increased dose of the VNS according to the detected increase.

Example 43. A method according to example 40, wherein the detecting comprises detecting an increase in movement of the subject, and wherein the determining comprises determining to provide a decreased dose of the VNS according to the detected increase.

Example 44. A method according to any one of examples 39 to 43, wherein the subject is diagnosed with dementia and/or with at least one sleeping disorder.

Example 45. A method for calibrating a vagal nerve stimulation (VNS) treatment, comprising: delivering VNS to a subject when the subject is asleep; measuring at least one body parameter of the subject before, during and/or following the delivering, wherein the at least one body parameter comprises a body movement related parameter and/or at least one physiological parameter, wherein the measuring comprises measuring the at least one body parameter during two or more sleep stages; determining a therapeutic effect of the delivered VNS on the subject in each of the two or more sleep stages based on the measuring; calibrating the VNS treatment by scheduling a delivery of the VNS to at least one sleep stage of the two or more sleep stages in which the determined therapeutic effect was the largest therapeutic effect, and wherein the at least one body parameter comprises at least one of, heart rate, heart rate variability (HRV), electrocardiogram (ECG), electromyography (EMG), electroencephalogram (EEG), electrooculogram (EOG), sweat level , respiration rate, oxygen saturation, and/or limb movement.

Example 46. A method for delivery of vagal nerve stimulation (VNS) for increasing probability of a subject to fall asleep, comprising: measuring EEG signals from a subject planning to fall asleep; detecting an increase in alpha waves in the measured EEG signals that is higher than a predetermined reference value; delivering VNS to the subject in response to the detecting, wherein the VNS is delivered with parameter values suitable to increase a level of theta waves in the measured EEG signals.

Example 47. A method for delivery of vagal nerve stimulation (VNS) for prolonging sleep in a subject, comprising: measuring when a subject is asleep, signals indicating activity of two brain hemispheres ; detecting a difference in activity between the two hemispheres; delivering in response to the detecting, VNS to at least one hemisphere of the two brain hemispheres, according to the detected difference.

Example 48. A method according to example 47, wherein the measuring comprises measuring the signals when the subject is in a deep sleep stage, and wherein the delivering comprises delivering the VNS with parameter values suitable to prolong the deep sleep stage.

Example 49. A method according to any one of examples 47 or 48, wherein the delivering comprises delivering VNS to a less active hemisphere of the two brain hemispheres with parameter values suitable to increase activity of the less active hemisphere.

Example 50. A device for delivery of vagal nerve stimulation (VNS), comprising: a memory, wherein the memory stores at least one VNS protocol configured to be used in a method of any one of examples 1, 13, 16, 39, 45 and 47, wherein the at least one VNS protocol comprises at least one VNS treatment session comprises at least one stimulation block, and wherein in the stimulation block active VNS stimulation is configured to be delivered intermittently to the subject; a pulse generator configured to generate an electric field and to deliver the electric field to at least one electrode connectable to the device; a control circuitry, wherein the control circuitry is configured to signal the pulse generator to generate the electric field according to the at least one VNS protocol, wherein the device.

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. 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.

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.

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.

A computer readable signal medium may include a propagated data signal with computer readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electro-magnetic, optical, or any suitable combination thereof. A computer readable signal medium may be any computer readable medium that is not a computer readable storage medium and that can communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

Program code embodied on a computer readable medium and/or data used thereby may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, RF, etc., or any suitable combination of the foregoing.

Computer program code for carrying out operations for some embodiments of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the "C" programming language or similar programming languages. The program code may execute entirely on the user's computer, partly on the user's computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer or entirely on the remote computer or server. 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).

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.

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

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

Some of the methods described herein are generally designed only for use by a computer, and may not be feasible or practical for performing purely manually, by a human expert. A human expert who wanted to manually perform similar tasks, such as determining a clinical state of a subject based on measured signals, 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.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

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 and/or images 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.

In the drawings:

FIG. 1A is a flow chart of a general process for delivery of cranial stimulation, for example vagal nerve stimulation (VNS), using a protocol that is suitable for a specific subject state, according to some embodiments of the invention;

FIG. IB is a flow chart of a process for programming of a stimulation device, according to some exemplary embodiments of the invention; FIG. 1C is a block diagram of a system for delivery of cranial stimulation, according to some exemplary embodiments of the invention;

FIG. ID is an image of a system for delivery of cranial stimulation that includes a head attachment portion, for example a headband, according to some exemplary embodiments of the invention;

FIG. IE is a schematic illustration showing flow of information between a stimulation device and a programming device, for example a mobile device, according to some exemplary embodiments of the invention;

FIG. 2 A is a flow chart of a general process for achieving improvement in a cognition- related score in a subject diagnosed with early Alzheimer’s Disease (AD) following delivery of cranial stimulation, according to some exemplary embodiments of the invention;

FIG. 2B is a flow chart of a process for delivery of cranial stimulation to a subject diagnosed with early AD or with MCI, according to some exemplary embodiments of the invention;

FIG. 2C is a schematic illustration showing an exemplary stimulation sequence, as performed in a study and according to some exemplary embodiments of the invention;

FIGs. 3A and 3B are graphs showing average changes in an Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-COG) score during and following vagal nerve stimulation (VNS);

FIGs. 4 A and 4B are graphs showing average changes in a verbal probing score during and following vagal nerve stimulation (VNS);

FIGs. 5A and 5B are graphs showing changes in a Mini-Mental State Examination (MMSE) score during and following vagal nerve stimulation (VNS);

FIGs. 6 A and 6B are graphs showing changes in a Color Trial Test (CTT) score during and following vagal nerve stimulation (VNS);

FIG. 7 is a schematic illustration of protocol blocks in which cranial nerve stimulation is delivered intermittently, according to some exemplary embodiments of the invention;

FIG. 8A is a schematic illustration depicting different stages in the process of falling asleep in synchronization with a stimulation process, according to some exemplary embodiments of the invention;

FIG. 8B is a flow chart of a process for delivery of cranial nerve stimulation before and/or after a subject falls asleep, according to some exemplary embodiments of the invention;

FIG. 8C is a flow chart of a process for delivery of cranial nerve stimulation in order to reach a desired sleep quality, according to some exemplary embodiments of the invention; FIG. 8D is a flow chart of a process for delivery of vagal nerve stimulation during sleep according to subject movements, according to some exemplary embodiments of the invention;

FIG. 8E is a flow chart of a process for calibrating a cranial nerve stimulation treatment according to sleep stage, according to some exemplary embodiments of the invention;

FIG. 8F is a flow chart of a process for delivery of cranial nerve stimulation to cause a subject fall asleep, according to some exemplary embodiments of the invention;

FIG. 8G is a flow chart of a process for delivery of cranial nerve stimulation treatment to balance activity of the two brain hemispheres, according to some exemplary embodiments of the invention;

FIG. 8H is a flow chart of a general process for delivery of at least one cranial nerve stimulation treatment by at least one stimulation device to treat two clinical conditions in a subject, according to some exemplary embodiments of the invention.

FIG. 9 is a flow chart of a process for delivery of cranial nerve stimulation according to changes in an EEG signal, according to some exemplary embodiments of the invention;

FIG. 10 is a flow chart of a process for delivery of cranial nerve stimulation when identifying an epileptic event in a subject according to some exemplary embodiments of the invention;

FIG. 11 is a flow chart of a process for delivery of cranial nerve stimulation to a subject diagnosed with Obstructive Sleep Apnea (OSA), according to some exemplary embodiments of the invention;

FIG. 12 is a flow chart of a process for delivery of cranial nerve stimulation to a subject having elevated blood pressure, according to some exemplary embodiments of the invention;

FIG. 13 is a flow chart of a process for delivery of cranial nerve stimulation to a subject in a risk for a brain ischemic event, for example stroke, according to some exemplary embodiments of the invention; and

FIG. 14 is a flow chart of a process for treating a subject diagnosed with a cardiac disorder or is in a risk for developing a cardiac disorder, according to some exemplary embodiments of the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to cranial nerve stimulation and, more particularly, but not exclusively, to cranial nerve stimulation in different clinical and/or physiological states. Overview

A broad aspect of some embodiments of the invention relates to delivery of cranial nerve stimulation, for example vagus nerve stimulation (VNS), with parameter values suitable for a specific state of the subject, for example a physiological state or a clinical state. In some embodiments, the VNS, for example auricular VNS, is delivered by a stimulation device that is programmed with the parameter values. In some embodiments, the device is programmed with a stimulation protocol which includes the parameter values. In some embodiments, the stimulation protocol is selected and/or at least one parameter of the stimulation is adjusted according to the subject state. Optionally, the stimulation protocol and/or at least one stimulation parameter is modified in response to at least one change in the subject state for example during active stimulation and/or during an interval between two consecutive active stimulations. As used hereon, an active stimulation means a duration in which a stimulation, optionally in a form of an electric field, is actively delivered to the subject body.

As used herein, cranial nerve stimulation is a stimulation that can be deliverd using an implantable stimulation device that includes an implantable electrode connected to the cranial nerve, or using a transcutaneous nerve stimulation device, having electrode placed on the skin near the cranial nerve. The stimulation can be optionally delivered using electrical stimulation. Alternatively or additionally, the stimulation can also be delivered using magnetic, mechanical or acoustic stimulation. In some embodiments, the VNS stimulation is delivered to the auricular branch of the vagus nerve, and therefore is considered as auricular branch stimulation or auricular VNS.

According to some embodiments, a subject state comprises at least one of, a mental or a cognitive disorder and/or a state in which the subject experiences at least one symptom of a disease or a disorder. In some embodiments, the cranial nerve stimulation is delivered by a device mounted on the subject body, for example mounted or attached to the subject head. In some embodiments, the device is positioned at least partly over at least one ear of the subject, at least partly inside the ear, at least partly behind an ear or entirely within the subject ear, for example within the ear canal or at least partly within the ear canal. Optionally, the device comprises a user interface, for example a display, for delivery of a cognitive stimulation.

An aspect of some embodiments relates to a programmable stimulation device that is configured to be programmed with at least one stimulation protocol or parameter values thereof. In some embodiments, the stimulation device or at least a portion thereof is configured to be mounted on a head of a subject. Optionally, the device or a portion thereof is configured to be associated with an ear of a subject, for example a human subject. In some embodiments, the device or at least one electrode of the device is configured to be associated with at least one ear of the subject, for example to be positioned behind the ear, within the ear canal and/or at a concha of the ear.

According to some embodiments, the device comprises at least one detector, for example at least one sensor configured to record brain activity signals and/or signals indicating at least one physiological parameter of the subject. In some embodiments, the at least one detector comprises at least two detectors. In some embodiments, programming of the device comprises selecting at least one detector of the at least two detectors of the device.

According to some embodiments, the device is programmed by loading a program, for example a software program to a memory of the device. In some embodiments, the program is selected based on a state of the subject, for example based on a clinical and/or a cognitive state of the subject. Alternatively or additionally, a state of a subject comprises at least one symptom of a disease which the subject experiences.

According to some exemplary embodiments, the device is reprogrammable, for example can be reprogrammed with a different protocol or parameter values which are suitable to treat a different subject state.

An aspect of some embodiments relates to achieving an improvement in a cognition- related score in patients diagnosed with Alzheimer’s Disease (AD) or early Alzheimer’s Disease (AD), for example with mild cognitive impairment (MCI), following cranial nerve stimulation, for example VNS. In some embodiments, the patients receive VNS during a time period of at least one day, at least one week, or at least one month. In some embodiments, the VNS is delivered while the patients are asleep. Alternatively, or additionally, the VNS is delivered while the patients are awake. In some embodiments, the VNS is delivered during the night.

According to some embodiments, the improvement comprises reduction in an Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score, following at least two weeks from initiating VNS treatment. Alternatively or additionally, the improvement comprises a reduction of at least 6 points in the ADAS-Cog score, at least one month after completing a VNS treatment. Alternatively or additionally, the improvement comprises a reduction of at least 8 points in the ADAS-Cog score, 3 months from completing the VNS treatment.

According to some embodiments, the improvement comprises an increase in a MiniMental State Examination (MMSE) score, following at least 1 month from initiating a VNS treatment. Alternatively or additionally, the improvement comprises an increase of at least 1 points 1 months from completing the treatment. Alternatively or additionally, the improvement comprises an increase of at least 1.5 points, 3 months from completing the treatment. According to some embodiments, the VNS treatment is delivered in one or more treatment sessions, for example a treatment session every day, every two days, every three days, every 4 days, once a week, twice a week, or any intermediate, smaller or larger number of treatment sessions per week. In some embodiments, each treatment session is divided into active stimulation blocks separated by no stimulation, washout blocks. In some embodiments, each active stimulation block comprises at least two active stimulation sessions delivered intermittently with intervals of at least 0.5 second, for example at least 1 second, at least 10 seconds, at least 30 seconds or any intermediate, shorter or longer intervals between at least two consecutive active stimulation sessions. In some embodiments, a duration of each interval between at least two consecutive active stimulation sessions is in a range between 0.5-240 seconds, for example between 1 second and 60 second, between 15 seconds and 45 seconds, between 1 second and 120 seconds, or any intermediate, smaller or larger range of values. In some embodiments, a length of each active stimulation session is in a range between 0.5-240 seconds, for example between 1 second and 60 second, between 15 seconds and 45 seconds, between 1 second and 120 seconds, or any intermediate, smaller or larger range of values.

An aspect of some embodiments relates to delivery of cranial nerve stimulation, for example VNS before a subject falls asleep. In some embodiments, the subject is a subject diagnosed with a sleeping disorder. In some embodiments, VNS is delivered during sleep, after the subject falls asleep. In some embodiments, VNS is delivered during one or more of sleeping stages, for example to keep the subject asleep and/or to improve the sleeping quality of the subject. In some embodiments, at least one parameter of the VNS is modified when the subject falls asleep, for example in response to a signal from a sleeping detector. Optionally, at least one stimulation parameter is modified when detecting that a subject is about to fall asleep compared to the at least one stimulation parameter when delivering VNS before the subject falls asleep.

According to some embodiments, the VNS treatment is delivered in one or more treatment sessions, for example a treatment session every day, every two days, every three days, every 4 days, once a week, twice a week, or any intermediate, smaller or larger number of treatment sessions per week. In some embodiments, each treatment session is divided into active stimulation blocks separated by no stimulation, washout blocks. In some embodiments, each active stimulation block comprises at least two active stimulation sessions delivered intermittently with intervals of at least 0.5 second, for example at least 1 second, at least 10 seconds, at least 30 seconds or any intermediate, shorter or longer intervals between at least two consecutive active stimulation sessions. In some embodiments, a duration of each interval between at least two consecutive active stimulation sessions is in a range between 0.5-240 seconds, for example between 1 second and 60 second, between 15 seconds and 45 seconds, between 1 second and 120 seconds, or any intermediate, smaller or larger range of values. In some embodiments, a length of each active stimulation session is in a range between 0.5-240 seconds, for example between 1 second and 60 second, between 15 seconds and 45 seconds, between 1 second and 120 seconds, or any intermediate, smaller or larger range of values.

An aspect of some embodiments relates to delivery of cranial nerve stimulation, for example VNS, when detecting abnormal brain activity. In some embodiments, the abnormal brain activity indicates a clinical state, for example, a stroke event, an upcoming stroke event, an epileptic event, and/or an upcoming epileptic event.

According to some embodiments, at least one electroencephalogram (EEG) signal is measured, for example to detect brain activity of the subject. In some embodiments, a relation between the detected brain activity and at least one reference indicating a target brain activity is determined, for example to identify the abnormal brain activity. In some embodiments, the abnormal brain activity is detected by identifying a relation between the measured EEG signal and a stored EEG signal, indicating the clinical state.

According to some embodiments, a specific VNS protocol that is associated with the clinical state, for example fits and/or suitable for treating the clinical state, is delivered to the subject, when detecting the abnormal brain activity or in a predetermined time period after the detection of the abnormal brain activity. In some embodiments, the specific VNS protocol is selected, optionally automatically. In some embodiments, the specific VNS protocol is selected to match a selected patient diagnosed with the clinical state or a patient that is expected to have this clinical state in the future. Alternatively, at least one parameter of an existing VNS protocol is modified according to clinical state.

An aspect of some embodiments relates to delivery of a cranial nerve stimulation, for example VNS, in at least two blocks of active stimulation delivery separated by a washout block when no stimulation or a different stimulation is delivered to the subject. In some embodiments, during each stimulation block, active stimulation is delivered intermittently in intervals that last between 1 second and 120 seconds (1-120 seconds) between stimulations, for example in intervals of 10-100 seconds, 10-40 seconds, 20-50 seconds, or any intermediate, shorter or longer time intervals. In some embodiments, the stimulation is delivered when the subject is asleep. Optionally the stimulation is delivered in synchronization with one or more sleeping stages of a sleep cycle, for example Nl, N2, N3 and/or rapid eye movement (REM) stages.

In some embodiments, during a washout block a different type of stimulation, for example mechanic and/or acoustic stimulation is delivered to the subject. Alternatively or additionally, during the washout block stimulation with different parameters compared to the stimulation parameters used during an active stimulation block, is delivered to the subject. For example, during a washout block high frequency stimulation with low current is delivered to the subject, optionally leading to generation of heat in the tissue resulting with increased blood flow to the treated region during the washout block. In some embodiments, stimulation during a washout block is delivered with a frequency higher than 100 Hz, for example higher than 150 Hz, higher than 200 Hz, higher than 300 Hz, or any intermediate, smaller or larger value. In some embodiments, stimulation during a washout block is delivered with a current, for example intensity, lower than 0.5 milliampere (mA), for example with a current lower than 0.3 mA, lower than 0.1 mA, lower than 0.05 mA, or any intermediate, smaller or larger value.

According to some embodiments, a duration of each active stimulation block is in a range between 1 minute and 60 minutes (1-60 minutes), for example 1-30 minutes, 10-40 minutes, 20- 50 minutes, or any intermediate, shorter or longer time period. In some embodiments, during each active stimulation block, stimulation is delivered in episodes that last between 1-120 seconds and in a frequency within a range between 1-100 Hertz (Hz) during the episodes, for example in frequency within a range between 1-50 Hz, 20-80 Hz, 40-100 Hz, or any intermediate, shorter or longer range of frequencies.

According to some embodiments, a device initiates the delivery of the active stimulation blocks when the subject falls asleep or up to 10 minutes before the subject falls asleep. In some embodiments, the device detects when a subject falls asleep or is about to fall asleep up to 10 minutes before falling asleep, based on changes in brain activity and/or changes in a physiological parameter, for example heart rate, heart rate variability, breathing, movement of the body of the subject, for example movement of a chest, and/or posture of the subject body.

According to some embodiments, the delivered VNS is configured to optimize or promote memory consolidation processes. In some embodiments, the VNS comprises in-body nerve stimulation, for example by at least one implanted electrode, and/or transcutaneous nerve stimulation. In some embodiments, the VNS is delivered during sleep. In some embodiments, the VNS stimulation includes two types of stimulation levels, a first level of long stimulation events and washout events, each having a duration of 5-60 min. In some embodiments, the first level of stimulation and washout events is aimed to address the physiological time needed for memory consolidation process. Optionally, the stimulation and washout events are synchronized with duration of one or more sleep cycles.

According to some embodiments, during the stimulation events, fast stimulation cycles having short stimulation burst time “on time” period followed by no stimulation “off time” periods, are delivered. In some embodiments, each stimulation cycle has a time period within a range between 1-120 seconds. In some embodiments, these fast cycles of stimulations with off time periods, allows, for example, to rebalance depleted neurotransmitter storages at the axon end.

According to some embodiments, stimulation is delivered during a second half of the sleep period, for example at a later stage of the sleep after 3-5 hours from falling asleep. In some embodiments, duration of sleeping cycles and/or stages in a specific subject are measured, and the interval between the stimulation events is synchronized according to the measured durations.

According to some embodiments, the total stimulation time during a single sleep period is at least 40 minutes, for example at least 60 minutes, at least 80 minutes, at least 90 minutes, at least 100 minutes, at least 120 minutes, at least 150 minutes, or any intermediate, shorter or longer time period. In some embodiments, active stimulation is delivered during at least 20% of a time of a single stimulation event, for example during at least 40%, during at least 50%, during at least 60%, during at least 70%, or any intermediate, smaller or larger percentage value. In some embodiments, a sleep period is a sleep stage comprising at least one of, sleep stage N1 defined as non-rapid eye movement (NREM) sleep 1 which optionally has an average length between 1-7 minutes, sleep stage N2 defined as non-rapid eye movement (NREM) sleep 2 which optionally has an average length between 10-25 minutes, sleep stage N3 defined as non-rapid eye movement (NREM) sleep 2 also known as slow-wave sleep, delta sleep or deep sleep which optionally has an average length between 20-40 minutes, and a REM sleep stage defined as rapid eye movement seep which lasts in average 10-60 minutes.

According to some embodiments, the total stimulation time during a night session is at least 30 minutes, for example at least 60 minutes, at least 120 minutes, at least 180 minutes or any intermediate, smaller or larger time period.

According to some embodiments, the number of all stimulation pulses during a night session is at least 10,000 pulses, for example at least 50,000 pulses, at least 200,000 pulses or any intermediate, smaller or larger number of stimulations.

According to some embodiments, the maximal number of all stimulation pulses during a night session is up to 500,000 pulses, for example up to 200,000 pulses, up to 100,000 pulses, or any intermediate, smaller or larger number of pulses.

According to some embodiments, the sum of all stimulation pulses time intervals during a night session is no more than 500 seconds, for example no more than 100 seconds, no more than 50 seconds, or any intermediate, smaller or larger time period. According to some embodiments, an intensity, for example an amplitude of the stimulation is adjusted to be lower than an amplitude that results with skin sensation in the subject. In some embodiments, the intensity is adjusted automatically, for example based on signals recorded from at least one detector. Alternatively or additionally, intensity is adjusted based on an input received from the subject. In a similar way, any other parameter of the stimulation is adjusted in order to prevent skin sensation or discomfort of the subject.

An aspect of some embodiments relates to delivery of cranial nerve stimulation, for example VNS, to a subject having and/or diagnosed with Obstructive Sleep Apnea (OSA). In some embodiments, the VNS is delivered to the subject when determining an expected OSA episodes, during an OSA episode and/or following an OSA episode. In some embodiments, the VNS is initiated before or when the subject falls asleep.

According to some embodiments, VNS is delivered based on measurements of brain activity or changes thereof indicating an expected OSA event or an OSA event. Alternatively or additionally, the VNS is delivered based on measurement of at least one physiological parameter or changes thereof, for example heart rate, heart rate variability, chest movement, breathing pattern, oxygenation level of the blood, and/or oxygen saturation.

An aspect of some embodiments relates to delivery of cranial nerve stimulation, for example VNS, to a subject having and/or diagnosed with a sleeping disorder, for example insomnia. In some embodiments, the VNS is initiated before or when the subject falls asleep. In some embodiments, the VNS is delivered during at least one sleep stage. Alternatively, the VNS is stopped when the subject falls asleep.

According to some embodiments, VNS is delivered based on measurements of brain activity or changes thereof indicating, that the subject falls asleep, that the subject is asleep, at least one sleep stage of the subject. In some embodiments, the VNS is delivered based on measurements of brain activity or changes thereof indicating that the subject woke up during a planned sleeping time or is expected to wake up. Alternatively or additionally, VNS is delivered based on measurements of brain activity or changes thereof indicating that a length of one or more sleeping stages is shorter than a target length and/or when a depth of sleep of the subject is shallow relative to a target sleeping depth. In some embodiments, VNS is stopped based on measurements of brain activity or changes thereof indicating, that the subject is asleep.

According to some embodiments, VNS is delivered based on measurements of a physiological parameter or changes thereof indicating that the subject falls asleep, that the subject is asleep, at least one sleep stage of the subject. Alternatively, VNS is stopped based on measurements of the physiological parameter or changes thereof indicating, that the subject is asleep. In some embodiments, VNS is delivered based on measurements of at least one physiological parameter or changes thereof indicating that the subject woke up during a planned sleeping time or is expected to wake up. Alternatively or additionally, VNS is delivered based on measurements of at least one physiological parameter or changes thereof indicating that a length of one or more sleeping stages is shorter than a target length and/or when a depth of sleep of the subject is shallow relative to a target sleeping depth. In some embodiments, the least one physiological parameter comprises at least one of, heart rate, heart rate variability, body movement, breathing patterns, and/or chest movement.

According to some embodiments, stimulation is provided for a predetermined or a selected time period before sleep (pre-sleep period), for a period between 1 to 60 minutes, for example, for a time period between 1-30 minutes, between 10-30 minutes, between 20-50 minutes, or any intermediate, shorter or larger time period, before the subject goes or falls asleep. Optionally, the stimulation parameters are selected to balance the brain neurotransmitters levels, and/or help to achieve better sleep quality. In some embodiments, the pre- sleep period is programmable and can be set to any value greater than 5 min before going to sleep.

According to some embodiments, when the system detects a change in posture, for example to a more horizontal posture when the subject lays down, stimulation stops for a predetermined time period, for example to allow the subject to fall asleep without any interference. In some embodiments, the predetermined time period is between 5-120 minutes, for example between 5-30 minutes, between 10-30 minutes, between 5-40 minutes, between 20 and 60 minutes, or any intermediate, shorter or longer time period.

Alternatively, when the system detects a change in posture, for example to a more horizontal posture when the subject lays down, stimulation is delivered in order to help falling asleep. In some embodiments, the stimulation delivery period is in a range between 1-120 min, for example in a range between 1-60 minutes, in a range between 10-40 minutes, in a range between 5-60 minutes, or any intermediate, shorter or longer time period.

An aspect of some embodiments relates to delivery of cranial nerve stimulation, for example VNS, to a subject having and/or diagnosed with epilepsy. In some embodiments, the VNS is delivered to the subject when identifying an expected epileptic event, during an epileptic event and/or following an epileptic event. In some VNS is delivered with parameter values selected to prevent an epileptic event, before or following an epileptic event. In some embodiments, VNS is delivered during an epileptic event, optionally with parameter values selected to stop or shorten the epileptic event. According to some embodiments, VNS is delivered based on brain activity measurements indicating an expected epileptic event. In some embodiments, the brain activity measurements comprise EEG measurements. In some embodiments, EEG measurements indicating an expect epileptic event comprise irregular EEG measurements between EEG signals measured from a left brain hemisphere and EEG signals measured from a right brain hemisphere. Alternatively or additionally, EEG measurements indicating an expected epileptic event comprise irregular EEG signals measured from one or more brain regions relative to reference EEG signals.

According to some embodiments, VNS is delivered based on measurements of at least one signal indicating an epileptic event, for example measurements of body posture, and/or body movements, or changes thereof. Alternatively or additionally, the at least one measured signal comprises an EEG signal.

An aspect of some embodiments relates to delivery of cranial nerve stimulation, for example VNS, to a subject having and/or diagnosed with elevated blood pressure (BP). In some embodiments, VNS is delivered when detecting that BP of the subject is higher than a predetermined target value. Additionally, the VNS delivery is stopped when detecting that the BP of the subject is lower than the predetermined target value.

According to some embodiments the VNS is delivered when the subject is awake and/or when the subject is asleep.

An aspect of some embodiments relates to delivery of cranial nerve stimulation, for example VNS, to a subject in a risk for an ischemic event, for example stroke, or cardiac ischemia. In some embodiments, the VNS is delivered to a subject diagnosed with or having a history of stroke events, a history of transient ischemic attack (TIA) events or others. Alternatively or additionally, the VNS is delivered to a subject having one or more risk factors for developing a cardiac ischemic event, for example family history, hypertension, diabetes, hyperlipidemia, cigarette use, obesity and/or lack of physical activity.

According to some embodiments, VNS is delivered when detecting brain activity or changes thereof indicating an expected stroke event or that a stroke event has initiated or occurred. Alternatively or additionally, the VNS is delivered when detecting changes in blood flow to the brain indicating a high risk for having a stoke event.

According to some exemplary embodiments, VNS is delivered when detecting indications of a currently occurring a cardiac ischemic event or when detecting indications of an upcoming cardiac ischemic event, for example changes in blood pressure changes in heart activity and/or any change in a physiological parameter indicating a current or expected cardiac ischemic event. In some embodiments, the VNS is delivered, optionally as a preventive treatment, to patients having an indication of a chronic cardiac ischemia, for example abnormal values of an electrocardiogram (ECG) ST segment and/or high occurrence of pre matured heart beats (for example a number of pre matured heart beats which is higher than 1%, 5%, 10%, 15% of the total number of heart beats). Alternatively or additionally, cardiac ischemia can be detected by a blood test, for example by detecting a change in the level of Troponin. Alternatively or additionally, cardiac ischemia can be detected by elevated heart rate or detection of coronary narrowing or occlusion in various imaging techniques including CT, SPECT, MRI.

According to some embodiments, a duration of each active VNS stimulation session and optionally each interval between active stimulation sessions is between about 1 second and about 120 seconds, for example between about 1 second and about 50 seconds, between about 10 seconds and about 40 seconds, between about 20 seconds and about 40 seconds, between about 20 seconds and about 100 seconds, between about 50 seconds and about 100 seconds, or any intermediate, smaller or larger value or range of values. In some embodiments, in each active stimulation session, stimulation, for example an electric field is delivered to the subject with a frequency between about 1 Hz and about 100 Hz, for example between about 1 Hz and about 50 Hz, between about 10 Hz and about 40 Hz, between about 20 Hz and about 80 Hz, between about 30 Hz and about 100 Hz, or any intermediate, smaller or larger value or range of values. In some embodiments, in each active stimulation session, stimulation, for example an electric field, is delivered to the subject with a stimulation amplitude, for example intensity, between about 0.1 mA and about 4 mA, or example between about 0.5 mA and about 2 mA, between about 1 mA and about 2.5 mA, between about 1.5 mA and about 2 mA, or any intermediate, smaller or larger value or range of values. In some embodiments, in each active stimulation session, stimulation, for example an electric field, is delivered to the subject with a pulse width between about 0.1 millisecond (ms) and about 2 ms, for example between about 0.1 ms and about 1 ms, between about 0.2 ms and about 0.7 ms, between about 0.5 ms and about 2 ms, or any intermediate, smaller or larger value or range of values.

An aspect of some embodiments relates to delivery of VNS, for example auricular VNS, to a subject suffering and/or diagnosed with a sleeping disorder. In some embodiments, the VNS is delivered to the subject with parameter values that are set or adjusted according to movement of the subject when the subject is asleep and/or is about to fall asleep. In some embodiments, VNS is delivered is synchronization with the subject movements when the subject is asleep and/or is about to fall asleep.

According to some embodiments, an increased stimulation dose is provided to the subject when detecting movement that is lower than a reference value. Alternatively, an increased stimulation dose is provided to the subject when detecting movement that is higher than a reference value.

According to some embodiments, a stimulation dose is increased in sleeping periods in which detected body movement is lower than a predetermined reference value, for example during deep sleep and/or REM sleep periods. Alternatively, a stimulation dose is increased in sleeping periods in which the detected body movement is higher than a predetermined reference value, for example during REM sleep in patients that move during REM sleep.

According to some embodiments, a stimulation dose is an amount of stimulation delivered during a predetermined time period, for example during at least one minute, during at least one hour, during an hour, or any intermediate, shorter or longer time period. In some embodiments, a stimulation dose is an amount of stimulation delivered during a physiologically-defined time period, for example when a subject is asleep, when the subject is awake, and/or when a physiological measure is within a specific range of values.

According to some embodiments, a small dose a short term dose is up to 50 seconds, up to 40 seconds, up to 30 seconds, or any intermediate, shorter or longer time period of active stimulation in which an electric field is delivered to the subject body, during stimulation periods. In some embodiments, increasing a stimulation dose comprises increasing active stimulation in at least 1 second, in at least 5 seconds, in at least 10 seconds, in at least 15 seconds, in a range between 1 second to 30 second, or an increase in any intermediate, shorter or longer duration value, relative to a previous active stimulation duration. In some embodiments, an increase in stimulation dose comprises increasing active stimulation duration from at least 5 seconds to at least 40 seconds, per 1 minute of stimulation period.

According to some embodiments, a long term dose is an overall active stimulation time period of at least about 10 minutes, for example of at least 10 minutes, of at least 15 minutes, of at least 20 minutes, of at least 30 minutes of active stimulation, during an overall stimulation time period which includes non- stimulation intervals, of at least about 1 hour of overall stimulation time period, for example of at least 70 minutes, of at least 80 minutes, of at least 90 minutes, or any intermediate, smaller or larger overall stimulation time period.

Alternatively, increasing a stimulation dose comprises increasing a frequency of stimulation in at least 1 Hz, for example in at least 3 Hz, in at least 5Hz, in at least 7Hz, or any intermediate, smaller or larger frequency value. In some embodiments, an increase in stimulation dose, comprises increasing a frequency of stimulation from at least about 20Hz, at least about 22 Hz, at least about 25Hz, to at least about 28Hz, to at least about 30Hz, to at least about 32 Hz, or any intermediate smaller or larger value. According to some embodiments, increasing a stimulation dose comprises at least one of, increasing a time period of stimulation in which an electric field is delivered to the subject body, increasing stimulation frequency, and/or increasing stimulation intensity. In some embodiments, increasing a stimulation dose comprises increasing the stimulation dose relative to a previously delivered dose or a reference stimulation dose, optionally delivered during a similar time period. In some embodiments, increasing a stimulation dose comprises delivering a higher stimulation dose to the subject relative to a previously delivered stimulation dose and/or relative to a reference stimulation dose.

According to some embodiments, the movement is detected by at least one detector, for example at least one sensor. In some embodiments, the at least one sensor comprises a wearable sensor, an implantable sensor, a sensor that is part of a stimulation device or a stimulation system, and/or a sensor that is in communication with the stimulation device or the stimulation system.

According to some embodiments, a stimulation dose is provided to the subject according to or as a function of the level of movement of the subject. In some embodiments, a stimulation dose is increased when movement is increased (correlated relation), or the stimulation dose is decreased when movement is increased (anti-correlated). In some embodiments, since we may expect different physiological response for each patient, a sleep test will be performed where the effect of the stimulation on sleep is evaluated. In some embodiments, based on this test a value of movement thresholds is set, and the device or an expert calibrating the device determines whether to deliver the subject a correlated or an anti correlated stimulation dose.

An aspect of some embodiments relates to calibrating a stimulation treatment delivered to a subject, optionally having a sleeping disorder, by monitoring the effect of stimulation on the subject during one or more sleeping stages. In some embodiments, the monitoring comprises determining an efficacy of the delivered stimulation during two or more sleeping periods and identifying a sleeping stage in which the determined efficacy is the higher relative to a at least one different sleeping stage or higher than a reference value.

According to some embodiments, the stimulation treatment schedule is adjusted according to the determined efficacy, for example stimulation is delivered during sleeping periods where the determined efficacy was shown to be high relative to other sleeping periods. Alternatively or additionally, stimulation is delivered with different parameter values during each stimulation stage, according to the determined efficacy. For example, at least one of stimulation duration, stimulation frequency and/or stimulation intensity, is increased in at least one sleeping stage where stimulation efficacy of a reference stimulation is low, compared to at least one sleeping stage where stimulation efficacy of the reference stimulation is high. According to some embodiments, stimulation efficacy is evaluated by measuring at least one parameter or changes thereof, for example a physiological parameter and/or a movement related parameter. In some embodiments, the at least one parameter comprises at least one of, heart rate, heart rate variability (HRV), electrocardiogram (ECG), electromyography (EMG), electroencephalogram (EEG), electrooculogram (EOG), sweat level , respiration rate, oxygen saturation, and/or limb movement.

According to some embodiments, stimulation efficacy is evaluated in a sleep lab, for example in a controlled environment and optionally under supervision.

An aspect of some embodiments relates to increasing a chance of a subject to fall asleep, by delivering VNS when intensity of alpha waves measured from the subject brain reach a predetermined threshold. In some embodiments, the subject has or is diagnosed with a sleeping disorder. In some embodiments, the alpha waves are measured from at least one EEG signal measured from the subject brain. In some embodiments, the VNS is delivered with parameter values suitable for inducing a transition from an awake state to a sleep state. In some embodiments, the VNS is delivered with parameter values suitable for triggering theta waves in the subject.

According to some embodiments, the predetermined threshold is determined based on measurements of alpha waves from a group of subjects optionally having similar characteristics, and determining a threshold level of alpha waves in the group or in a sub-group of the subjects, based on the measurements of the alpha waves. In some embodiments, a threshold is defined as an increase in an amplitude of alpha waves in a predetermined time period (for example a time period between 0.1 minute and 10 minutes) by more than at least 1%, for exmaple at least 10%, at least 20%, at least 50%, or any intermediate, smaller or larger percentage value.

An aspect of some embodiments relates to determining activity of each hemisphere of the brain during sleep, for example deep sleep, and delivering VNS to induce symmetrical, or balanced activity of the two hemispheres. In some embodiments, VNS is delivered with stimulation parameter values suitable to increase an activity of the less active brain hemisphere. Alternatively, VNS is delivered with stimulation parameter values suitable for decreasing or attenuating an activity of the more active brain hemisphere.

An aspect of some embodiments relates to a device that is used for treating dementia, for example AD in a subject, and at least one additional clinical condition in the same subject, by delivery of VNS. In some embodiments, VNS is delivered with at least one first set of VNS parameter values for treating dementia, and with at least one second set of VNS parameter values for treating the at least one additional clinical condition. In some embodiments, the at least one additional condition comprises a sleeping disorder or a symptom thereof.

According to some embodiments, for dementia patient, for example AD patients with sleep disorders, a first stimulation is provided upon detecting alpha waves onset or after predetermined time period (pending on patient typical getting to sleep time). In some embodiments, additional stimulation periods are optionally provided every time the movement is above or below a set threshold. In some embodiments, the device may have adaptive threshold values that would try to keep an overall stimulation time during a full night's sleep to be within the range of a therapeutic dose. Optionally, between 2-3 hours of stimulation periods.

According to some embodiments, in case there are no sleeping disorder, AD patients will be provided with 4-6 stimulation periods tuned to have each period in one sleep cycle, typically every 90 minutes, where a stimulation period increases from one simulation period to the following stimulation period.

According to some embodiments, a device for delivery of VNS is used to treatment a sleeping disorder, in a subject optionally diagnosed with dementia, for example AD. In some embodiments, the device stores in a memory at least two protocols of VNS, at least one protocol for delivery of VNS to treatment of the dementia, and at least one additional protocol for treating the sleeping disorder. In some embodiments, the at least two protocols are identical. In some embodiments, the at least two protocols are used at different time periods of the day, and/or when the subject is in a different physiological condition. For example, a protocol for treating dementia is used when the subject is awake, and the protocol for treating a sleeping disorder is used when the subject is asleep.

According to some embodiments, the device switches between the two protocols or selects a protocol out of the at least two protocols automatically, for example based on signals received form at least one detector. Alternatively, the subject receiving the VNS switches manually between the two protocols or selects a protocol manually, optionally in response to an indication generated by the device.

According to some embodiments, a subject, for example patient having difficulties to fall asleep, receives a cranial nerve stimulation, optionally VNS, after a sufficient increase of Alpha waves detected after starting of treatment, for example as described in fig. 8F, and in addition a VNS treatment which includes several stimulation cycles that occurs every about 60 minutes to about 90 minutes where in each stimulation cycle, VNS is provided within a time period of between about 20 minutes to about 40 minutes. According to some embodiments, a subject having difficulty to have a deep sleep receives a VNS treatment when movement level is below a predetermined set threshold, and in addition a VNS treatment which includes several stimulation cycles that occurs every about 60 minutes to about 90 minutes where in each stimulation cycle, VNS is provided within a time period of between about 20 minutes to about 40 minutes, during periods in which a low movement level is detected or expected.

According to some embodiments, a subject having restless sleeping receives a a VNS treatment when movement level is above a predetermined set threshold, for example as described in fig. 8D, and an additional VNS treatment of several stimulation cycles that occurs every about 60 minutes to about 90 minutes where in each stimulation cycle, VNS is provided within a time period of between about 20 minutes to about 40 minutes, during periods in which a high movement level is detected or expected.

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 of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

Exemplary cranial nerve stimulation for a specific state of a subject

According to some exemplary embodiments, cranial nerve stimulation, for example vagus nerve stimulation is delivered to a subject, with parameter values suitable for treatment a specific subject state, for example a clinical state, a functional state, and/or a cognitive state. In some embodiments, the parameter values comprise stimulation intensity, stimulation duration, and/or stimulation frequency. In some embodiments, the parameter values are parameter values of a protocol for the specific state. In some embodiments, the protocol is loaded into a memory of the stimulation device by the subject from a remote device, for example a remote computer, or a remote storage and/or processing server, and/or from a remote database. In some embodiments, the protocol is already stored in the memory of the device.

According to some exemplary embodiments, adjustments of an existing stimulation protocol are performed, for example to personalize the stimulation protocol to a specific subject and/or to the specific state of the subject. In some embodiments, parameter values of the stimulation protocol are adjusted according to sensitivity to pain of the subject due to the stimulation. In some embodiments, a test stimulation is delivered, and the stimulation parameter values are adjusted according to the results of the test stimulation. In some embodiments, the stimulation parameter values are adjusted according to an effect of the stimulation on the state of the subject. For example, the stimulation parameter values are adjusted according to an ability of the stimulation to attenuate or prevent symptoms of the subject state and/or to have less side effects on the subject.

Reference is now made to fig. 1A, depicting a process for delivery of cranial nerve stimulation for treating a specific subject state, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject with a specific state is selected at block 102. In some embodiments, the subject is diagnosed with the specific state. In some embodiments, the specific state comprises at least one of, a clinical state, a physiological state, a functional state, and/or a cognitive state. In some embodiments, the selected subject is a subject that is predicted to have the specific state in the future.

According to some exemplary embodiments, a stimulation device having a suitable protocol for treating the subject state or symptoms thereof, now or in the future, is provided at block 104. In some embodiments, the device is provided to the subject by an expert, for example a physician or a therapist. Alternatively, in some embodiments, the stimulation device is provided with a request to download the suitable protocol from a remote device. Alternatively, the expert or a subject modifies an existing protocol stored in a memory of the device to have parameter values that are suitable for treating the specific state of the subject. In some embodiments, the subject modifies the existing protocol based on instructions received form the expert or from the remote device.

According to some exemplary embodiments, the device is activated at block 106. In some embodiments, activating the device comprises inserting the device into a standby mode. In some embodiments, during a standby mode the device monitors signals from one or more detectors, for example sensors, to determine when to deliver VNS. Alternatively or additionally, during the standby mode, the device waits for a signal from a remote device or from a remote control to deliver the VNS. Alternatively or additionally, during the standby mode the device activates a timer for initiating VNS.

According to some exemplary embodiments, the device optionally detects at least one body parameter, at block 108. In some embodiments, the at least one body parameter comprises a physiological parameter and/or a brain activity parameter, or changes thereof. In some embodiments, the physiological parameter comprises heart rate, heart rate variability, body movement, chest movements, head movements, body posture, blood pressure, breathing, and/or blood oxygenation, brain electrical activity, eye movements. According to some exemplary embodiments, the cranial nerve stimulation, for example VNS, is delivered to the subject at block 110. In some embodiments, the VNS is delivered according to the protocol and/or parameter values described at block 104. In some embodiments, the VNS is delivered in response to the detection of the at least one body parameter, for example when identifying that the subject is asleep based on the detected body parameter. In some embodiments, the VNS is delivered transcutaneously. Alternatively, the VNS is delivered by at least one implanted electrode or by at least one electrode attached to the subject skin.

Exemplary programming a stimulation device

According to some exemplary embodiments, a stimulation device is or is part of a stimulation platform, for example a programmable stimulation platform. In some embodiments, a user of the device can download to the device a stimulation program or stimulation parameters from a remote device. In some embodiments, the user of the device selects the program or parameter values according to a state of the user, for example a clinical state and/or cognitive state. In some embodiments, when the state of the user changes, the device can be reprogrammed with a new program or new stimulation parameter values.

Reference is now made to fig. IB depicting a process for programming of a stimulation platform, for example a stimulation device, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a stimulation device is provided at block 103. In some embodiments, the stimulation device is a device that is shaped and sized to be coupled to a head of a human subject or to a portion of a head of a human subject. In some embodiments, the device is shaped and sized to be placed at least partly in association with an ear of the subject. In some embodiments, at least one or two electrodes of the device are configured to be coupled to an ear, for example to be positioned behind the ear, inside the ear canal and/or at a concha of the ear.

According to some exemplary embodiments, the device comprises a communication circuitry and is configured to communicate with an external device, for example with a mobile device, a cellular device or with a remote control, optionally using wireless signals, for example infra-red, radio, Wi-Fi™ , and /or Bluetooth® signals. In some embodiments, the device comprises at least one electrode, for example at least two electrodes for delivery of the stimulation, for example an electric field to the subject body. In some embodiments, the device comprises at least one detector, for detecting brain activity or for recording signals indicating a physiological parameter of the subject, for example heart rate, blood flow, blood pressure, blood oxygenation level, and/or oxygen saturation level in the blood. Optionally, the stimulation device is in communication with at least one different device that comprises at least one detector.

According to some exemplary embodiments, the stimulation device is provided to a subject, for example to a user of the device, by an expert, for example a physician. Optionally, the expert provides a prescription for the device. Optionally, the expert provides a prescription for a program of the device. Alternatively, the subject purchase the device from a seller, for example a retailer.

According to some exemplary embodiments, the device is programmed at block 105. In some embodiments, programming comprises downloading to the device memory a program, for example a stimulation program. In some embodiments, the program is a software program, for example a software application (App). In some embodiments, the program comprises at least one of, values of at least one parameter of a stimulation, and/or a procedure for measurements of at least one of, brain activity and/or at least one physiological parameter.

According to some exemplary embodiments, the program is a program suitable for treating a state of the subject, for example a clinical state and/or a cognitive state pf the subject. Alternatively or additionally, the program is a program suitable for treating at least one symptom of a clinical state and/or a cognitive state of the subject. In some embodiments, the program includes activation information of the device, for example when treating a subject having the clinical and/or cognitive state or at least one symptom thereof.

According to some exemplary embodiments, the device is mounted on a head or a portion thereof, at block 107. In some embodiments, the device is mounted on the head or a portion thereof, before or after the programming performed at block 105. In some embodiments, mounting the device on a subject head comprises attaching the device to an ear of the subject. In some embodiments, at least part of the device is placed behind the ear, over the ear, in the ear canal and/or at a concha of the ear.

According to some exemplary embodiments, the device is activated, at block 109. In some embodiments, activating the device at block 109 comprises initiating the program installed in the device, for example in the device memory. In some embodiment the program installed in the device, is the program programmed into the device at block 105. Optionally, activating the device comprises activating the device in a stand-by mode.

According to some exemplary embodiments, the device is optionally reprogrammed at block 111. In some embodiments, the device is reprogrammed by programming the device with a different program. Alternatively, the device is programmed by modifying at least one parameter of a program currently installed in the device memory. In some embodiments, the device is reprogrammed, for example, when there is a change in a state of the subject. In some embodiments, the device is reprogrammed with a program that is suitable for treating a new state of the subject. In some embodiments, the device is reprogrammed, for example as described at block 105.

Exemplary stimulation device

According to some exemplary embodiments, a stimulation device comprises a control unit that is connectable to a stimulation unit. In some embodiments, the stimulation unit comprises at least two electrodes. In some embodiments, the control unit and the stimulation are placed in a shared housing. In some embodiments, the stimulation into is shaped and sized to be mounted on at least a part of a head of the subject, for example a human subject. In some embodiments, the stimulation unit is attached at least partly to an ear or part of an ear, of the subject. In some embodiments, at least one electrode of the stimulation unit is attached to a skin surface behind the ear, to a concha region of the ear, or is placed within the ear canal.

Reference is now made to fig. 1C, depicting a stimulation device, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a stimulation device 120 comprises a control circuitry 122, for example a processor, and a memory 124. In some embodiments, the memory 124 stores one or more stimulation protocols, for example one or more VNS stimulation protocols. Alternatively, or additionally, the memory 124 stores values of one or more parameters of the stimulation, for example values of one or more parameters of an electric field delivered during stimulation. In some embodiments, the one or more parameter values comprises at least one of, intensity, frequency, duration of stimulation events, duration of stimulation episodes within a stimulation event, duration of intervals between stimulation episodes, duration of intervals between stimulation events, overall stimulation delivery time during a day or during sleeping time of a subject per day.

According to some exemplary embodiments, the control circuitry 122 is configured to select a specific protocol from a list of protocols stored in the memory 124. Alternatively or additionally, the control circuitry is configured to modify values of at least one parameter of stimulation stored in the memory 124. In some embodiments, the control circuitry 122 selects a specific stimulation protocol and/or modifies at least one parameter of the stimulation based on input received from a user of the device 120 or from an expert, for example a physician or a therapist. Alternatively, the control circuitry 122 selects a specific stimulation protocol and/or modifies at least one parameter of the stimulation based on signals received from for at least one detector, for example at least one sensor or a camera, in communication with the control circuitry 122.

According to some exemplary embodiments, the device 122 comprises a pulse generator 126 functionally coupled to the control circuitry 122 and/or to a power source 128. In some embodiments, the power source 128 comprises a battery, for example a replaceable and/or a rechargeable battery. In some embodiments, the device 122 is functionally coupled to at least one electrode, for example electrodes 130. In some embodiments, the control circuitry 122 is configured to signal the pulse generator 126, for example a stimulation pulse generator, to generate and deliver an electric field with parameter values stored in the memory 124 to the electrodes 130. In some embodiments, the electric field is delivered as one or more pulses of stimulation.

According to some exemplary embodiments, the electrodes 130, for example at least two electrodes, are attached to a head of a subject. Optionally, the electrodes 130 are part of a head unit configured to be placed on a head of the subject, or surround at least partly the head or neck of the subject. In some configurations, the head unit is attached to the head or neck of the subject using sticker. In some embodiments, one or more of the electrodes 130 is associated with an ear of the subject, for example the electrode is placed behind the ear, at a concha region or within the ear canal. Alternatively, one or more of the electrodes 130 are at least partly implanted in the subject body, and is configured to deliver the electric field to the cranial nerve from within the subject body. In some embodiments, one or more of the electrodes is configured to deliver the electric field transcutaneously, for example through the skin of the subject.

According to some exemplary embodiments, a housing 121 of the device 120 is configured to associate at least one electrode of the electrodes 130 with at least one ear of the subject. In some embodiments, the housing 121 is configured to securely position the at least one electrode behind the ear, in the ear canal or at a concha of the ear. In some embodiments, the housing comprises at least one fastener for fastening the device, or at least one electrode to an ear of the subject. In some embodiments, the at least one fastener comprises an adhesive or a mechanical attachment or fastener. In some embodiments, the housing comprises an ear cover configured to hold the electrodes in place and coupled to at least one ear. Optionally, the ear cover is part of the head unit 152 shown in fig. ID.

According to some exemplary embodiments, the electrodes 130 are part of the device 120. Alternatively, the device 120 is connectable to the electrodes 130.

According to some exemplary embodiments, the device 120 comprises at least one detector 132, for example a sensor, and electrode, a camera and/or a microphone. In some embodiments, the at least one detector is configured to record at least one signal indicating brain activity of a subject, for example using at least one EEG electrode. Alternatively or additionally, the at least one detector is configured to record at least one signal indicating a physiological parameter, for example heart rate, heart rate variability, blood oxygenation level, blood pressure, level of sweat, breathing patterns, sounds, muscle activity, eye movement. Alternatively or additionally, the at least one detector is configured to record at least one signal indicating body movement and/or posture of the subject body, for example a gyroscope and/or an accelerometer.

According to some exemplary embodiments, the at least one detector 132 is part of the device 120. Alternatively, the device 120 is connectable to the at least one detector 132, for example when the at least one detector 132 is at least one sensor of a wearable device, for example a smartwatch, or a mobile device. In some embodiments, the at least one detector comprises at least one of, one or more electrodes for recording EEG, one or more electrodes for recording ECG and one or more electrodes for recording electromyography (EMG). In some embodiments, the at least one detector is configured also to measure sweat level and optionally includes one or more movement sensors.

According to some exemplary embodiments, the at least one detector comprises a movement sensor configured to measure movement of one or more of the following body portions, head, hand, leg, chest, and/or belly. In some embodiments, the at least one detector comprises a wearable or an implantable sensor, and is optionally a part of the stimulation device or is optionally external to the device having wire or wireless communication with the stimulation device. For example, the at least one detector is included in the external device 138 or is an external detector, for example external detector 178 shown in fig. IE.

According to some exemplary embodiments, the device 120 comprises at least one user interface 134. In some embodiments, the user interface is configured to generate indications, for example human detectable indications. Additionally or alternatively, the user interface is configured to receive an input signal from a user of the device 120. In some embodiments, the human detectable indications comprise audio, visual, and/or tactile indications, for example vibrations.

According to some exemplary embodiments, the device 120 comprises a communication circuitry 136. In some embodiments, the communication circuitry 136 is configured to transmit and/or receive signals from an external device 138. In some embodiments, the signals are wireless signals. In some embodiments, the external device comprises a remote device for example a remote computer, a server, a cloud storage device, a database. In some embodiments, the external device comprises a mobile device, a cellular device, a smartwatch and/or a wearable device.

According to some exemplary embodiments, the device 120 is functionally coupled to an external user interface 140, for example a display. In some embodiments, the user interface 140 is configured to deliver a human detectable indication, for example a visual and/or an audio interface. Optionally, the device 120 is configured to deliver human detectable indications to the user via the external user interface 140 before, during and/or after stimulation delivery. In some embodiments, the human detectable indications comprise cognitive stimulation, for example as part of cognitive training.

Reference is now made to fig. ID, depicting a device for delivery of stimulation, for example VNS, that includes a head unit, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, the device 150 comprises a head unit 152 functionally coupled to a control unit 154. In some embodiments, the head unit 152 is configured to be coupled or mounted on a head of a subject. In some embodiments, the head unit 152 comprises at least one electrode, for example at least two electrodes 130, positioned on the head for delivery of the VNS. In some embodiments, the head unit 152 comprises one or more openings and/or one or more alignment markings, for example to allow positioning of the head unit 152 in a specific orientation on the subject head such that the at least two electrodes are in contact or face a target location on the subject head selected for delivery of the stimulation.

Optionally, the head unit 152 comprises at least one detector 132, for example at least one sensor or an electrode. In some embodiments, the at least one detector comprises at least one EEG electrode for recording brain activity of the subject.

In some embodiments, the control unit 154 comprises a user interface, for example user interface 156, for delivery of human detectable indications to the subject. In some embodiments, the user interface 156 comprises a display. In some embodiments, the device 150 delivers cognitive stimulation and/or human detectable indications to the subject during stimulation, for example during active delivery of an electric field to the subject and/or between active delivery of the electric field.

According to some exemplary embodiments, a stimulation device, for example device 120 is programmed with two or more different activation programs, each for a different state of a subject. In some embodiments, each activation program of the two or more different activation programs comprises different values of at least one stimulation parameter, for example different values for intensity, frequency, duration, and/or selection of electrodes for delivery of the electric field. Alternatively, or additionally, each activation program of the two or more different activation programs comprises a different stimulation application sequence, for example a different number of stimulation blocks, for example stimulation blocks 252, a different number of washout blocks 254, different length for one or more stimulation blocks and/or washout blocks.

According to some exemplary embodiments, the stimulation device is configured to deliver VNS to a subject using at least two different activation programs each for treating a different cognitive state, or a different symptom of at least one cognitive state. In some embodiments, the different states comprise at least one of, different sleeping stages, sleep or awake states, rest and exercise states, states of posture (when the subject laying down, sitting, standing, walking, running), and/or different types of cognitive efforts, for example learning, reading, playing music, dancing, high concentration, and/or low concentration. In some embodiments, the device differentiates between two or more cognitive states based on signals recorded from the body of the subject or other measurements, for example signals indicating autonomic nervous activity, and/or heart rate variability (HRV) measurements.

It should be understood that the stimulation device and/or stimulation sown in figs. ID and IE, are used, in some embodiments, to deliver VNS, for exmaple auricular VNS in one or more of the methods described herein in this application.

Exemplary device communication

According to some exemplary embodiments, the stimulation device, for example device 120 shown in fig. 1C is a programmable device. In some embodiments, the device is programmed by communicating with one or more external devices. In some embodiments, one or more programs, optionally device activation programs, are downloaded to the device memory. Optionally, the device can be reprogrammed, for example by at least one of, replacing an existing program with a new program, selecting a different program from a collection of programs installed in a memory of the device, and/or modifying an existing program for example by modifying values of at least one parameter of the existing program.

Reference is now made to fig. IE, depicting interactions between a stimulation device, a mobile, for example a cellular device, and a remote device, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a stimulation device, for example device 170 is shaped and sized to be mounted on a head of a subject 172. In some embodiments, the stimulation device is configured to be associated, for example attached or placed in contact, with at least one ear of a subject, for example a human subject or an animal subject. In some embodiments, the device is similar to the device 120 described in fig. 1C. In some embodiments, the device 170 comprises at least one detector, for example at least one electrode and/or at least one sensor. In some embodiments, the at least one detector is configured to record signal indicating brain activity or changes thereof. Alternatively, the at least one detector is configured to record signals indicating a level of a physiological parameter or changes thereof. In some embodiments, the device 170 comprises at least one detector for recording brain activity, for example an EEG electrode, and/or at least one detector, for example a sensor, for recording signals indicating physiological parameter or changes thereof.

According to some exemplary embodiments, the device 170 is in communication with a mobile device, for example a cellular device 174. In some embodiments, the device 170 is in communication with the mobile device by wireless signals. In some embodiments, the stimulation device 170 delivers information to the mobile device 174, for example information regarding at least one of, measurements of the at least one physiological parameter, measurements of brain activity and/or information regarding the activity of the stimulation device 170. In some embodiments, the stimulation device 170 receives information from the mobile device with information regarding a protocol, values of at least one parameter of a treatment program, and/or values of at least one stimulation parameter.

According to some exemplary embodiments, the mobile device 174 activates a software program, for example a software application, which is configured to receive and/or transmit information to the stimulation device 170. In some embodiments, the software application in the memory of the mobile device 174 comprises a user interface that generates and delivers a human detectable information to a user of the stimulation device 170 with information received from the stimulation device 170. In some embodiments, the user interface of the software application is configured to receive input from the user of the stimulation device 170 before, during and/or after active delivery of stimulation to the subject body. In some embodiments, the software program is configured to process the received input and to generate an output signal to the user using the user device, and/or to an expert, with the processing results and/or with the input information received form the user of the stimulation device.

According to some exemplary embodiments, the mobile device is in communication with a remote device 176. In some embodiments, the remote device 176 is a device located at a distance which is larger than an effective distance for communication using infra-red, WIFI , and /or Bluetooth signals, for example a distance of at least 30 meters. In some embodiments, the remote device comprises a remote computer, a remote cellular device, a remote mobile device, a database, a server, and/or a cloud storage and/or processing device. In some embodiments, the mobile device 174 is in communication with at least one external detector 178, for example at least one of a camera, a wearable detector or a wearable device having at least one detector

According to some exemplary embodiments, the mobile device 174 downloads or receives information with at least one program, for example a treatment program from the remote device, for example from a software application collection of plurality of software applications stored in the remote device 176. In some embodiments, the mobile device 174 programs the stimulation device 170 with the at least one program received from the remote device. In some embodiments, the mobile device 174 transmits to the remote device information on a state of the subject, information on an operation of the stimulation device 170, information on a progress of the treatment delivered to the subject using the stimulation device 170, input information received from the subject and/or input received from the external detector 178.

According to some exemplary embodiments, the software program of the mobile device 174 is used to control and/or monitor the activation of the device 170. In some embodiments, when a state of the subject changes, the mobile device downloads a different program to the stimulation device 170, or performs modification in one or more stimulation parameters and/or treatment parameters. Alternatively or additionally, the mobile device modifies an existing treatment program stored in the mobile device, for example in a software program in the mobile device 174.

Exemplary cognition improvement

According to some exemplary embodiments, stimulation, for example cranial nerve stimulation is delivered to a subject for improving a cognitive state of the subject. In some embodiments, the cranial nerve stimulation, for example VNS, is delivered in order to improve at least one cognition-related score of the subject, including for example ADAS-COG, MMSE, MOCA, GDS, CDR. In some embodiments, the subject is diagnosed with cognitive impairment or is cognitively impaired. In some embodiments, the subject is diagnosed with early AD, or with MCI. In some embodiments, the subject achieves an ADAS-COG score in a range between 10-50 points for ADAS COG 13, 10-40 points for ADAS COG 11, and/or a MMSE score within a range of 10-25 points.

According to some exemplary embodiments, the subject is impaired in one or more cognitive domains, for example sensation, perception, motor skills and construction, attention and concentration, memory, executive functioning, processing speed, and/or language or verbal skills. In some embodiments, the cognitive domains comprise at least one of, language, memory, praxis and/or orientation. Reference is now made to fig. 2A depicting a process for improving cognition of a subject by cranial nerve stimulation, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject with cognitive impairment is identified at block 200. In some embodiments, cognitive impairment is identified in the subject using one or more cognitive assessment tests, for example ADAS-COG and MMSE. In some embodiments, the cognitive impairment is identified based on a score in the one or more cognitive assessment test that is not within a target range of values indicating normal cognition.

According to some exemplary embodiments, the subject is optionally diagnosed with early AD, or with MCI, at block 202. In some embodiments, the subject is diagnosed with early AD or with MCI based on the identification of the cognitive impairment at block 200. In some embodiments, the subject is diagnosed with early AD or with MCI by an expert, for example a physician, a neurologist, a psychiatrist, and/or a gerontologist.

According to some exemplary embodiments, VNS treatment is delivered to the subject, at block 204. In some embodiments, the VNS treatment is delivered to the subject according to a specific stimulation protocol and/or with specific stimulation parameters, selected according to the impairment identified at block 200. Alternatively or additionally, the VNS treatment is delivered to the subject based on the subject diagnosis performed at block 202.

According to some exemplary embodiments, the VNS treatment is delivered in one or more sessions for a time period of at least one day or at least one week. In some embodiments, the VNS treatment is delivered in a frequency of at least one active stimulation session per day or per week, and/or at least one active stimulation session per a sleeping period of the subject that lasts at least 1 hour.

According to some exemplary embodiments, in each stimulation session, the stimulation protocol comprises blocks of active stimulation delivery separated by a washout blocks, for example when stimulation is not delivered to the subject. In some embodiments, a duration of each active stimulation block and/or a duration of a washout block, is in a range between 1 minute and 120 minutes (1-120 minutes), for example 1-30 minutes, 10-40 minutes, 20-50 minutes, 30-120 minutes or any intermediate, shorter or longer time period. In some embodiments, during each stimulation block, active stimulation is delivered intermittently in intervals that last between 1 second and 120 seconds (1-120 seconds) between stimulations, for example in intervals of 10-100 seconds, 10-40 seconds, 20-50 seconds, or any intermediate, shorter or longer time intervals. In some embodiments, the stimulation is delivered when the subject is asleep. Optionally the stimulation is delivered in synchronization with sleeping stages, for example Nl, N2, N3 and/or rapid eye movement (REM) stages. In some embodiments, during each active stimulation block, stimulation is delivered in episodes that last between 1-120 seconds and in a frequency within a range between 1-100 Hertz (Hz) during the episodes, for example in frequency within a range between 1-50 Hz, 20-80 Hz, 40-100 Hz, or any intermediate, shorter or longer range of frequencies.

According to some exemplary embodiments, cognitive stimulation is optionally provided to the subject, at block 206. In some embodiments, the cognitive stimulation is provided while actively delivering VNS, for example an electric filed, ot the subject. Alternatively or additionally, the cognitive stimulation is provided before and/or after the active delivery of the VNS.

According to some exemplary embodiments, an improvement in a cognitive state of the subject is achieved at block 208. In some embodiments, an improvement in at least one domain of the cognition, is achieved at block 208. In some embodiments, the improvement is achieved at least one hour from initiating the vagal stimulation, for example at least 1 day, at least 1 week, at least 1 month, or any intermediate, shorter or longer time period from initiating the vagal stimulation treatment. In some embodiments, achieving cognitive improvement comprises achieving improvement in a score of a cognition related scale, relative to a score calculated prior to initiating the vagal stimulation. In some embodiments, achieving cognitive improvement comprises achieving cognitive improvement relative to a cognitive state of the subject prior to initiating the VNS.

According to some exemplary embodiments, a reduction in an ADAS-COG score is optionally achieved following initiation of the VNS treatment, for example VNS stimulation, at block 210. In some embodiments, a reduction of at least 2 points, for example a reduction of at least 4 points, or any intermediate, smaller or larger number of points, is achieved at least two weeks from initiating the VNS treatment. In some embodiments, a reduction of at least 4 points in the ADAS-COG score is achieved at least 1 month from initiating the VNS treatment. In some embodiments, a reduction of at least 5 points, for example at least 6 points, in the ADAS-COG score is achieved at least 3 month from initiating the VNS treatment. In some embodiments, a reduction of at least 7 points in the ADAS-COG score is achieved at least one month from completing VNS treatment period, optionally from completing 3 months of VNS treatment.

According to some exemplary embodiments, an increase in a MMSE score is optionally achieved following initiation of the VNS treatment, for example the VNS stimulation, at block 212. In some embodiments, an increase of at least 1.5 points, or any intermediate, smaller or larger number of points, in MMSE score is achieved at least a month from initiating the VNS treatment. In some embodiments, an increase of at least 1.5 points in the MMSE score is achieved at least one month from completing the VNS treatment, optionally from completing 3 months of VNS treatment.

Reference is now made to fig. 2B, depicting a process for monitoring a change in a cognition related score during and/or following VNS, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, after delivering at least one session of VNS at block 222, and optionally at least one session of cognitive stimulation at block 224, a cognition related score is calculated at block 226. In some embodiments, the cognition related score is calculated by receiving input from a subject receiving the VNS and/or by receiving input from an expert or from a caregiver. In some embodiments, the input comprises the score. Alternatively, the stimulation device calculates the score, for example in case where a cognitive assessment exam is performed using a user interface of the device, for example user interface 134 shown in fig. 1C.

According to some exemplary embodiments, a change in the cognition related score is determined at block 228. In some embodiments, a change between the score calculated at block 226 and a previously calculated score or indications thereof stored in a memory, for example memory 124, is determined at block 228.

According to some exemplary embodiments, if the determined change is a target change, for example a desired change, then at least one additional session of VNS is delivered to the subject at block 232, optionally with an additional cognitive stimulation at block 234. Alternatively, if the determined change is not a target change, then at least one parameter of the vagal stimulation treatment is modified at block 236 or a change in the at least one parameter is suggested by the device and/or is evaluated by a an expert.. In some embodiments, the at least one parameter comprises a length of active stimulation blocks, and/or a length of washout no- stimulation/different stimulation blocks, per a treatment session. Alternatively or additionally, the at least one parameter comprises number of stimulation blocks and/or number of washout no- stimulation/different stimulation blocks per a treatment session. Alternatively or additionally, the at least one parameter comprises duration, frequency and/or intensity of stimulation delivered during each stimulation block in a plurality of stimulation sessions.

According to some exemplary embodiments, if the determined change in score is smaller than an expected change in the score, then the number and/or length of the stimulation blocks is increases. Alternatively or additionally, the number and/or length of washout no- stimulation/different stimulation blocks is increased, for example to allow better synchronization of the stimulation with neurotransmitter recycling and/or recovery process, or better synchronization with a response time of the nerve cells to the stimulation.

Alternatively or additionally, if the determined change in score is smaller than an expected change in the score, stimulation current amplitude is increased. In some embodiments, in case of a single side stimulation, a side of stimulation is changed, for example by changing an ear to be stimulated, or the single side stimulation is changed to a dual-side stimulation. In some embodiments, in case of a dual-side stimulation, stimulation is changed from alternating stimulation between sides to synchronized stimulation in both sides.

Alternatively or additionally, if the determined change in score is smaller than an expected change in the score, stimulation timing is changed between stimulation during sleep to stimulation when the subject is awake. Alternatively or additionally, if the determined change in score is smaller than an expected change in the score, a stimulation electrode contact area with the body is changed.

In a validation study, VNS treatment was provided to selected subjects diagnosed with early AD or with MCI. In some embodiments, prior to the VNS treatment, the selected subjects achieved an ADAS-COG score within a range between 10-50 points for ADAS COG 13, and/or a MMSE score within a range between 10-25 points. In some embodiments, the selected subjects received VNS stimulation every day while they were asleep, and during an overall time period of 3 months.

The study included 36 treatment patients and 15 Control patients. A sub group of 19 treated patients and 7 control patients extended their treatment period to 6M.

As shown on figs. 2C, in some embodiments and in the study, optionally during each sleeping period, a VNS treatment session 250 included at least two stimulation blocks 252 separated by at least one washout no- stimulation/diff erent stimulation block, for example blocks 254. Table A below describes the duration (in minutes) of the stimulation and washout blocks per a single VNS treatment session, per day:

According to some exemplary embodiments and in the study, the stimulation, for example the electric field, is delivered with a frequency in a range between about 1 Hz and about 100 Hz, for example between about 1 Hz and about 50 Hz, between about 20 Hz and 40 Hz, between about 30 Hz and 100 Hz, between about 20 Hz and 30 Hz, or any intermediate, smaller or larger range of values. In some embodiments and in the study, the stimulation, is delivered to the subject with a stimulation amplitude, for example intensity, between about 0.1 mA and about 4 mA, or example between about 0.4 mA and about 2 mA, between about 1 mA and about 2.5 mA, between about 1.5 mA and about 2 mA, or any intermediate, smaller or larger value or range of values. In some embodiments and in the study, stimulation is delivered to the subject with a pulse width between 0.1 millisecond (ms) and 2 ms, for example between 0.1 ms and 1 ms, between 0.2 ms and 0.7 ms, between 0.5 ms and 2 ms, or any intermediate, smaller or larger value or range of values.

Fig. 3A includes a graph showing an average change in an ADAS-COG score, 3 months from initiating the VNS treatment. The VNS treatment was provided during the 3 months, in a single treatment session per day, for example the treatment session 250 shown in fig. 2C. Reduction in an ADAS-COG scale score indicates cognitive improvement of a subject. As shown in the graph, in a group of 36 treatment patients vs. 15 sham treatment patients a reduction of at least 4 points relative to baseline was observed 1 month from initiating the treatment in the treatment group 260. The graph also shows that after 3 months from initiating the VNS treatment, a reduction of at least 6 points relative to baseline was observed in the treatment group 260. In comparison, an increase in the ADAS-COG score relative to baseline was observed after 3 months in the sham control group 262.

Fig. 3B includes a graph showing an average change in an ADAS-COG score, up to 6 months from initiating the VNS treatment. As shown in the graph, in a sub group of 19 treatment patients vs. 7 sham treatment patients, a reduction of at least 8 points relative to baseline was observed in the treatment group 260 6 months from initiating the VNS treatment. In comparison, an increase in the ADAS-COG score relative to baseline was observed after 6 months in the sham control group 262.

Fig. 4 A includes a graph showing an average change in a Verbal Probing score, 3 months from initiating the VNS treatment. The VNS treatment was provided during the 3 months, in a single treatment session per day, for example the treatment session 250 shown in fig. 2C. An increase in the Verbal Probing score indicates cognitive improvement of a subject. As shown in the graph, in a group of 36 treatment patients vs. 15 sham treatment patients, after 1 month from initiating the VNS treatment, an increase of at least 1 point in average relative to baseline was observed in the treatment group 260. In comparison, a decrease in the Verbal Probing score relative to baseline was observed after 3 months in the sham control group 262.

Fig. 4B includes a graph showing an average change in the Verbal Probing score up to 6 months from initiating the VNS treatment. As shown in the graph, in a sub group of 19 treatment patients vs. 7 sham treatment patients, an increase of at least 0.8 points relative to baseline was observed 6 months from initiating the VNS treatment, in the treatment group 260. In comparison, a decrease in the Verbal Probing score relative to baseline was observed after 6 months in the sham control group 262.

Fig. 5A includes a graph showing an average change in a MMSE score, 3 months from initiating the VNS treatment. The VNS treatment was provided during the 3 months, in a single treatment session per day, for example the treatment session 250 shown in fig. 2C. An increase in the MMSE score indicates cognitive improvement of a subject. As shown in the graph, in a group of 36 treatment patients vs. 15 sham treatment patients, after 1 month from initiating the VNS treatment, an increase of at least 2 points in average relative to baseline was observed in the treatment group 260. In comparison, an increase smaller than 1.5 points in the MMSE score relative to baseline was observed after 1 month in the sham control group 262. In addition, the graph shows that after 3 months from initiating the VNS treatment, an increase of at least 1.5 points in average relative to baseline was observed in the treatment group 260. In comparison, an increase smaller than 1.5 points in the MMSE score relative to baseline was observed after 3 months in the sham control group 262.

Fig. 5B includes a graph showing an average change in the MMSE score up to 6 months from initiating the VNS treatment. As shown in the graph, an increase of at least 1.5 points relative to baseline was observed at least 4 months and at least 6 months from initiating the VNS treatment, in the treatment group 260. In comparison, an increase smaller than 1.5 points in the MMSE score relative to baseline was observed after at least 4 months and at least 6 months in the sham control group 262. Fig. 6A includes a graph showing an average change in a Color Trial Test (CTT) score, 3 months from initiating the VNS treatment. The VNS treatment was provided during the 3 months, in a single treatment session per day, for example the treatment session 250 shown in fig. 2C. An increase in the CTT score indicates cognitive improvement of a subject. As shown in the graph, after 1 month from initiating the VNS treatment, an increase of at least 8 points in average relative to baseline was observed in the treatment group 260. In comparison, a decrease in the CTT score relative to baseline was observed after 1 month in the sham control group 262. In addition, the graph shows that after 3 months from initiating the VNS treatment, an increase of at least 5 points in average relative to baseline was observed in the treatment group 260. In comparison, an increase smaller than 3 points in the CTT score relative to baseline was observed after 3 months in the sham control group 262.

Fig. 6B includes a graph showing an average change in the CTT score up to 6 months from initiating the VNS treatment. As shown in the graph, an increase of at least 4 points in the CTT score relative to baseline was observed at least 4 months and at least 6 months from initiating the VNS treatment, in the treatment group 260. In comparison, an increase smaller than 2 points in the CTT score relative to baseline was observed after at least 4 months and at least 6 months in the sham control group 262.

Exemplary stimulation treatment protocol

According to some exemplary embodiments, a stimulation treatment, for example a VNS stimulation treatment is delivered to a subject in one or more, or a plurality of treatment sessions. In some embodiments, at least one treatment session is delivered per day. Optionally, the at least one treatment session is delivered when the subject is asleep. Alternatively or additionally, the at least one treatment session is delivered before and/or after the subject is asleep.

According to some exemplary embodiments, a stimulation treatment includes at least one treatment session, at least 5 treatment sessions, at least 10 treatment sessions, at least 20 treatment sessions, at least 30 treatment sessions, at least 50 treatment sessions, or any intermediate, smaller or larger number of treatment sessions. In some embodiments, the stimulation treatment is delivered for an overall time period of at least 1 day, at least 5 days, at least 1 week, at least 10 days, at least two weeks, at least 3 weeks, at least 4 weeks, at least 1 month, at least 2 months, or any intermediate, shorter or longer time period. In some embodiments stimulation is delivered continuously, for example as a lifetime treatment with optional periodic breaks. Reference is now made to fig. 7 depicting a scheme of a single session of a stimulation treatment, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a stimulation treatment session 702 comprises two or more blocks of active stimulation, for example blocks 704, with intervals of washout blocks, for example blocks 704. In some embodiments, during a washout blocks, active stimulation, for example delivery of an electric field, is not delivered to the subject. Alternatively, during the washout blocks, stimulation is delivered with parameter values that are different from the stimulation provided during the stimulation blocks 702. In some embodiments, and without being bound by any theory or mechanism during the washout blocks one or more of the following changes occur, neural networks gradually return to their pre- stimulation state or acquire a new basal steady state, neurotransmitter levels are re-balanced, and/or neuroplasticity processes are initiated or take place.

According to some exemplary embodiments, duration of each stimulation block 704 and/or washout block 706 is within a range between 1-60 minutes, for example the duration is within a range between 1-30 minutes, between 20-40 minutes, between 25-50 minutes, between 20-60 minutes, or ant intermediate, smaller or larger range of values.

According to some exemplary embodiments, for example as shown in fig. 7, during each stimulation block 702, active stimulation is delivered intermittently in active stimulation “on” sessions 266, separated by no stimulation “off’ sessions 268. In some embodiments, a duration of each active stimulation session 226 and each interval 268 between active stimulation sessions is within a range between about 1 second and aboutl20 seconds, for example between about 1 second and about 50 seconds, between about 10 seconds and about 40 seconds, between about 20 seconds and about 40 seconds, between about 20 seconds and about 100 seconds, between about 50 seconds and about 100 seconds, or any intermediate, smaller or larger value or range of values. In some embodiments, in each active stimulation session 266, stimulation, for example an electric field is delivered to the subject with a frequency in a range between about 1 Hz and about 100 Hz, for example between about 1 Hz and about 50 Hz, between about 20 Hz and 40 Hz, between about 30 Hz and 100 Hz, or any intermediate, smaller or larger range of values. In some embodiments, in each active stimulation session 266, stimulation, for example an electric field, is delivered to the subject with a stimulation amplitude, for example intensity, between about 0.1 mA and about 4 mA, or example between about 0.5 mA and about 2 mA, between about 1 mA and about 2.5 mA, between about 1.5 mA and about 2 mA, or any intermediate, smaller or larger value or range of values. In some embodiments, in each active stimulation session 266, stimulation, for example an electric field, is delivered to the subject with a pulse width between 0.1 millisecond (ms) and 2 ms, for example between 0.1 ms and 1 ms, between 0.2 ms and 0.7 ms, between 0.5 ms and 2 ms, or any intermediate, smaller or larger value or range of values.

Stimulation before and/or during sleep

According to some exemplary embodiments, cranial nerve stimulation, for example VNS, is delivered to a subject before and/or during a sleeping period, for example before and/or after the subject falls asleep. In some embodiments, stimulation is delivered before and after the subject falls asleep with different stimulation parameters. Alternatively, when the subject falls asleep, stimulation is stopped. In some embodiments stimulation is continued after subject falls asleep. In some embodiments, the stimulation allows, for example, to affect neural circuits that control sleeping quality and/or an ability of a subject to fall asleep. In some embodiments, delivery of stimulation before the subject falls asleep may assist the subject to fall asleep. In some embodiments, delivery of stimulation during sleep, after the subject is asleep, may assist in prolonging at least one stage of sleep and/or increase the depth and quality of the sleep.

Reference is now made to fig. 8A, depicting different stages in the process of falling asleep, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, during a pre-sleep stage 802, subject is awake and in a sleep body posture, for example in a horizontal posture, optionally lying in bed. In some embodiments, during the pre-sleep stage 802, a pre-sleep stimulation, for example VNS, is delivered to the subject. In some embodiments, the pre-sleep stimulation is delivered with parameter values, for example duration, intensity and/or frequency, selected to assist the subject with falling asleep.

According to some exemplary embodiments, a falling asleep stage 804 initiates when the subject falls asleep, for example when the subject moves between an awake state to a sleep state. Optionally, the transition between an awake state and a sleep state is determined based on recordings of signals indicating brain activity or changes thereof, for example EEG signals, and/or based on measurements of at least one physiological parameter indicating that the subject falls asleep, for example heart rate, heart rate variability, body movements, chest movements, and/or breathing of the subject. In some embodiments, during falling asleep stage 804, the subject body is in a sleep posture, as in stage 802.

According to some exemplary embodiments, when the subject falls asleep, for example when the stimulation device detects that the subject falls asleep or is in the falling asleep stage, stimulation, for example the pre-sleep stimulation, is stopped. In some embodiments, the stimulation is stopped, for example not to interfere with falling asleep. In some embodiments, the stimulation is stopped up to 1 minute, up to 30 minutes, up to 10 minutes or any intermediate, shorter or longer time period before the subject falls asleep. In some embodiments, the device predicts when the subject is about to fall asleep based on the measurements of brain activity and/or the measurements of the at least one physiological parameter.

According to some exemplary embodiments, at a sleep stage 806 the subject is asleep. In some embodiments, the sleep stage starts up to 1 minute, for example up to 30 seconds, up to 10 seconds, or any intermediate, shorter or longer time period after the subject falls asleep. In some embodiments, during sleep stage, stimulation is resumed. In some embodiments, the stimulation is resumed and is delivered with different parameter values. In some embodiments, delivery of stimulation during the sleep stage 806 allows, for example to prolong the sleep stage 806, and/or to increase the depth of sleep in the subject during the sleep stage 806.

Reference is now made to fig. 8B, depicting a process for delivery of stimulation to a subject, for example VNS, before and/or after the subject falls asleep, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject suffering from a sleeping disorder is optionally selected at block 810. In some embodiments, the subject is diagnosed with a sleeping disorder. Alternatively or additionally, the subject suffers from at least one symptom of the sleep disorder. In some embodiments, the sleep disorder comprises insomnia, and/or disrupted sleep.

According to some exemplary embodiments, stimulation parameter values are optionally set, at block 814. In some embodiments, setting stimulation parameter values comprises selecting a stimulation treatment protocol. In some embodiments, the stimulation parameter values are set and/or the stimulation treatment protocol is selected according to the sleeping disorder of the subject.

According to some exemplary embodiments, stimulation, for example VNS is initiated at block 816. In some embodiments, the initiated VNS comprises the parameter values that were set at block 814. In some embodiments, the stimulation device initiates the VNS, for example delivery of an electric field to the subject.

According to some exemplary embodiments, the stimulation device detects that the subject is about to fall asleep or falls asleep, at block 818. In some embodiments, the device detects that the subject is about to fall asleep or is asleep based on signals received from at least one detector, for example at least one sensor, of the device or in communication with the device. Alternatively or additionally, the device detects that the subject is about to fall asleep or is asleep by measuring brain activity or changes thereof. Alternatively or additionally, the device detects that the subject is about to fall asleep or is asleep by measuring at least one physiological parameter. Alternatively or additionally, the device detects that the subject is about to fall asleep or is asleep by receiving at least one signal from an external device, for example a wearable or a mobile device, that is in communication with the stimulation device.

According to some exemplary embodiments, if the device detects that the subject is not about to fall asleep or is not asleep, after a predetermined time period, then optionally one or more of the stimulation parameters are modified at block 820. In some embodiments, the one or more stimulation parameters are modified, for example to promote a transition of the subject from an awake stage to a sleeping stage.

According to some exemplary embodiments, stimulation is optionally delivered with the modified parameters at block 822.

According to some exemplary embodiments, if the device detects that the subject is asleep or is about to fall asleep, then the stimulation initiated at block 816 or optionally delivered at block 822, is stopped at block 824. In some embodiments, the stimulation is stopped in order not to interfere with the falling asleep of the subject.

According to some exemplary embodiments, the device optionally detects that the subject is asleep, at block 826. In some embodiments, the device optionally modifies stimulation parameters at block 828. In some embodiments, modifying the stimulation parameters at block 826 comprises selecting a different stimulation protocol. In some embodiments, the stimulation parameters are modified to fit a sleeping stage of the subject, or at least one sleeping stage of the subject. In some embodiments, the parameter values are modified to parameter values that are sufficient or selected to prolong at least one sleeping stage of the subject and/or to increase a sleeping depth of the subject.

According to some exemplary embodiments, stimulation is optionally resumed at block 830. In some embodiments, the stimulation is resumed using the modified stimulation parameter values, selected or modified at block 828. In some embodiments, the stimulation is resumed using a different selected protocol having the modified parameter values.

Reference is now made to fig. 8C depicting a process for delivery of stimulation in order to reach a target sleep quality, for example a target sleep quality, that can be measured for example by the length of deep sleep periods during night and/or a target sleep length, according to some exemplary embodiments of the invention. In some embodiments, the stimulation, for example the stimulation treatment is delivered to a subject diagnosed with at least one sleeping disorder or to a subject suffering from at least one symptom of the sleeping disorder. According to some exemplary embodiments, the sleeping disorder comprises inability to reach REM sleep. In some embodiments, to treat this disorder, the stimulation is optionally delivered until reaching REM sleep.

According to some exemplary embodiments, the sleeping disorder comprises too short deep sleep periods, for example periods shorter than 10 minutes, for example shorter than 8 minutes, shorter than 5 minutes, shorter than 3 minutes, shorter than 1 minute, or any intermediate, smaller or larger value. In some embodiments, in order to treat this disorder, stimulation is delivered to prolong a deep sleep period, for example when detecting an onset of a deep sleep period.

According to some exemplary embodiments, the sleeping disorder comprises waking up during a REM sleep period. In some embodiments, to treat this disorder, the stimulation is optionally delivered when detecting onset of REM sleep.

According to some exemplary embodiments, the sleeping disorder comprises waking up during a REM sleep period or movement during REM sleep. In some embodiments, to treat these disorders, the stimulation is optionally delivered when detecting an onset of REM sleep.

According to some exemplary embodiments, the sleeping disorder comprises a restless leg syndrome. In some embodiments, to treat this disorder, the stimulation is optionally delivered when detecting leg movement which exceeds a predetermined movement threshold.

According to some exemplary embodiments, the sleeping disorder comprises a hypersomnia. In some embodiments, to treat this disorder, the stimulation is optionally delivered, prior to a predetermined waking time, for example 1-30 minutes prior to a predetermined waking time.

According to some exemplary embodiments, a subject suffering from a sleeping disorder is optionally selected at block 832. Alternatively, a subject suffering from at least one symptom of a sleeping disorder is selected at block 832.

Alternatively, a subject having short sleep and/or short rapid eye movement (REM) sleep is optionally selected at block 832.

According to some exemplary embodiments, stimulation treatment parameters are optionally set at block 834, for example as described at block 814 in fig. 8B. In some embodiments, setting stimulation parameter comprises selecting a stimulation protocol that includes the stimulation parameters.

According to some exemplary embodiments, a target sleeping duration and/or a target sleep depth, and/or a target sleep quality is set, at block 836. In some embodiments, a device, for example the stimulation device 120 shown in fig. 1C receives an input signal with the target sleeping duration and/or the target sleep depth and/or the target sleep quality from at least one of, a user of the device, an expert and/or an external device. Optionally, the device receives the input signal via the user interface 134 and/or the communication circuitry 136, shown in fig. 1C.

According to some exemplary embodiments, the device optionally detects that the subject is asleep, at block 838. In some embodiments, the device detects that the subject is optionally asleep based on measurements of brain activity and/or measurements of at least one physiological parameter. In some embodiments, the device detects that the subject is asleep based on signals received from one or more of the detectors 132, shown in fig. 1C.

According to some exemplary embodiments, the device optionally detects at least one sleep stage, at block 840. In some embodiments, the sleep stage comprises at least one of, N1 sleep stage, N2 sleep stage, N3 sleep stage and/or REM sleep. In some embodiments, the device detects least one sleep stage based on measurements of brain activity and/or measurements of at least one physiological parameter. In some embodiments, the device detects at least one sleep stage based on signals received from one or more of the detectors 132, shown in fig. 1C.

According to some exemplary embodiments, stimulation, for example VNS, is initiated at block 842. In some embodiments, the stimulation is delivered with the parameters that were optionally set at block 834. In some embodiments, the stimulation is delivered via at least two electrodes, for example electrodes 130 shown in fig. 1C.

According to some exemplary embodiments, sleep quality, for example sleep depth and/or sleep length, is optionally determined at block 843. In some embodiments, the sleep quality is determined based on signals indicating brain activity that were recorded while the subject is asleep. In some embodiments, the signals are EEG signals. Alternatively or additionally, the sleep quality is determined based on measurements of at least one physiological parameter. In some embodiments, determining sleep quality comprises determining a length of at least one sleep stage based on the brain activity measurements and/or measurements of the physiological parameter. Optionally, the determined length of the at least one sleep stage indicates the sleep quality, for example a time length of the REM sleep stage or a time length of the deep sleep stage during the sleep period or the overall sleep period indicates sleep quality.

According to some exemplary embodiments, the sleep quality is determined by detecting changes in brain activity measurements and/or changes in the physiological parameter measurements indicating sleep quality, for example heart rate (HR), heart rate variability (HRV), EEG, electromyography (EMG), and electrooculogram (EOG).

According to some exemplary embodiments, the device determines if the target sleep duration was reached, at block 844. In some embodiments, the device determines if a target sleep duration was reached by determining a relation between the sleep duration of the subject measured by the device and the target sleep duration.

According to some exemplary embodiments, if the target sleep duration and/or the target sleep quality was not reached, then at least one parameter of the stimulation is modified at block 848, and the stimulation is re-initiated or resumed with the at least one modified parameter at block 842.

According to some exemplary embodiments, if the target sleep duration and/or the target sleep quality has reached, stimulation is stopped, at block 846. In some embodiments, the stimulation is stopped, in order to induce awakening of the subject and/or completion of at least one sleep stage.

Alternatively, if the sleep quality was reached, stimulation is continued, optionally with different parameter values, to maintain the sleep quality while the subject is asleep and/or during at least one sleep stage.

According to some exemplary embodiments, if a target stimulation quality, for example target stimulation depth and/or quality was not reached, at least one parameter of the stimulation or stimulation treatment is modified and is repeated in the following sleep period. Optionally, the parameters are modified until reaching a specific set of parameters of the stimulation that allow to reach the target sleep quality.

Exemplary stimulation according to movements during sleep

According to some exemplary embodiments, stimulation, for example VNS or auricular VNS, is delivered to a subject when the subject is asleep. In some embodiments, the stimulation is delivered to a subject having one or more symptoms of a sleeping disorder, and is optionally diagnosed with dementia, for example with AD.

Reference is now made to fig. 8D, depicting a process for delivery of stimulation to a subject who is asleep based on the subject movements, according to some exemplary embodiments of the invention. In some embodiments, the subject is a subject diagnosed with dementia, for example AD, having sleeping disorders.

According to some exemplary embodiments, a device for delivery of VNS is functionally coupled to a subject body, and at least one stimulation program is initiated at block 860. In some embodiments, initiating a stimulation program comprises shifting the device from a standby mode to an active mode, for example to a program where a control circuitry of the device receives signals and/or transmits signals according to a program installed in the memory of the device. In some embodiments, the device is device 120 shown in fig. 1C. According to some exemplary embodiments, the device measures at least one parameter, for example a physiological parameter or a movement-related parameter, at block 862. In some embodiments, the device measures the at least one parameter by at least one detector, for example a sensor, functionally coupled to the control circuitry of the device, for example control circuitry 122. In some embodiments, the detector, for example detector 132, comprises a wearable detector or an implanted detector. In some embodiments, the detector is integrated with the device, or is a detector of an external device, for example external device 138 that is in communication with the device 120.

According to some exemplary embodiments, measuring of the parameter at block 862 comprises measuring at least one of, heart rate, HRV, ECG, EMG, EEG, EOG, sweat level, respiration rate, oxygen saturation, body movement and/or limb movement. In some embodiments, the measurements of the at least one parameter are performed periodically during the activation of the device, optionally before the subject falls asleep, when the subject is asleep and after the subject is awake.

According to some exemplary embodiments, the device identifies that the subject is asleep at block 864. In some embodiments, the device identifies that the subject is asleep based on the measurements performed at block 862. Optionally, in some embodiments, the device identifies that the subject is about to fall asleep at block 864.

According to some exemplary embodiments, movement of the subject is detected, at block 866. In some embodiments, the movement is detected after the subject falls asleep. In some embodiments, the movement is detected based on the measurements performed at block 862. In some embodiments, detecting movement of the subject comprises measuring at least one parameter related to the subject movement, for example duration of the movement, movement range, length of intervals between movement episodes, and/or identity of moving limb, or moving organ.

According to some exemplary embodiments, the device optionally determines a sleeping stage, at block 868. In some embodiments, the device optionally determines a sleeping stage based on the movements detected at block 866, and/or based on the measurements of the at least one parameter at block 862. In some embodiments, the device optionally determines the sleeping stage using at least one algorithm, formula or a lookup table stored in a memory of the device that optionally correlates one or more sleep stages and movement and/or parameter measurements.

According to some exemplary embodiments, the device determines a stimulation dose to be provided to the subject at block 870. In some embodiments, a stimulation dose is the amount of stimulation to be provided to the subject during a predetermined time period. In some embodiments, determining a stimulation dose comprises, determining duration and/or intensity of stimulation to be provided to the subject during a predetermined time period. In some embodiments, the stimulation dose is determined according to at least one of, movement of the subject detected at block 866, measurements of the parameter at block 862, and/or a sleeping stage optionally determined at block 868.

According to some exemplary embodiments, the stimulation dose is set to be higher than a reference, a baseline or a default stimulation dose, during sleeping periods with lower movement of the subject, for example during deep sleep and/or REM sleep periods. Alternatively, the stimulation dose is set to be higher than a reference, a baseline or a default stimulation dose, during high movement and elevated heart rate.

According to some exemplary embodiments, the stimulation dose is set to be higher than a reference, a baseline or a default stimulation dose, during sleeping periods, in which movement of the body is above a predetermine first threshold value. Alternatively, the stimulation dose is set to be higher than a reference, a baseline or a default stimulation dose, during sleeping periods, in which movement of the body is lower than a predetermine second threshold value.

A potential advantage of increasing a dose of stimulation may be to provide more relaxation and reduce chances to wake up during the sleep time.

According to some exemplary embodiments, stimulation parameters are adjusted at block 872. In some embodiments, the stimulation parameters are adjusted according to the determined dosage, for example according to parameters of the stimulation dosage that were determined at block 870.

According to some exemplary embodiments, stimulation is delivered at block 874. In some embodiments, stimulation is delivered according to the determined dosage and optionally in synchronization with the subject movements. In some embodiments, synchronization with the subject movements means at the same time the subject moves and/or during sleeping periods when movement is higher or lower than a reference value. Alternatively, stimulation is delivered after detecting movement for a predetermined time period. For example, in some embodiments, stimulation is delivered after detecting an increase in body movement during a time window of between 5 seconds and 30 seconds, for example during a time window of between 5 seconds and 15 seconds, of between 10 seconds and 20 seconds, of between 15 seconds and 30 seconds, or any intermediate, shorter or longer time window. In some embodiments, stimulation is delivered after detecting a reduction in body movement during a time window of between 5 seconds and 30 seconds, for example during a time window of between 30 seconds and 90 seconds, for example during a time window of between 30 seconds and 60 seconds, of between 40 seconds and 70 seconds, of between 50 seconds and 70 seconds, of between 60 seconds and 90 seconds, or any intermediate, shorter or longer time window.

According to some exemplary embodiments, the device determines a dose to be provided to the subject according to the detected movement, for example using at least one algorithm, formula or a lookup table stored in a memory of the device, for example memory 124 of the device 120 shown in fig. 1C, or any memory of an external device in communication with the device 120. In some embodiments, VNS parameters are adjusted according to the determined dose at block 872 and VNS is delivered to the subject according to the adjusted parameters.

According to some exemplary embodiments, the device determines to provide an increased dose of the VNS, and delivers the increased dose during and/or following a time period in which the subject is asleep and movement is detected, for example when the detected movement is higher than at least one first reference value, or when the detected movement is lower than at least one second value. In some embodiments, both the at least one first reference value and the at least one second reference value are stored in a memory of the device, or in a memory associated with the device.

According to some exemplary embodiments, determining a dose at block 870 comprises determining to modify duration in which active VNS stimulation is delivered to the subject body and/or determining t modify frequency of the VNS. In some embodiments, determining a dose comprises modifying duration of active delivery of the VNS and/or modifying VNS frequency.

Exemplary adjustment of stimulation parameters

According to some exemplary embodiments, parameters of stimulation, for example VNS, are adjusted according to the effect of stimulation, for example therapeutic effect and/or side effect of the stimulation. In some embodiments, adjustment of stimulation parameters comprises adjustment of stimulation parameter values, for example adjustment of stimulation timing, intensity, and frequency and/or stimulation target. In some embodiments, the stimulation parameters are adjusted in order to generate a maximal net therapeutic effect having a maximal therapeutic effect with minimal side effects, during at least one specific sleeping stage. Alternatively or additionally, a sleeping stage in which stimulation delivery achieves the highest net therapeutic effect is selected.

According to some exemplary embodiments, parameters of stimulation, for example VNS, are adjusted according to the effect of stimulation, measured when the subject is asleep, optionally in a sleep lab. In some embodiments, the effect of stimulation is tested at different sleep stages and in response to different movement levels. In some embodiments, the effect of stimulation is tested by measuring a physiological response of the subject to stimulation. For example, VNS is delivered with different parameter values during one or more periods of high movement levels. In some embodiments, the measured physiological effect is a beneficial or a therapeutic effect when the delivered VNS induces a relaxation response, in which body movements are reduced.

Alternatively, VNS is delivered after periods with low movement periods. In some embodiments, measurements are performed to check if the delivered VNS induces a target relaxation period, having a target duration and/or target movement level. In some embodiments, the VNS is delivered with different parameter values in order to determine which set of parameter values induces a target relaxation period, in a specific subject.

Reference is now made to fig. 8E, depicting a process for calibrating a stimulation treatment delivered when the subject is asleep in order to reach a target net therapeutic effect, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject, for example a human subject, is received in a medical facility, at block 876. In some embodiments, the medical facility comprises a clinic or a lab for monitoring sleeping disorders, for example a sleep lab. In some embodiments, the subject is a subject diagnosed or having a sleeping disorder or at least one symptom thereof, for example having physical and/or mental tiredness. Additionally or optionally, the subject is diagnosed with or suffering from at least one symptom of dementia, for example AD.

According to some exemplary embodiments, a stimulation device or a portion thereof, is coupled to the subject, at block 878. In some embodiments, at least two electrodes, for example electrodes 130 of device 120 shown in fig. 1C, are coupled to the subject.

According to some exemplary embodiments, values of at least one body parameter are measured at block 880. In some embodiments, the body parameter comprises a physiological parameter and/or a movement-related parameter. In some embodiments, the measurements comprise at least one of, heart rate, HRV, ECG, EMG, EEG, EOG, sweat level, respiration rate, oxygen saturation, body movement and/or limb movement.

According to some exemplary embodiments, a system or a device monitoring a state of the subject identify that the subject is asleep, at block 882. In some embodiments, the device is a stimulation device. In some embodiments, a healthcare professional, for example a nurse or a physician identify that the subject is asleep ay block 882. In some embodiments, the identification that the subject is asleep is based on the measurements of the at least one body parameter performed at block 880. For example, measurements of EEG signals, respiration rate, EMG and/or body movement may be indicative of a sleeping state of the subject. According to some exemplary embodiments, stimulation, for example VNS, is initiated at block 884. In some embodiments, initiating stimulation comprises initiating a stimulation program. In some embodiments, stimulation is initiated after the subject is asleep. Optionally, stimulation is initiated when the subject is about to fall asleep or when the subject is awake and plans to go to sleep.

According to some exemplary embodiments, at least one body parameter is measured at block 886. In some embodiments, the body parameter is as described above at block 880.

According to some exemplary embodiments, a sleep stage is detected at block 888. In some embodiments, the sleep stage is detected based on the measurements of the body parameter at block 886.

According to some exemplary embodiments, an effect of the stimulation delivered to the subject is determined at block 890. In some embodiments, determining stimulation effect comprises determining at least one therapeutic effect of the stimulation and/or determining at least one side effect of the stimulation, at block 890. In some embodiments, determining an effect of the stimulation comprises determining a therapeutic effect of the stimulation in one or more, or all stages of sleep.

According to some exemplary embodiments, determining a stimulation effect at block 890 comprises determining in which sleep stage the delivered stimulation had a target or a desired effect on the subject, for example determining in which sleep stage the delivered stimulation induced the largest therapeutic effect and optionally with the minimal side effects. In some embodiments, determining a stimulation effect at block 890 comprises determining in which sleep stage the delivered stimulation induced a therapeutic effect that is larger than a reference effect or a reference value, and optionally with side effects that are lower than a reference effect or a reference value.

According to some exemplary embodiments, the stimulation treatment is adjusted, at block 892. In some embodiments, adjusting stimulation treatment comprises adjusting one or more stimulation parameters, for example to increase a therapeutic effect and/or to lower one or more side effects, as determined at block 890. In some embodiments, adjusting stimulation treatment comprises selecting a sleeping stage in which the determined stimulation shown to be a target, or a desired stimulation effect.

Exemplary improvement of falling asleep

According to some exemplary embodiments, subjects having sleeping disorders having difficulties to fall asleep. In some embodiments, subjects under medication, subjects diagnosed with dementia, and/or subjects diagnosed with a mental disorder or having at least one symptom of a mental disorder, have difficulties to fall asleep. In some embodiments, delivery of stimulation, for example VNS, promotes generation of a brain waves pattern measured during sleep or when a subject falls asleep.

Reference is now made to fig. 8F, depicting a process for promoting transition of a subject into sleep, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a device, for example a stimulation device or a device communicating with the stimulation device, optionally identifies that a subject plans to fall asleep, at block 861. In some embodiments, the device identifies that the subject plans to fall asleep, for example by detecting a change in measurements of at least one parameter of the subject body indicating that the subject plans to fall asleep. For example, the device detects a change in the subject posture, a change in the subject heart rate, a change in breathing rate, and/or a change in brain activity, indicating that the subject plans to fall asleep.

According to some exemplary embodiments, the device measures brain wave signals, at block 863. In some embodiments, the brain waves signals comprise EEG signals measured by at least one electrode coupled to the subject head, for example at least one electrode coupled to scalp or implanted at least partly in the skull.

According to some exemplary embodiments, the device detects that alpha waves in the measured brain wave signals are above a predetermined threshold, for example a reference value, at block 865.

According to some exemplary embodiments, the device delivers stimulation with parameter values suitable to increase theta waves in the measured brain wave signals, at block 867. In some embodiments, stimulation is delivered with one or more parameter values and/or according to a protocol as described in Broncel A. et.al, 2019 “hippocampal theta rhythm induced by vagal nerve stimulation: The effect of modulation of electrical coupling”, and in Broncel A. et.al, 2019 “medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation”.

According to some exemplary embodiments, the device determines is the subject is asleep at block 869. In some embodiments, the device determines is the subject is asleep, for example as described t block 882 in fig. 8E.

According to some exemplary embodiments, if the subject is not asleep, stimulation continues at block 871. In some embodiments, if the subject is asleep, stimulation stops at block 873. Exemplary process for prolonging sleep

Reference is now made to fig. 8G, depicting a process for prolonging sleep, for example deep sleep, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a device identifies that a subject is in deep sleep, at block 875. In some embodiments, the device is a stimulation device, or an external device in communication with the stimulation device. In some embodiments, the subject is diagnosed with dementia or has one or more dementia-related symptoms. Alternatively or additionally, the subject is diagnosed with a sleeping disorder or has at least one symptom of a sleeping disorder.

According to some exemplary embodiments, the device identifies that the subject is in deep sleep by measuring signals from the subject brain, for example brain wave signals. In some embodiments, the measured signals comprises EEG signals. Optionally, the device identifies that the subject is in deep sleep, for example as describes at blocks 886 and 888 in fig. 8E, and/or based on measurements of at least one parameter as described at block 862 in fig. 8D.

According to some exemplary embodiments, activity of each brain hemisphere is measured at block 877. In some embodiments, the activity is measured separately for each brain hemisphere. In some embodiments, the activity is measured by measuring EEG signals. In some embodiments, the EEG signals are measured by at least two electrodes, each of the electrodes is positioned above a different brain hemisphere.

According to some exemplary embodiments, the device detects imbalanced activity, at block 879. In some embodiments, detecting imbalanced activity comprises detecting that activity of a first brain hemisphere is larger than activity of a second brain hemisphere. In some embodiments, the imbalanced activity is detected based on the measurements performed at block 877.

According to some exemplary embodiments, detecting imbalanced activity comprises detecting a difference in activity of at least 2%, of at least 5%, of at least 10%, of at least 20%, of at least 30%, of at least 50%, or any intermediate, smaller or larger percentage value, between the two hemispheres.

According to some exemplary embodiments, stimulation, for example VNS, is delivered to at least one hemisphere of the two hemispheres with parameter values suitable to increase activity balance between the two hemispheres, at block 881. For example, in some embodiments VNS is delivered, optionally to a less active brain hemisphere of the two hemispheres, with parameter values suitable to increase activity of the less active brain hemisphere. Alternatively or additionally, VNS is delivered, optionally to a more active brain hemisphere, with parameter values suitable to attenuate activity of the more active brain hemisphere.

According to some exemplary embodiments, stimulation is delivered via at least one electrode positioned adjacent and/or above the less active brain hemisphere. Alternatively, stimulation is delivered to a neural network innervating one or more brain regions of the less active hemisphere.

According to some exemplary embodiments, the device determines if activity of the two hemispheres is balanced, at block 883. In some embodiments, the device determines if the activity of the two hemispheres is balanced based on activity measurements performed for example as described at block 877. In some embodiments, determining that activity is balanced comprises determining that a difference in activity between the two hemispheres is smaller than 10%, smaller than 20%, smaller than 30%, smaller than 40%, smaller than 50%, or any intermediate, smaller or larger percentage value.

According to some exemplary embodiments, if activity is not balanced, stimulation initiated at block 881 continues. Alternatively, if activity is balanced, stimulation delivered at block 881 is stopped.

Exemplary multipurpose stimulation

According to some exemplary embodiments, stimulation, for example VNS, is used to treat more than one clinical condition in the same subject, for example human subject. In some embodiments, stimulation is delivered with a first set of parameter values and/or according to a first protocol to treat a first clinical condition, and with a second set of parameter values and/or according to a second protocol to treat a second clinical condition. In some embodiments, a difference between the stimulation protocols can be in a timing of the stimulation, stimulation schedule, stimulation intensity, stimulation location, stimulation frequency, stimulation duration, and/or length of interval between two active stimulation episodes in which an electric field is actively delivered to a subject body by a stimulation device, for example device 120 shown in fig. 1C.

According to some exemplary embodiments, a memory of the stimulation device, for example memory 124 or a memory of an external device, for example external device 138, in communication with the stimulation device, includes two or more stimulation protocols, each for treating a different clinical state. Alternatively, the memory includes a single stimulation protocol for treating at least two clinical states, by optionally providing stimulation with different parameter values, to different body locations, at different timing and/or with respect to different measurements of body parameters, for example as described herein in the application.

Reference is now made to fig. 8H, depicting a process for delivery of at least two different stimulation treatments to the same subject, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject is diagnosed with dementia or has at least one symptom of dementia, and with at least one sleeping disorder, at block 891. In some embodiments, the dementia comprises, AD, vascular dementia, dementia with lewy bodies, frontotemporal dementia, dementia due to Parkinson’s disease, dementia due to Huntington’s disease, and mixed dementia. In some embodiments, the dementia is characterized as in the Diagnostic and Statistical Manual of Mental Disorders (DSM), for example a 5^th edition of the DSM.

According to some exemplary embodiments, a stimulation device is provided to the subject, at block 893. In some embodiments, the stimulation device is provided to the subject following the diagnosis at block 891. In some embodiments, the stimulation device is the stimulation described herein in the application, for example stimulation device 120 shown in fig. 1C.

According to some exemplary embodiments, a first VNS treatment to treat dementia and/or dementia symptoms, is delivered to the subject at block 895. In some embodiments, the first VNS treatment comprises the treatment described in figs. 2A and 2B. In some embodiments, the first VNS treatment is delivered according to at least one protocol stored in a memory of the device, for example memory 124, or in a memory of an external device, for example external device 138. In some embodiments, the first VNS treatment is delivered by the device 120.

According to some exemplary embodiments, a second VNS treatment to treat the at least one sleeping disorder is provided at block 897. In some embodiments, the second VNS treatment is provided according to the at least one protocol, or according to at least one different protocol stored in the same memory. In some embodiments, the control circuitry selects a stimulation protocol according to the subject state, for example if the subject is awake or plans to go to sleep. For example, VNS stimulation for treating dementia or at least one symptom thereof is delivered to the subject when the subject is awake and/or when the subject is asleep. In some embodiments, VNS stimulation for treating at least one sleeping disorder is delivered to the subject when the subject is asleep, is about to fall asleep, or plans to fall asleep.

According to some exemplary embodiments, the second VNS treatment is delivered to the subject, for example, as described in figs. 8B-8G. According to some exemplary embodiments, the second VNS treatment is delivered before, during and/or after the delivery of the first VNS treatment. Optionally, the first and second VNS treatment are delivered to the subject in synchronization. In some embodiments, the memory stores at least one treatment protocol for synchronizing the first treatment and the second treatment.

Exemplary simulation in response to EEG measurements

According to some exemplary embodiments, brain activity is measured and monitored prior to stimulation, for example to detect a state of a subject, for example a clinical state and/or a physiological state. In some embodiments, brain activity is monitored by measuring EEG signals from the subject brain. In some embodiments, the EEG signals are measured by at least one electrode coupled to the subject head. In some embodiments, stimulation, for example VNS is delivered to the subject based on the measured EEG signals, for example when the EEG signals indicate an upcoming subject state or the initiation of a subject state. In some embodiments, VNS is delivered when the subject state is detected or when the subject state is expected.

Reference is now made to fig. 9, depicting delivery of VNS in response to EEG measurements, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, at least one EEG signal is measured at block 902. In some embodiments, the at least one EEG signal is measured while the subject is asleep. Alternatively, the EEG signal is measured when the subject is awake, and is optionally engaged in everyday activities. In some embodiments, the EEG signal is measured by at least one electrode or a plurality of electrodes, for example electrodes that are coupled to the subject head. In some embodiments, the EEG signal is measured continuously or intermittently.

According to some exemplary embodiments, an irregular EEG signal is detected at block 904. In some embodiments, detecting an irregular EEG signal comprises detecting an EEG signal that is different from a reference EEG signal. In some embodiments, detecting an irregular EEG signal comprises detecting changes during the measurements of the EEG signal, at block 902. In some embodiments, a control circuitry of a device, for example a stimulation device, or a device that controls a stimulation unit, receives or measured the EEG signals and detects changes in the EEG signals.

According to some exemplary embodiments, a subject state is determined based on the detected changes in the EEG signals, at block 906. In some embodiments, the subject state is determined by the control circuitry, optionally automatically. In some embodiments, determining the subject state comprises determining initiation of the subject state or predicting a subject state in the future. In some embodiments, for example, the subject state comprises at least one of, a stroke event, an epileptic event, obstruction in blood flow to the brain.

According to some exemplary embodiments, VNS is delivered to the subject at block 908. In some embodiments, the VNS is delivered after determining the subject state at block 906. In some embodiments, VNS delivery is planned in response to the determining of a state that is a predicted state. Alternatively, when determining the predicted state, VNS is delivered, for example to prevent an appearance of the predicted state in the future. In some embodiments, VNS is delivered with parameters that are suitable for treating or preventing the specific determined state. Alternatively, VNS is delivered using a protocol selected for the treating or preventing the specific determined state.

According to some exemplary embodiments, at least one EEG signal is measured during the delivery of the VNS and/or following the delivery of the VNS, at block 909. In some embodiments, the at least one EEG signal is measured as described at block 902.

According to some exemplary embodiments, the device determines if the EEG signal measured at block 909 during and/or following the VNS is a target signal, at block 910. In some embodiments, determining if a measured EEG signal is a target signal comprises determining if the measured EEG signal is a signal indicating a change in the subject state or in a prediction of the subject state, in a desired direction. For example, determining if the measured EEG signal is a signal indicating a change in the subject state comprises determining that an initiated subject state has stopped. Alternatively or additionally, determining a change in a prediction of a subject state comprises determining a delay in the future occurrence of the subject state or determining that there is no occurrence of the predicted subject state in the future.

According to some exemplary embodiments, if the measured EEG signal is a signal indicating a change in the subject state in a desired direction, for example in a direction that delays or prevents a future subject state or in a direction that stops a current subject state, the VNS is optionally stopped, at block 912.

Alternatively, if the measured EEG signal is not a target signal, then at least one stimulation parameter is optionally changed at block 914. In some embodiments, the at least one stimulation parameter comprises duration, intensity and/or frequency of stimulation. Alternatively or additionally, a stimulation parameter comprises a selection of electrodes, for example an electrode pair, for delivery of the stimulation. In some embodiments, changing a stimulation parameter comprises selecting a different stimulation protocol with the changed stimulation parameter. According to some exemplary embodiments, VNS is delivered with the changed parameter or with the different stimulation protocol, at block 908.

In some embodiments to the stimulation is a dual sides stimulation. In some embodiments, in a dual sides stimulation, the stimulation is delivered to both sides of the brain, optionally via electrodes at both left and right ears, positioned for example at a concha of the ears. In some embodiments, in case there is a difference in detected EEG activity between different brain hemispheres, stimulation is delivered to the more active side, for example to attenuate activity. Alternatively, stimulation is delivered to the less active side of the brain, for example to increase its activity.

In some embodiments, activity of the brain hemispheres is detected during deep sleep of the subject. In some embodiments, stimulation is delivered to the more active side, for example to attenuate activity. Alternatively, stimulation is delivered to the less active side of the brain, for example to increase its activity.

Exemplary epileptic event treatment

According to some exemplary embodiments, stimulation is delivered to a subject when identifying an expected epileptic event and/or when detecting an epileptic event. In some embodiments, stimulation is delivered when the subject is asleep and/or when the subject is awake. Optionally, stimulation is delivered to a subject that is in a risk for developing an epileptic event, for example to a subject diagnosed with epilepsy, to a subject that had a previous epileptic event, and/or to a subject undergoing treatment which increase a risk for experiencing an epileptic event

According to some exemplary embodiments, stimulation is delivered when detecting a seizure onset or changes in an EEG signal indicating the seizure onset.

Reference is now made to fig. 10 depicting a process for delivering stimulation to a subject having or expecting an epileptic event, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject in a risk for having an epileptic event is optionally selected at block 1002. In some embodiments, the selected subject is diagnosed with epilepsy. In some embodiments, the selected subject experienced one or more of epilepsy symptoms, for example, temporary confusion, a staring spell, stiff muscles, uncontrollable movements of arms and/or legs, loss of consciousness or awareness and/or physiological symptoms such as fear, anxiety or deja vu. According to some exemplary embodiments, a signal indicating brain activity is measured at block 1004. In some embodiments, a stimulation device or a control unit of a stimulation device, measures at least one signal indicating brain activity, at block 1004. In some embodiments, the at least one signal is an EEG signal, measured for example by at least one electrode, for example at least two electrodes attached to the head of the subject. In some embodiments, the measured signal indicates an activity of at least one brain region, for example an anatomical or a functional brain region. In some embodiments, brain activity of a left brain hemisphere and/or brain activity of a right brain hemisphere is measured at block 1004.

According to some exemplary embodiments, the signal is continuously measured, for example every time period that is smaller than 1 second, for example every time period that is smaller than 0.5 seconds, smaller than 0.1 seconds, smaller than 0.05 seconds, or ant intermediate, smaller or larger value. Alternatively, the signal is measured intermittently, for example every time period that is larger than 1 second, for example every time period larger than 1.5 seconds, larger than 3 seconds, or any intermediate, smaller or larger value.

According to some exemplary embodiments, changes in the measured brain activity signal are detected at block 1006. In some embodiments, the changes are detected by determining a relation between a signal measured at block 104 and at least one reference, for example a reference signal, a reference signal pattern and/or a reference value or indications thereof. In some embodiments, the reference is stored in a memory of the stimulation device or in a memory of a control unit of the stimulation device. In some embodiments, the reference value is stored in a memory of an external device, for example a remote computer, a mobile device, a remote server or a remote database, in communication with the stimulation or the control device.

According to some exemplary embodiments, an epileptic event is identified at block 1008. In some embodiments, identifying the epileptic event comprises identifying an onset of a seizure. In some embodiments, identifying an epileptic event comprises identifying initiation of an epileptic event or predicting occurrence if an epileptic event in the future. In some embodiments, the epileptic event is identified based on the changes detected at block 1006. In some embodiments, the epileptic event is identified by determining a relation between the changes detected at block 1006 and/or the signal measured at block 1004, and at least one reference, for example a reference indicating the epileptic event. In some embodiments, the reference is stored in a memory of the stimulation device or in a memory of a control unit of the stimulation device. In some embodiments, the reference value is stored in a memory of an external device, for example a remote computer, a mobile device, a remote server or a remote database, in communication with the stimulation or the control device. According to some exemplary embodiments, stimulation, for example VNS, is delivered at block 1010. In some embodiments, the stimulation is delivered optionally by the stimulation device, in response to the identified epileptic event. In some embodiments, if identifying the epileptic event comprises identifying initiation of an epileptic event, then the stimulation is delivered with parameter values selected to stop or attenuate the epileptic event or at least one symptom thereof. Alternatively, if identifying the epileptic event comprises predicting an epileptic event in the future, then the stimulation is delivered at block 1010 with parameter values selected to prevent or delay the predicted epileptic event.

According to some exemplary embodiments, at least one brain activity signal is measured at block 1011. In some embodiments, the brain activity signal, for example EEG signal, is measured during and/or following the delivery of stimulation at block 1010.

According to some exemplary embodiments, the stimulation device determines if the measured brain activity signal is a target signal or indicates a target brain activity, at block 1012. In some embodiments, a target signal is a signal indicating a stop or attenuation of an epileptic event, and/or a signal indicating prevention or delay in an expected epileptic event. In some embodiments, the stimulation device determines if the measured brain activity signal is a target signal by determining a relation between the brain activity signal measured at block 1011 and at least one reference indication of the target signal or of the target brain activity.

According to some exemplary embodiments, if the brain activity signal is not a target signal or does not indicate a target brain activity, the at least one parameter of the stimulation is changed at block 1014. In some embodiments, stimulation is delivered at block 1010 with the at least one changed stimulation parameter.

According to some exemplary embodiments, if the brain activity signal is a target signal or indicates a target brain activity, then stimulation is stopped at block 1016.

Exemplary Obstructive Sleep Apnea (OSA) treatment

According to some exemplary embodiments, a stimulation device or a stimulation system is used for preventing and/or treating OSA. In some embodiments, stimulation, for example VNS, is delivered prior to an expected OSA episode or after an initiation of OSA.

According to some exemplary embodiments, the stimulation device, or at least a stimulation unit of the device is coupled to the subject while the subject is asleep. In some embodiments, the stimulation unit delivers stimulation when identifying an expected OSA event or when identifying initiation of an OSA episode. According to some exemplary embodiments, stimulation is delivered to a subject that is in a risk for developing an OSA episode, for example to a subject diagnosed with OSA, and/or to a subject that had a previous OSA episode.

Reference is now made to figure 11, depicting a process for delivering stimulation to a subject having or expecting an OSA episode, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject diagnosed with OSA is selected at block 1102. Alternatively, the selected subject is a subject in a risk for having an OSS episode.

According to some exemplary embodiments, stimulation, for example, VNS stimulation, is optionally delivered to the subject at block 1104, before the subject goes to sleep or is asleep. In some embodiments, the stimulation is delivered at block 1104 with parameter values selected to prepare the subject body to sleep, and optionally to delay or prevent an OSA episode during sleep.

According to some exemplary embodiments, the subject is detected to be asleep at block 1106. In some embodiments, the device detects that the subject is asleep based on measurements of brain activity, or measurements of at least one physiological parameter.

According to some exemplary embodiments, at least one physiological parameter is measured at block 1108. In some embodiments, the at least one physiological parameter comprises at least one of, heart rate, heart rate variability, breathing, oxygen saturation, body movement, and/or movements of the chest. In some embodiments, measurements of the at least one physiological parameter are initiated before and/or after the subject is asleep. In some embodiments, the measurements are performed continuously or intermittently.

According to some exemplary embodiments, changes in the physiological parameter are detected at block 1110. In some embodiments, the changes are detected relative to a reference value, or relative previous measurements.

According to some exemplary embodiments, an OSA episode is identified at block 1112. In some embodiments, identifying an OSA episode comprises identifying an initiation of an OSA episode. Alternatively, identifying an OSA episode comprises predicting an occurrence of an OSA episode in the future.

According to some exemplary embodiments, stimulation, for example VNS is delivered at block 1114. In some embodiments, the stimulation is delivered in response to the identifying results. In some embodiments, if an OSA episode is identified, then the stimulation is delivered at block 1114 with parameter values selected to stop the OSA episode, or to attenuate at least one symptom of the OSA episode. In some embodiments, if an OSA episode is predicted, then the stimulation is delivered with parameter values selected to prevent or delay the predicted OSA episode.

According to some exemplary embodiments, a physiological parameter is measured during and/or following the stimulation delivery, at block 1116.

According to some exemplary embodiments, the stimulation device determined if values of the measured physiological parameter are target values, at block 1118. In some embodiments, the device determines a relation between the values of the physiological parameter measured during and/or following stimulation, and at least one reference, for example reference values or indication thereof. In some embodiments, the target values indicate that the OSA episode was stopped. Alternatively, the target values indicate that an expected OSA episode was prevented or delayed.

According to some exemplary embodiments, if the measurements are not target measurements indicating that the OSA episode is stopped, or that an expected OSA episode is prevented or delayed, then at least one stimulation parameter is optionally changed at block 1120. In some embodiments, stimulation is delivered at block 1114 using the at least one changed stimulation parameter. Alternatively, if the measurements are not target measurements indicating that the OSA episode is stopped, or that an expected OSA episode is prevented or delayed, stimulation is continued with previously used parameter values.

Alternatively, if the measurements are target measurements indicating that the OSA episode is stopped, or that an expected OSA episode is prevented or delayed, stimulation is optionally stopped, at block 1122.

Exemplary elevated blood pressure treatment

According to some exemplary embodiments, stimulation, for example VNS is used to treat subject suffering from high blood pressure (BP). In some embodiments, stimulation is delivered continuously or intermittently, for example to maintain blood pressure within a target range of values indicating normal BP for a specific subject. Alternatively or additionally, stimulation is delivered to a subject when detecting an increase in BP values, for example when BP level are not within the target range of values.

Reference is now made to fig. 12 depicting a process for delivering stimulation to a subject having high blood pressure, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject diagnosed with elevated BP is selected at block 1202. According to some exemplary embodiments, BP level is detected in the subject at block 1204. In some embodiments, the BP level is detected based n signals received from at least one sensor, for example a blood pressure sensor. In some embodiments, BP level is detected based on measurements of at least one physiological parameter indicating blood level.

According to some exemplary embodiments, high BP level is identified at block 1206. In some embodiments, the high BP level is identified based in the measurements performed at block 1204.

According to some exemplary embodiments, stimulation, for example VNS, is delivered to the subject in response to the detection of high BP, at block 1208.

According to some exemplary embodiments, BP level is detected during and/or following the stimulation delivery, at block 110. In some embodiments, BP level is detected as explained above at block 1204.

According to some exemplary embodiments, the device, for example stimulation device determines if the BP level detected at block 1210 is within a target range of values at block 1212.

According to some exemplary embodiments, if the BP level detected at block 1210 is not within the target range of values, for example a target values range indicating a normal range of values for the subject, then values of at least one stimulation parameter are optionally changed at block 1214. Alternatively, stimulation continuous with the previously used parameter values. In some embodiments, following the changing of the at least one stimulation parameter values, stimulation is delivered to the subject with the changed parameter values, at block 1208.

According to some exemplary embodiments, if the BP level detected at block 1210 is within the target range of values, for example a target values range indicating a normal range of values for the subject, then stimulation is optionally stopped at block 1216, or modified, for example reduced. In some embodiments, the stimulation is modified, for example by reducing at least one of, intensity, frequency and/or duration, for example to maintain a desired effect optionally with less side effects and/or with less energy consumption.

Exemplary brain ischemic event treatment

According to some exemplary embodiments, stimulation, for example VNS is delivered to a subject when detecting an ischemic event or changes, for example changes in brain activity or brain blood flow indicating an ischemic event or high risk for developing an ischemic event. In some embodiments, an ischemic event comprises stroke. In some embodiments, stimulation is delivered as a preventive treatment to prevent an ischemic event in the future. Alternatively or additionally, stimulation is delivered when detecting an ischemic event. In some embodiments, the stimulation is delivered to the subject when the subject is asleep. Alternatively or additionally, the stimulation is delivered to the subject when the subject is awake.

Reference is now made to fig. 13, depicting a process for delivering stimulation to a subject having an ischemic event, according to some exemplary embodiments of the invention.

According to some exemplary embodiments, a subject in a risk for having a brain ischemic event, for example stroke, is selected at block 1302. In some embodiments, the subject is diagnosed with recurrent ischemic stroke. In some embodiments, the subject already experienced an ischemic stroke in the past. In some embodiments, the subject is in high risk for having an ischemic stroke, for example, due to a treatment, for example a pharmaceutical treatment administered to the subject. Alternatively or additionally, the subject is diagnosed with at least one condition that increases a risk for having a brain ischemic event, for example at least one of, high blood pressure, diabetes, heart and/or blood vessel diseases, conditions that can cause blood clots or other blockages include coronary heart disease, atrial fibrillation, heart valve disease, carotid artery disease, High LDL cholesterol levels, and/or smoking.

According to some exemplary embodiments, a device, for example a stimulation device optionally detects that a subject is asleep, at block 1304. In some embodiments, the device detects that the subject is asleep based on measurements of brain activity and/or based on measurements of at least one physiological parameter.

According to some exemplary embodiments, brain activity and/or blood flow to the brain is detected at bock 1306. In some embodiments, brain activity is detected using EEG measurements, In some embodiments, blood flow to the brain is detected based on signals from at least one sensor detecting blood flow and/or blood oxygenation levels in one or more carotid arteries.

According to some exemplary embodiments, changes in brain activity and/or blood flow are identified at block 1308. In some embodiments, the changes indicate initiation of a brain ischemic event or predicts a brain ischemic event. In some embodiments, the changes are identified in signals recorded during block 1306.

According to some exemplary embodiments, stimulation, for example VNS, is delivered to the subject in response to the identification of the changes, at block 1310. In some embodiments, the stimulation is delivered with stimulation parameter values selected to stop the ischemic event, and/or to shorten the ischemic event. Alternatively, the stimulation is delivered with parameter values selected to prevent a predicted brain ischemic event or to delay a predicted ischemic event. According to some exemplary embodiments, brain activity and/or brain blood flow are detected at block 1312, during the stimulation delivery at block 1310. Alternatively or additionally, brain activity and/or brain blood flow are detected at block 1312, following the stimulation delivery at block 1310.

According to some exemplary embodiments, the device determines if the brain activity and/or brain blood flow is within a target range of values, at block 1314, for example based on the detection performed at block 1312. In some embodiments, the device determines if the brain activity and/or brain blood flow is within a target range of values based on measurements performed at block 1312. In some embodiments, the target range of values is a range of values indicating a normal state of the specific subject.

According to some exemplary embodiments, if the brain activity and/or brain blood flow are not within a target range of values, values of at least one stimulation parameter are changed at block 1316. In some embodiments, following changing of the stimulation parameter values, stimulation is delivered to the subject using the changed parameter values at block 1310. Alternatively, stimulation is continued.

According to some exemplary embodiments, if the brain activity and/or brain blood flow are within a target range of values, then stimulation delivery is stopped, at block 1318.

Exemplary cardiac disorder treatment

According to some exemplary embodiments, the stimulation treatment is delivered to a subject in a risk for developing at least one cardiac disorder, or when detecting an onset of the at least one cardiac disorder. In some embodiments, the at least one cardiac disorder comprises ischemia and/or arrhythmia. In some embodiments, the stimulation treatment is configured to prevent an onset of an event of the cardiac disorder, for example by delivering VNS stimulation prior to a detection of an event onset. Alternatively or additionally, the stimulation, optionally with different parameters compared to the parameters of the preventive stimulation treatment, is configured to be delivered when detecting an onset of a cardiac disorder event.

Reference is now made to fig. 14, depicting a process for treating a subject diagnosed with a cardiac disorder, according to some exemplary embodiments.

According to some exemplary embodiments, a subject is diagnosed with a cardiac disorder, at block 1402. In some embodiments, the cardiac disorder comprises cardiac ischemia and/or cardiac arrhythmia. In some embodiments, the diagnosed subject is selected for the stimulation treatment, for example by an expert. According to some exemplary embodiments, at least one physiological parameter is measured at block 1404. In some embodiments, the at least one physiological parameter comprises at least one of, HR, HRV, and/or BP. Alternatively or additionally, the at least one physiological parameter comprises electrical activity of the heart, as measured by electrocardiogram (ECG). Alternatively or additionally, the at least one physiological parameter comprises blood content, for example level of Troponin protein in the blood.

According to some exemplary embodiments, an onset of a cardiac disorder event is detected at block 1406. In some embodiments, the event onset is detected based on changes in the measured physiological parameter. In some embodiments, the onset of the cardiac disorder event is detected based on signals received from one or more detectors of the device and/or based on signals received from one or more detectors in communication with the device, for example a blood pressure detector.

According to some exemplary embodiments, the event onset, for example an onset of an arrhythmia event is detected based on abnormal HR, for example elevated HR, and/or based on changes in a ST segment of ECG, for example ST elevation or ST depression. Optionally the changes indicate an onset of an atrial arrhythmia event or a ventricle tachycardia event. In some embodiments, an onset of a cardiac ischemic event is detected based on troponin level in the blood and/or based on changes in a ST segment of ECG, for example ST elevation or ST depression.

According to some exemplary embodiments, stimulation, for example VNS, is delivered at block 1408. In some embodiments, stimulation delivery is initiated when detecting an onset of the cardiac disorder event.

According to some exemplary embodiments, the physiological parameter is measured at block 1410. In some embodiments, the physiological parameter is measured during and/or following delivery of stimulation at block 1408.

According to some exemplary embodiments, if the measurements of the physiological parameter indicate that the cardiac disorder event has stopped or passed, then stimulation delivery is optionally stopped at block 1416.

According to some exemplary embodiments, if the physiological measurements indicate that the cardiac disorder event continuous, then optionally, values of at least one parameter of the stimulation are changed at block 1414, and stimulation is delivered at block 1408 using the changed parameter values. Alternatively, stimulation delivery continues at block 1408 with the previously used parameter values. Exemplary VNS for increasing ubiquitin enzymes activity

According to some exemplary embodiments, VNS treatment, for example auricular VNS, is delivered for enhancing the expression of Ubiquitin- specific protease (USP). In some embodiments, the VNS treatment is delivered using the methods described herein, for example the methods in figures 1A, IB. In some embodiments, the VNS treatment is delivered using the device or system described herein, for example the device or system described in figs. 1C-1E. In some embodiments, the VNS treatment is delivered using the stimulation protocol and method described in figs. 2C and 7.

According to some exemplary embodiments, the VNS treatment is delivered to a subject diagnosed or suffering from at least one symptom of dementia, for example AD. In some embodiments, the VNS treatment enhances an expression of USP, for example to increase a removal process of proteins shown to be involved in AD development, for example beta- amyloid, Tau or phospho-tau, from the brain, for example as discussed in Chenchen Xie et al., “USP10 is a potential mediator for vagus nerve stimulation to alleviate neuroinflammation in ischaemic stroke by inhibiting NF-KB signalling pathway” (2023).

Exemplary VNS for increasing satiety level

According to some exemplary embodiments, VNS treatment, for example auricular VNS, is delivered for increasing satiety level of a subject. In some embodiments, the VNS treatment is delivered using the methods described herein, for example the methods described in figures 1A, IB. In some embodiments, the VNS treatment is delivered using the device or system described herein, for example the device or system described in figs. 1C-1E. In some embodiments, the VNS treatment is delivered using the stimulation protocol and method described in figs. 2C and 7.

According to some exemplary embodiments, the delivered VNS treatment increases a satiety level of a subject, for example by increasing levels and/or secretion of glucagon-like peptide- 1 (GLP1) hormone, optionally in the gastrointestinal (GI) system, for example as described in A S Rocca et al. “role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide- 1 secretion” (1999). Alternatively or additionally, the delivered VNS treatment activates a signaling pathway to the brain which imitates GLP1 neuronal signaling.

According to some exemplary embodiments, the VNS treatment is delivered to a subject that wants to increase a level of Satiety. Alternatively or additionally, the VNS treatment is delivered to a subject which is overweight, for example having a body mass index (BMI) of 25 or higher, for example having a BMI of at least 25, at least 27, at least 30, at least 35, or any intermediate, smaller or larger value.

According to some exemplary embodiments, the VNS treatment includes activating stimulation of the vagus nerve when needed, for example before, during and/or after eating. In some embodiments, at least one parameter of the VNS treatment is adjusted according to a state, for example a clinical state or a physiological state of the subject, for example according to the subject weight and/or according to the subject BMI. Alternatively or additionally, at least one parameter of the VNS treatment is adjusted according to type of food and/or beverages included in a meal or are planned to be consumed by the subject. In some embodiments, the at least one parameter comprises a parameter described in the application, for example stimulation duration, stimulation intensity, stimulation frequency, number of stimulation blocks, length of intervals between stimulation sessions or active stimulation blocks.

According to some exemplary embodiments, the VNS treatment is provided when the subject is asleep. Alternatively or additionally, the VNS treatment is provided during the day, optionally when the subject is awake, for example according to a stimulation protocol that includes alternating stimulation of 0.1-60 minutes of active stimulation delivery, followed by one or more intervals lasting 0.1-60 minutes. In some embodiments, the stimulation is as described in figs. 2C and 7.

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

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

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.

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.

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

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.

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.

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 or attenuating an appearance of clinical symptoms.

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.

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. 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 to treat a predetermined subject population diagnosed with Alzheimer’s disease (AD), comprising: selecting subjects diagnosed with early AD or having at least one symptom of early AD, with a goal to improve a score of said subjects in an assessment scale in at least one point, wherein said assessment scale comprises at least one of, an Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or variations thereof, and a Mini-Mental State Examination (MMSE) scale or variations thereof; delivering auricular VNS treatment to said subjects for a time period of at least one month; identifying an improvement of at least one point in said scale in said subjects following said delivering.

2. A method according to any one of the previous claims, wherein said identifying comprises identifying an increase of at least 1.5 points in a score of said MMSE, after at least one month of said delivering.

3. A method according to any one of the previous claims, wherein said delivering comprises delivering said VNS treatment to said subjects for a time period of at least 3 months, and wherein said identifying comprises identifying an increase of at least 1.5 points in a score of said MMSE, after 3 months of said delivering.

4. A method according to any one of the previous claims, wherein said identifying comprises identifying a an increase of at least 1.5 points in a score of said MMSE, up to 3 months from completing said delivering.

5. A method according to any one of the previous claims, wherein said selecting comprises selecting subjects that achieved a MMSE score within a range between 10 and 25 points.

6. A method according to any one of the previous claims, comprising associating at least part of a VNS device configured to deliver said VNS treatment with an ear of a subject prior to said delivering.

7. A method according to claim 6, wherein said associating comprising positioning at least one electrode of said VNS in contact with an ear of said subject.

8. A method according to any one of the previous claims, wherein said delivering comprises delivering said VNS treatment while said subjects are asleep and/or in synchronization with at least one sleeping stage.

9. A method according to any one of the previous claims, wherein said delivering comprises delivering said VNS treatment which comprises one or more VNS treatment sessions, each includes separate active stimulation blocks, and wherein said VNS is actively delivered intermittently during said active stimulation blocks.

10. A method according to claim 9, wherein each active stimulation block comprises two or more active stimulation sessions in which stimulation is actively delivered via a least one electrode, and wherein an interval duration between two consecutive active stimulation sessions in an active stimulation block is within a range between 0.5 second and 240 seconds.

11. A method according to any one of the previous claims, wherein said delivering comprises delivering during said VNS treatment an electric field with parameter values suitable to affect an auricular branch of the vagus nerve via at least one electrode positioned behind the ear, within the ear canal and/or at a concha of the ear.

12. A method according to claim 11, wherein said parameter values comprise an intensity in a range between about 0.1 mA and about 4 mA, and/or wherein said parameter values comprise a frequency in a range between about 1 Hertz (Hz) and about 100 Hz, and/or wherein said parameter values comprise a pulse width in a range between about 0.1 millisecond (ms) and about 2 ms.

13. A method to treat a predetermined subject population diagnosed with MCI or early AD, comprising: selecting subjects diagnosed with early AD or mild cognitive impairment (MCI); delivering VNS to at least one cranial nerve of said subjects via one or more electrodes; achieving based on parameters of said VNS a reduction of at least 4 points in an ADAS-Cog scale, at least one month from initiating said delivering.

14. A method according to claim 13, wherein said achieving comprises achieving based on parameters of said VNS a reduction of at least 4 points in said ADAS -Cog, at least 3 months from initiating said delivering.

15. A method according to any one of claims 13 or 14, wherein said achieving comprises achieving based on parameters of said VNS a reduction of at least 4 points in said ADAS-Cog, up to 3 months from completing said delivering.

16. A method for delivery of vagal nerve stimulation (VNS) stimulation, comprising: providing a VNS stimulation treatment protocol comprising at least one stimulation treatment session, wherein said at least one stimulation treatment session is divided into two or more separate stimulation blocks, and wherein in each stimulation block of said two or more stimulation blocks, active VNS stimulation is delivered intermittently to the subject; delivering VNS to said subject according to the provided protocol.

17. A method according to claim 16, wherein a duration of each stimulation block or an interval between two consecutive stimulation blocks is in a range between 1 minute and 60 minutes.

18. A method according to any one of claims 16 or 17, comprising positioning at least one electrode of a VNS stimulation device in contact with at least one part of an ear of said subject prior to aid delivering.

19. A method according to claim 18, wherein said positioning comprises positioning said at least one electrode in contact with a concha of said ear, and wherein said delivering comprises delivering an electric field via said at least one electrode intermittently during each stimulation block, wherein parameter values of said electric field are sufficient to affect an auricular branch of a vagus network in said subject.

20. A method according to claim 19, wherein said parameter values of said electric field comprise an intensity in a range between about 0.1 mA and about 4 mA, and/or wherein said parameter values comprise a frequency in a range between about 1 Hertz (Hz) and about 100 Hz, and/or wherein said parameter values comprise a pulse width in a range between about 0.1 millisecond (ms) and about 2 ms.

21. A method according to claim 20, wherein said two or more separate stimulation blocks are separated by interval blocks in which an electric field is not delivered via said at least one electrode with parameter values sufficient to affect said auricular branch, or in which no electric field is delivered to the subject via said at least one electrode.

22. A method according to any one of claims 16 to 21, wherein said delivering comprises delivering said VNS when said subject is asleep.

23. A method according to claim 22, detecting that said subject is asleep prior to said delivering.

24. A method according to any one of claims 22 or 23, wherein said delivering comprises delivering said VNS in synchronization with at least one sleeping stage of a sleep cycle, and/or wherein said at least one sleeping stage comprises Nl, N2, N3 and/or rapid eye movement (REM) stages.

25. A device for delivery of vagal nerve stimulation (VNS), comprising: a memory, wherein said memory stores at least one VNS protocol which comprises at least one VNS treatment session divided into two or more separate stimulation blocks, and wherein in each stimulation block of said two or more stimulation blocks, active VNS stimulation is configured to be delivered intermittently to the subject; a pulse generator configured to generate an electric field and to deliver said electric field to at least one electrode connectable to said device; a control circuitry, wherein said control circuitry is configured to signal said pulse generator to generate said electric field according to said at last one stored VNS protocol.

26. A device according to claim 25, wherein said at least one VNS protocol comprises parameter values suitable to affect an auricular branch of the vagus nerve, and wherein said control circuitry is configured to signal said pulse generator to generate said electric field using said parameter values.

27. A device according to any one of claims 25 or 26, comprising said at least one electrode, wherein said at least one electrode is shaped and sized to be placed in contact with at least part of an ear of a subject.

28. A device according to claim 27, wherein said at least one electrode is shaped and sized to be placed in contact with a concha region of said ear.

29. A device according to any one of claim 25 to 28, wherein in said stored VNS treatment protocol a duration of each stimulation block or an interval between two consecutive stimulation blocks is in a range between 1 minute and 60 minutes.

30. A device according to any one of claims 25 to 29, comprising a communication circuitry configured to transmit and/or receive one or more signals from a remote device, wherein said device is programmed with said at least one protocol by receiving said one or more signals from said remote device.

31. A device according to claim 30, wherein said memory stores at least two different VNS protocols of said at least one VNS protocol, and wherein said control circuitry is configured to select a VNS protocol for treating a specific subject from said at least two different VNS protocols based on said one or more signals received using said communication circuitry.

32. A device according to claim 31, wherein said one or more signals comprise results of an assessment scale achieved by said subject.

33. A device according to claim 32, wherein said assessment scale comprises at least one of, ADAS-COG or variations thereof, and a MMSE or variations thereof.

34. A device according to any one of claims 31 to 33, wherein said one or more signals comprise an indication that said subject is identified with cognitive impairment.

35. A device according to any one of claims 25 to 34, comprising a user interface configured to receive one or more input signals, wherein said device is programmed with said at least one protocol based on said received one or more input signals.

36. A device according to claim 35, wherein said memory stores at least two different VNS protocols of said at least one VNS protocol, and wherein said control circuitry is configured to select a VNS protocol for treating a specific subject from said at least two different VNS protocols based on said one or more input signals received by said user interface.

37. A device according to claim 36, wherein said one or more input signals comprise results of an assessment scale achieved by said subject, wherein said assessment scale comprises at least one of, ADAS-COG or variations thereof, and a MMSE or variations thereof.

38. A device according to any one of claims 25 to 37, comprising at least one detector configured to record at least one signal related to at least one parameter of a body of said subject, wherein said control circuitry is further configured to: measure values of said at least one body parameter; determine a subject state based on said measured values, wherein said subject state comprises at least one of, if said subject is asleep, at least one sleep stage, subject movement, activity of the subject brain and/or activity of each brain hemisphere of the subject; and deliver VNS to said subject according to said determined subject state by signaling said pulse generator to generate an electric field according to at least one set of parameter values and/or according said at least one VNS protocol stored in said memory.

39. A method for delivery of vagal nerve stimulation (VNS) to a subject, comprising: functionally coupling a stimulation device configured to deliver VNS, to a subject body; detecting movement of the subject when the subject is asleep; determining a dose of VNS to be provided to said subject according to said detected movement, delivering VNS to said subject according to said determined dose.

40. A method according to claim 39, comprising identifying at least one period when the subject is asleep and in which the detected movement is lower than a reference value, wherein said determining comprises determining to provide an increased dose of said VNS to said subject, and wherein said delivering comprises delivering said increased dose of said VNS to said subject during and/or following the said period.

41. A method according to claim 40, comprising identifying at least one period when the subject is asleep and in which the detected movement is higher than a reference value, wherein said determining comprises determining to provide an increased dose of said VNS to said subject, and wherein said delivering comprises delivering said increased dose of said VNS to said subject during and/or following the said period.

42. A method according to claim 40, wherein said detecting comprises detecting an increase in movement of the subject, and wherein said determining comprises determining to provide an increased dose of said VNS according to said detected increase.

43. A method according to claim 40, wherein said detecting comprises detecting an increase in movement of the subject, and wherein said determining comprises determining to provide a decreased dose of said VNS according to said detected increase.

44. A method according to any one of claims 39 to 43, wherein said subject is diagnosed with dementia and/or with at least one sleeping disorder.

45. A method for calibrating a vagal nerve stimulation (VNS) treatment, comprising: delivering VNS to a subject when said subject is asleep; measuring at least one body parameter of said subject before, during and/or following said delivering, wherein said at least one body parameter comprises a body movement related parameter and/or at least one physiological parameter, wherein said measuring comprises measuring said at least one body parameter during two or more sleep stages; determining a therapeutic effect of said delivered VNS on said subject in each of said two or more sleep stages based on said measuring; calibrating said VNS treatment by scheduling a delivery of said VNS to at least one sleep stage of said two or more sleep stages in which said determined therapeutic effect was the largest therapeutic effect, and wherein said at least one body parameter comprises at least one of, heart rate, heart rate variability (HRV), electrocardiogram (ECG), electromyography (EMG), electroencephalogram (EEG), electrooculogram (EOG), sweat level , respiration rate, oxygen saturation, and/or limb movement.

46. A method for delivery of vagal nerve stimulation (VNS) for increasing probability of a subject to fall asleep, comprising: measuring EEG signals from a subject planning to fall asleep; detecting an increase in alpha waves in said measured EEG signals that is higher than a predetermined reference value; delivering VNS to said subject in response to said detecting, wherein said VNS is delivered with parameter values suitable to increase a level of theta waves in said measured EEG signals.

47. A method for delivery of vagal nerve stimulation (VNS) for prolonging sleep in a subject, comprising: measuring when a subject is asleep, signals indicating activity of two brain hemispheres ; detecting a difference in activity between the two hemispheres; delivering in response to said detecting, VNS to at least one hemisphere of the two brain hemispheres, according to said detected difference.

48. A method according to claim 47, wherein said measuring comprises measuring said signals when said subject is in a deep sleep stage, and wherein said delivering comprises delivering said VNS with parameter values suitable to prolong said deep sleep stage.

49. A method according to any one of claims 47 or 48, wherein said delivering comprises delivering VNS to a less active hemisphere of the two brain hemispheres with parameter values suitable to increase activity of the less active hemisphere.

50. A device for delivery of vagal nerve stimulation (VNS), comprising: a memory, wherein said memory stores at least one VNS protocol configured to be used in a method of any one of claims 1, 13, 16, 39, 45 and 47, wherein said at least one VNS protocol comprises at least one VNS treatment session comprises at least one stimulation block, and wherein in said stimulation block active VNS stimulation is configured to be delivered intermittently to the subject; a pulse generator configured to generate an electric field and to deliver said electric field to at least one electrode connectable to said device; a control circuitry, wherein said control circuitry is configured to signal said pulse generator to generate said electric field according to said at least one VNS protocol, wherein said device.